PHOTOACID COMPOUNDS, AND RELATED COMPOSITIONS, METHODS AND SYSTEMS

Abstract

A photoacid compound having a light absorbing moiety attaching a payload moiety through a linker, in which the linker comprises a geminal dialkyl linked to a carbonyl group attaching the payload moiety, and the linker is configured to present the carbonyl oxygen for reaction with a hydroxyl group presented on the light absorbing moiety in ortho position to the linker.

Description

CROSS REFERENCE TO RELATED APPLICATIONS

The present application claims priority to U.S. Provisional Application No. 61/568,046, entitled “Long Wavelength activation of bioactive compounds” filed on Dec. 7, 2011 with docket number CIT-6041-P, and is related to PCT application Ser. No. ______ entitled “Caged compound delivery and related compositions, methods and systems” filed on Dec. 7, 2012, with docket number P1130-PCT2, each of which is incorporated herein by reference in its entirety.

FIELD

The present disclosure relates to compounds capable to deliver a payload in a controlled fashion. In particular, the present disclosure relates to photoacid compounds and related compositions methods and systems.

BACKGROUND

Molecular delivery has been a challenge in the field of molecule analysis, in particular when aimed at obtaining controlled delivery of analytes of interest to specific environments. Whether for chemical, biological or medical applications or for fundamental studies, several methods are commonly used for the delivery of various classes of compounds including biomaterials and biomolecules.

Controlled delivery of targets to specific environments, e.g. delivery of pesticides, delivery of chemicals such as a fluorescent dye on a biological or non-biological system, such as specific cell types and/or tissues of individuals in vitro and/or in vivo is currently still challenging, especially when directed at providing controlled release of the target in a controllable conformation, typically associated to a biological or chemical activity.

SUMMARY

Described herein are photoacid compounds and related compositions, methods, and systems that in some embodiments permit the uncaging and release of a payload molecule upon irradiation with a suitable wavelength light.

According to a first aspect, a photoacid compound is described. The photoacid compound comprises a light absorbing moiety attaching a payload moiety through a linker moiety. In the photoacid compound, the linker moiety comprises a geminal dialkyl moiety linked to an ester group having a carbonyl oxygen, the carbonyl group of the ester attaching the payload moiety. In the photoacid compound, the light absorbing moiety attaches the linker moiety in ortho position to a hydroxyl group and the linker is configured to present the carbonyl oxygen for reaction with the hydroxyl group.

According to a second aspect, a photoacid compound is described, the photoacid having the general structure according to formula (I):

wherein:

• • R⁴ is a light-absorbing moiety presenting a hydroxyl group for interaction with the carbonyl oxygen of the R³(CO)O group, wherein the light-absorbing moiety is a substituted or unsubstituted polycyclic aromatic hydrocarbon, a substituted or unsubstituted closed chain cyanine, or a substituted or unsubstituted hemicyanine, and wherein the hydroxyl group is covalently bonded to the polycyclic aromatic hydrocarbon, the closed chain cyanine, or the hemicyanine, and the hydroxyl group is in a position ortho to X¹;
  • R³ is a payload moiety, wherein the payload moiety is a substituted or unsubstituted alkyl, aryl, heteroaryl, alkoxy, alkylamino, or dialkylamino moiety;
  • X¹ is independently selected from the group consisting of C and O;
  • m is between 0 and 3; and
  • R¹ and R² are independently C₁-C₆ alkyl groups, cycloalkyl, or substituted or unsubstituted hydrocarbylene groups wherein when R¹ and R² are substituted or unsubstituted hydrocarbylene R¹ and R² they are linked together to form a cyclic moiety.

According to a third aspect, a method to deliver a compound is described, the method comprises providing a caged compound, the caged compound being caged as a payload moiety within the photoacid compound herein described and in particular with a photoacid compound of Formula (I), the photoacid compound being in a ground state in which the hydrogen substituted heteroatom presented on the light absorbing moiety of the photoacid compound has a ground state pK_a. The method for uncaging the caged compound by irradiating the photoacid compound with light at a wavelength suitable to promote the photoacid compound to an excited state wherein the hydrogen substituted heteroatom presented on the light absorbing moiety of the photoacid compound has an excited state pK_a lower than the ground state pK_a.

According to a fourth aspect, a system to deliver a compound is described, the system comprising at least two of: one or more photoacids compounds, and in particular one or more photoacid compounds of Formula (I) and a light source suitable to irradiate light at a suitable wavelength, for simultaneous, combined or sequential use in methods herein described.

Photoacid compounds herein described and related compositions, methods and systems allow in several embodiments controlled release of a payload moiety in various chemical and biological environments. In particular, in several embodiments, photoacid compounds herein described and related compositions methods and systems allow controlled release of a payload moiety upon irradiation at a wavelength of at least about 750 nm or higher.

Photoacid compounds herein described and related compositions, methods and systems can be used in connection with applications wherein controlled delivery of a compound is desired. Exemplary applications comprise applications in medical field, biological and chemical research, such as drug development, molecule studies, light-activated therapies and strategies for imaging biological systems.

The details of one or more embodiments of the disclosure are set forth in the accompanying drawings and the description below. Other features and objects will be apparent from the description and drawings, and from the claims.

BRIEF DESCRIPTION OF DRAWINGS

The accompanying drawings, which are incorporated into and constitute a part of this specification, illustrate one or more embodiments of the present disclosure and, together with the description of example embodiments, serve to explain the principles and implementations of the disclosure.

FIG. 1 shows a schematic illustration of photoacid compounds herein described and of related methods and systems. In particular FIG. 1A shows a schematic representation of a method to uncage a drug comprised as a payload in photoacid compound wherein the light absorbing moiety is formed by a NIR absorber. FIG. 1B shows a known reaction scheme of uncaging of a water molecule in a photoacid after protonation of a hydroxyl group wherein the protonation is induced by the increase in acidity of the photoacidic hydrogen. FIG. 1C shows a schematic of the novel protonation of a carbonyl group in a linking moiety and subsequent uncaging of a payload moiety of a generic photoacid compound after irradiation of the light absorbing moiety with light resulting in an increase in the acidity of the photoacidic proton. FIG. 1D shows the uncaging of a particular photoacid compound by irradiation of the photoacid compound with light resulting in the release of hydrocinnamic acid. FIG. 1E shows a schematic structure of an exemplary generic photoacid compound with an acene light absorbing moiety in which expansion of the acene chromophores allows absorption of a longer wavelength light. FIG. 1F shows an exemplary photoacid compound as herein described with a retinal/carotene-type light absorbing moiety. FIG. 1G shows an exemplary photoacid compound as herein described with a cyanine-type light absorbing moiety. FIG. 1 H shows the uncaging of a particular photoacid compound by irradiation of the photoacid compound with light resulting in the release of γ-aminobutyric acid with concomitant decarboxylation to release CO₂.

FIG. 2 shows a schematic of a ring opening reaction of a fluorescein molecule that results in fluorescence.

FIG. 3 shows a schematic of a synthetic scheme for the synthesis of photoacid compounds with a naphthol-based light absorbing moiety.

FIG. 4 shows a schematic of a synthetic scheme for the synthesis of photoacid compounds with a cyanine-based light absorbing moiety.

FIG. 5 shows a schematic of a synthetic scheme for the synthesis of photoacids with a cyanine-based light absorbing moiety.

FIG. 6 shows LC-MS traces for an exemplary photoacid compound as herein described before and after irradiation with light to uncage the payload moiety.

FIG. 7 shows a schematic of a synthetic scheme for the synthesis of a photoacid compound with X¹ is C.

FIG. 8 shows a schematic of general synthetic schemes for the synthesis of cyanine-based photoacid compounds as herein described. FIG. 8A shows a general synthetic strategy to synthesize photoacid compounds of Formula (I) using a common precursor (ortho dihydroxyarene; 32). FIG. 8B shows a general synthetic scheme for the synthesis of closed chain cyanines with a variable-length polyene and variable heteroaryl groups. FIG. 8C shows an exemplary application of the synthesis shown in FIG. 8B to the general synthesis of photoacid compounds with cyanine light absorbing moieties. FIG. 8D shows a photoactive molecule with a particular desired absorbance wavelength (compound 40) and an analogous photoactive compound as herein described (compound 41) incorporating compound 40 as the light absorbing moiety. FIG. 8E shows the synthesis of a quinolinium compound that can be used in the synthesis of cyanines. FIG. 8D shows a photoactive molecule with a particular desired absorbance wavelength (compound 40) and an analogous photoactive compound as herein described (compound 41) incorporating compound 40 as the light absorbing moiety.

DETAILED DESCRIPTION

Described herein are photoacid compounds and related compositions, methods, and systems that in some embodiments permit the uncaging and release of caged payload molecules upon irradiation with long wavelength light.

The term “photoacid” as used herein refers to a compound that can be switched from a ground state to an excited state upon absorption of light, and that has an excited state acidity associated to the excited states higher than a ground state acidity associated to the ground state. The term “excited state” as used herein refers to an electronic state of a moiety in which the molecule has absorbed light energy and been promoted to a higher energy state. This process is referred to as “excitation.” The term “ground state” refers to the electronic state of a moiety in which the electrons are in their lowest energy molecular orbitals. In photoacid compounds, the excitation can be accomplished, for example, by irradiating a photoacid molecule with light of energy equal to the difference in energy between the ground state and the excited state. The energy of the light is determined by the wavelength of the light according the relationship E=hc/λ, where E is the energy of the photon, h is Plank's constant, and λ is the wavelength of the light. In particular, in some embodiments, the light used to effect the excitation is infrared or near infrared light.

In particular, molecules that can undergo excitation to an excited state are typically molecules comprising systems of conjugated π bonds such as those present in polyaromatic (e.g. polycyclic aromatic hydrocarbons) and polyene (e.g. cyanine and carotene molecules) molecules. In particular, the energy required to excite a molecule such as a photoacid can be decreased, which results in light of longer wavelengths being able to excite the molecule, by increasing the size of the system of conjugated π bonds (see, e.g., [Ref 1]).

Determination of the excited states for a certain compound and the related level of energy can be performed by a skilled person using methods and techniques identifiable by a skilled person. By way of example, the excited states can be determined by measuring the absorption spectrum of a compound and thus the wavelengths of light absorbed by the compound via spectrophotometry.

In particular, a “photoacid” in the sense of the present disclosure typically comprises a light absorbing moiety presenting an hydrogen substituted heteroatom. A shift in acidity following light absorbance by the light absorbing moiety can be detected by detecting the pK_a of a hydrogen substituted heteroatom which is presented on the light absorbing moiety of the photoacid. Detection of the pK_a of the hydrogen substituted heteroatom can be performed according to techniques and methods identifiable by a skilled person (see e.g. [Ref 2] and [Ref 3]). Exemplary photoacids include hydroxyaryls such as 2-naphthol which displays a ground state pK_a of 9.5 and an excited state pK_a (pK_a*) of 2.8 (see, e.g., [Ref 4]). The pK_a* of a photoacid can be determined, for example, by combining the Förster cycle with the pK_a of the photo acid in its ground state to perform calculations known to those in the art, as well as by fluorescence titrations (see, e.g., [Ref 2] and [Ref 3]).

In embodiments herein described, the photoacid compound of the disclosure comprise a light absorbing moiety which is attached to a payload moiety through a linker comprising a geminal dialkyl moiety which presents a carbonyl group attaching the payload moiety. In particular, in photoacid compounds of the disclosure the linker is configured to present the carbonyl oxygen in proximity to the hydroxyl of the light absorbing moiety and is further configured such that the hydroxy is ortho to the linker.

The term “attach” or “attached” as used herein, refers to connecting or uniting by a covalent bond in order to keep two or more components together, which encompasses either direct or indirect attachment where, for example, a first moiety is directly bound to a second moiety, or one or more intermediate moieties are disposed between the first moiety and the second moiety.

The term “present” as used herein with reference to a compound or functional group indicates attachment performed to maintain the chemical reactivity of the compound or functional group as attached. Accordingly, for example a carbonyl group presented on a linker, is able to perform under the appropriate conditions the one or more chemical reactions that chemically characterize the carbonyl group. The wording “present for reaction”, with reference to a compound or a functional group indicates attachment performed to maintain the chemical reactivity of the compound or functional group as attached, such that the attachment is performed in a configuration that allow the specific reaction mentioned. Accordingly, a carbonyl group presented for reaction with an hydroxyl group indicates a configuration in which the carbonyl group is in a position allowing a chemical reaction with the hydroxyl group.

The term “light absorbing moiety” as used herein indicates moiety that is converted to an excited states upon absorption of light at a predetermined wavelength. Exemplary light absorbing moieties comprise long wavelength absorbing moieties (LWAP) able to absorb light at a wavelength greater than or equal to 750 nm, and more particularly a wavelength in a range from about 900 to about 1100 nm. Additional exemplary light absorbing moieties comprise short wavelength light absorbing moieties (SWAP) able to absorb light at a wavelength less than 750 nm and in particular at a wavelength from about 500 nm to about 750 nm and a wavelength from about 600 nm to about 750 nm.

In some embodiments, the light absorbing moiety comprises a substituted or unsubstituted polycyclic aromatic hydrocarbon or substituted or unsubstituted closed chain cyanine or hemicyanine dye presenting a hydroxyl group in which the hydroxyl group is covalently bound to the substituted or unsubstituted polycyclic aromatic hydrocarbon or substituted or unsubstituted closed chain cyanine or hemicyanine dye. In particular, in some embodiments, the hydroxyl group can be covalently bound to a carbon of the substituted or unsubstituted polycyclic aromatic hydrocarbon or substituted or unsubstituted closed chain cyanine or hemicyanine dye such that the hydroxyl is ortho to the linker herein described.

The term “linker” as used herein indicates to an organic structure configured to connect two moieties to form a stable chemical structure. In particular, linker in the sense of the present disclosure can be formed by a mono or dialkoxy moiety comprising the dialkyl germinal group and presenting the carbonyl group for reaction.

The term “payload” as used herein refers to a moiety carried by a compound in a configuration that allows the relevant delivery under controllable parameters. In particular, in embodiments herein described a payload is a moiety is connected to the linker and forms part of the photoacidic compounds herein described. In particular in embodiments herein a payload indicates an organic moiety configured to attach the carbonyl group of the linker of a photoacid compound herein described.

In particular, in some embodiments, a photoacid compound herein described has of the general structure according to Formula (I):

wherein:

• • R⁴ is a light-absorbing moiety presenting a hydroxyl group for interaction with the carbonyl oxygen of the R³(CO)O group, wherein the light-absorbing moiety is a substituted or unsubstituted polycyclic aromatic hydrocarbon, a substituted or unsubstituted closed chain cyanine, or a substituted or unsubstituted hemicyanine, and wherein the hydroxyl group is covalently bonded to the polycyclic aromatic hydrocarbon, the closed chain cyanine, or the hemicyanine, and the hydroxyl group being in a position ortho to X¹;
  • R³ is a payload moiety, wherein the payload moiety is a substituted or unsubstituted alkyl, aryl, heteroaryl, alkoxy, alkylamino, or dialkylamino moiety; and
  • X¹ is independently selected from the group consisting of C and O;
  • m is between 0 and 3; and
  • R¹ and R² are independently C₁-C₆ alkyl groups, cycloalkyl, or substituted or unsubstituted hydrocarbylene groups wherein when R¹ and R² are substituted or unsubstituted hydrocarbylene groups they are linked together to form a cyclic moiety.

In particular, in the photoacid compound of formula (I) and other embodiments herein described, the moiety of Formula (II)

is the linker.

In particular, in some embodiments, R⁴ can be a moiety of Formula (III):

wherein n is between 0 and 5.

In particular, in some, R⁴ can be a moiety of Formula (IV):

where n is between 0 and 5, and m is between 1 and 3.

In particular, in some embodiments, R⁴ can be a moiety of Formula (V):

wherein R^a and R^b are independently H, alkyl, or O-alkyl; Y is N, O, or S; and p is between 1 and 4.

In particular, in some embodiments, R⁴ can be a moiety of Formula (VI):

wherein R^c and R^d are independently alkyl and q is between 1 and 4.

In particular, in some embodiments, R⁴ can be a moiety of Formula (VII):

wherein r is between 1 and 4.

In particular, in some embodiments, R⁴ can be a moiety of Formula (VIII):

A skilled person will understand, upon a reading of the present disclosure, that the light absorbing moiety and herein described can be substituted or unsubstituted and in particular have additional substituents which can be added to impart additional functionalities such as, for example, hydrophilic substituents (e.g. sulfonate, and in particular polysulfonates such as polysulfonate peptides or oligopeptides, as well as polyethylene glycol groups), and functional groups and/or moieties to connect the photoacid compounds herein described to other molecules and/or substances (e.g. for connection to carbon nanotubes, fullerenes, antibodies, polymers, proteins, lipids, carbohydrates, and others identifiable to a skilled person).

In embodiments herein described the photoacid attaches a payload and in particular a payload R³ in a photoacid of Formula (I).

In particular, R³ can be an organic moiety such as, for example a substituted or unsubstituted alkyl, aryl, heteroaryl, alkoxy, alkylamino, or dialkylamino moiety. In some embodiments, and in particular in embodiments where R³ is a substituted or unsubstituted alkyl, aryl, heteroaryl molecule, R³ is adapted to exist in a carboxylic acid form wherein the carboxylic acid form can be used to provide the carbonyl group of the linker of Formula (II) (see Example 1 and Example 3).

In particular, in some embodiments, R³ can be a moiety of Formula (IX):

wherein q is between 0 and 5, R^α is H, or substituted or unsubstituted alkyl, alkylamino, alkoxy, aryl, arylamino, aryloxy, heteroaryl, hetroarylamino, and heteroaryloxy; X is C or N; and wherein when q is greater than 1, each R′ is independent of the other R^α substituents.

In particular, in some embodiments wherein R³ is according to Formula (IX), R³ can be selected from the group consisting of Formulas (X)-(XII):

In particular, in some embodiments, R³ can be a moiety of Formula (XIII):

wherein n is between 1 and 5, R^α, R^β, and R^γ are independently H, or substituted or unsubstituted alkyl, alkylamino, alkoxy, aryl, arylamino, aryloxy, heteroaryl, hetroarylamino, and heteroaryloxy; and wherein when n is greater than 1, the R^α and R^β of each C(R^α)(R^β) unit are independent of the R^α and R^β of the other units.

In particular, in some embodiments wherein R³ is according to Formula (XIII), R³ can be selected from the group consisting of Formulas (XIV) and (XV):

In particular, in some embodiments, R³ can be a moiety of Formula (XVI):

wherein p is between 1 and 5, R^α, R^β, and R^γ are independently H, or substituted or unsubstituted alkyl, alkylamino, alkoxy, aryl, arylamino, aryloxy, heteroaryl, hetroarylamino, and heteroaryloxy; wherein R^δ is H, substituted or unsubstituted alkyl, acyl, aryl; and wherein when p is greater than 1, the R^α and R^β of each C(R^α)(R^β) unit are independent of the R^α and R^β of the other units.

In particular, in some embodiments wherein R³ is according to Formula (XVI), R³ can be of Formula (XVII):

In particular, in some embodiments wherein R³ is according to Formula (XVI) and R^δ is acyl, R³ can be a peptide or oligopeptide such that the peptide or oligopeptide is attached to the linker via the N-terminus of the peptide or oligopeptide.

In particular, in some embodiments, R³ can be a moiety of Formula (XVIII):

wherein m is between 1 and 5, R^α, R^β, and R^γ are independently H, or substituted or unsubstituted alkyl, alkylamino, alkoxy, aryl, arylamino, aryloxy, heteroaryl, hetroarylamino, and heteroaryloxy; and wherein when m is greater than 1, the R^α and R^β of each C(R^α)(R^β) unit are independent of the R^α and R^β of the other units.

In particular, in some embodiments, R³ can be a moiety of Formula (XIX):

wherein q is between 0 and 4, R^α is H, or substituted or unsubstituted alkyl, alkylamino, alkoxy, aryl, arylamino, aryloxy, heteroaryl, hetroarylamino, and heteroaryloxy; c is a substituted or unsubstituted hydrocarbylene, X is C or N; and wherein when q is greater than 1, each R^α is independent of the other R^α substituents.

In some embodiments, the payload moiety and in particular the payload molecule R³ is a molecule for which controlled disconnection and release from the photoacid compound is desired. Exemplary payload molecules include imaging agents, drug molecules, fluorescent dyes, pesticides, pigments, neurotransmitter; anti-cancer agents; sedatives; antibodies; protein therapeutics and others identifiable to a skilled person upon a reading of the present disclosure.

In some embodiments herein described the payload R³ can be attached to R⁴ through the linker of formula (II). In particular in the linker of formula (II), X¹ can be independently O or C.

In some embodiments, R¹ and R² are methyl groups or other C₁-C₆ alkyl groups or cycloalkyl. In other embodiments, R¹ and R² are linked to form a cyclic moiety such as a cyclopentyl or cyclohexyl moiety.

In particular, in some embodiments, the light absorbing moiety R⁴ is a moiety according to Formula (III); and the linker is a linker of Formula (II) wherein X¹ is O and R¹ and R² are methyl, ethyl, or linked together to form a cyclopentyl or cyclohexyl moiety. In particular, in other embodiments the light absorbing moiety R⁴ is a moiety according to Formula (III), the linker is a linker of Formula (II) wherein X¹ is C and R¹ and R² are methyl, ethyl, or linked together to form a cyclopentyl or cyclohexyl moiety.

In particular, in some embodiments, the light absorbing moiety R⁴ is a moiety according to Formula (III) wherein n is 0; and the linker is a linker of Formula (II) wherein X¹ is O and R¹ and R² are methyl, ethyl, or linked together to form a cyclopentyl or cyclohexyl moiety. In particular, in other embodiments the light absorbing moiety R⁴ is a moiety according to Formula (III) wherein n is 0, the linker is a linker of Formula (II) wherein X¹ is C and R¹ and R² are methyl, ethyl, or linked together to form a cyclopentyl or cyclohexyl moiety.

In particular, in some embodiments, the light absorbing moiety R⁴ is a moiety according to Formula (IV); and the linker is a linker of Formula (II) wherein X¹ is O and R¹ and R² are methyl, ethyl, or linked together to form a cyclopentyl or cyclohexyl moiety. In particular, in other embodiments, the light absorbing moiety R⁴ is a moiety according to Formula (IV); and the linker is a linker of Formula (II) wherein X¹ is C and R¹ and R² are methyl, ethyl, or linked together to form a cyclopentyl or cyclohexyl moiety

In particular, in some embodiments, the light absorbing moiety R⁴ is a moiety according to Formula (IV) wherein m is 2 and n is 0; and the linker is a linker of Formula (II) wherein X¹ is O and R¹ and R² are methyl, ethyl, or linked together to form a cyclopentyl or cyclohexyl moiety. In particular, in other embodiments, the light absorbing moiety R⁴ is a moiety according to Formula (IV) wherein m is 2 and n is 0; and the linker is a linker of Formula (II) wherein X¹ is C and R¹ and R² are methyl, ethyl, or linked together to form a cyclopentyl or cyclohexyl moiety.

In particular, in some embodiments, the light absorbing moiety R⁴ is a moiety according to Formula (V); and the linker is a linker of Formula (II) wherein X¹ is 0 and R¹ and R² are methyl, ethyl, or linked together to form a cyclopentyl or cyclohexyl moiety. In particular, in other embodiments, the light absorbing moiety R⁴ is a moiety according to Formula (V); and the linker is a linker of Formula (II) wherein X¹ is C and R¹ and R² are methyl, ethyl, or linked together to form a cyclopentyl or cyclohexyl moiety.

In particular, in some embodiments, the light absorbing moiety R⁴ is a moiety according to Formula (VI), and the linker is a linker of Formula (II) wherein X¹ is O and R¹ and R² are methyl, ethyl, or linked together to form a cyclopentyl or cyclohexyl moiety. In particular, in other embodiments, the light absorbing moiety R⁴ is a moiety according to Formula (VI); and the linker is a linker of Formula (II) wherein X¹ is C and R¹ and R² are methyl, ethyl, or linked together to form a cyclopentyl or cyclohexyl moiety.

In particular, in some embodiments, the light absorbing moiety R⁴ is a moiety according to Formula (VI) wherein q is 2, and the linker is a linker of Formula (II) wherein X¹ is O and R¹ and R² are methyl, ethyl, or linked together to form a cyclopentyl or cyclohexyl moiety. In particular, in other embodiments, the light absorbing moiety R⁴ is a moiety according to Formula (VI) wherein q is 2; and the linker is a linker of Formula (II) wherein X¹ is C and R¹ and R² are methyl, ethyl, or linked together to form a cyclopentyl or cyclohexyl moiety.

In particular, in some embodiments, the light absorbing moiety R⁴ is a moiety according to Formula (VII), and the linker is a linker of Formula (II) wherein X¹ is O and R¹ and R² are methyl, ethyl, or linked together to form a cyclopentyl or cyclohexyl moiety. In particular, in other embodiments, the light absorbing moiety R⁴ is a moiety according to Formula (VII); and the linker is a linker of Formula (II) wherein X¹ is C and R¹ and R² are methyl, ethyl, or linked together to form a cyclopentyl or cyclohexyl moiety.

In particular, in some embodiments, the light absorbing moiety R⁴ is a moiety according to Formula (VII) wherein r is 2, and the linker is a linker of Formula (II) wherein X¹ is O and R¹ and R² are methyl, ethyl, or linked together to form a cyclopentyl or cyclohexyl moiety. In particular, in other embodiments, the light absorbing moiety R⁴ is a moiety according to Formula (VII) wherein r is 2; and the linker is a linker of Formula (II) wherein X¹ is C and R¹ and R² are methyl, ethyl, or linked together to form a cyclopentyl or cyclohexyl moiety.

In particular, in some embodiments, one or more hydrophilic substituent that can be added to the light absorbing moiety and/or can be comprised in the payload moiety to provide or increase a desired water solubility.

In embodiments herein described, the photoacid compounds of the disclosure can be used in methods and systems to deliver the payload R³ in a controlled fashion.

In particular, a payload R³ can be released or decaged by providing the light absorbing moiety of the photoacid with a wavelength suitable to switch the state of the light absorbing moiety R⁴ from a ground state to an excited state.

The term “cage” as used herein relates to the interaction between a first chemical moiety and a second chemical moiety that minimizes the participation in physical chemical or biological reactions of the second chemical moiety. In particular, the payload is caged by the linker moiety through covalent bond of the carbonyl group of the linker with a suitable functional group in the linker. The terms “decage” or “uncage” herein are defined as a modification of a caging interaction between a first and second chemical moiety to the chemical moiety, forming liberating the second molecule to participate in chemical or biological reactions. In embodiments herein described, decaging is performed through cleavage of the covalent bond between carbonyl group and the payload. Decaging of a compound can be detected by identifying the decaged activity of the uncaged compound or by LC-MS spectroscopy to identify either the caged compound, the first moiety, or the second moiety.

Determination of a suitable wavelength to perform the switching from a ground state to an excited state can be performed by a skilled person based on the structural and chemical properties of the light absorbing moiety. For example, in some embodiments, a suitable wavelength can be selected based on known photoactive molecules (e.g. polycyclic aromatic hydrocarbons and/or cyanine; see, e.g., [Ref 1]) which can then be subjected to the appropriate preparation methods exemplified in Examples 1-4 and Examples 7-8.

In embodiments of photoacids of the present disclosure, the wavelength is selected so that the promotion of the light absorbing moiety R⁴ from a ground state to an excited state results in a decrease of the pK_a of the photoacidic R⁴OH group relative to the pK_a of the same OH group in the ground state. The consequent shifting of the acid base equilibrium of the photoacid results in the release of payload R³. Accordingly, detection of the successful switching to an excited state by the light absorbing moiety R⁴ following irradiation of the photoacids with a suitable wavelength can be performed by detecting a switching in acidity in the reaction solution performed by measuring pK_a of the photoacidic R⁴ hydroxyl group.

Accordingly, according to methods and systems herein described, providing a caged compound can be performed by synthesizing a photoacid of Formula (I) including the compound caged as a payload moiety. The photoacid compound is selected to have a light absorbing moiety with a OH group such that upon irradiation with light at a wavelength exciting the light absorbing moiety the pK_a of the OH group is lowered.

In some embodiments, the light absorbing moiety can be formed by a LWAP which is promoted to an excited state upon irradiation with an infrared light or a near infrared light (or NIR). The term “infrared light” as used herein refers to light in the infrared region of the electromagnetic spectrum from approximately 0.75 μm to 1000 μm. The term “near infrared” refers to a region of the infrared spectrum from approximately 0.75 μm (750 nm) to 1.4 μm (1400 nm).

In this connection, reference is made to the schematic illustration of FIG. 1 in which the FIG. 1A presents a schematic illustration of a light activated photoacid releasing according to the present disclosure, where a long-wavelength absorber is linked to the exemplary payload moiety formed by a drug, the drug being replaceable by an imaging agent or other payload molecule as will be understood by a skilled person. FIG. 1B shows a UV-activated photoacid releasing water, through photoactive protonation of an hydroxyl alcohol presented by a naphthyl moiety resulting in the release of water to be considered in comparison with FIG. 1C showing an exemplary light activated photoacid releasing according to the present disclosure in which the light absorbing moiety is a napthol. In FIG. 1C, the system is designed to have a photoacidic group (the OH), and an ester that can intramolecularly hydrogen bond to the OH. In FIG. 1C, excitation with light can increase the acidity of the OH, and a proton transfer occurs. In the illustration of FIG. 1C, the ester is a derivative of a t-butyl ester, a class that is especially sensitive to acid-catalyzed ester cleavage. t-Butyl esters suitable for inclusion in a linker herein described comprise t-butyl esters commonly used in commercial solid phase peptide synthesizers and t-butyl esters that are part of the common Boc protecting group. In particular, in several suitable t-butyl esters, the standard t-butyl cleavage mechanism can produce a generic carboxylate. In the illustration of FIG. 1C, cleavage in this system releases the generic entity RCO₂H, a carboxylic acid, which, under physiological conditions will be in its deprotonated, carboxylate form (structure in box). Computational studies show that the intramolecular hydrogen bond shown in FIG. 1C is viable.

In some compounds herein described, the photochemical excited state can increase the acidity of appropriate groups by as many as 10 orders of magnitude ([Ref 5] and [Ref 6]). Such an increase in acidity is intramolecular and hence usually does not alter the pH of the surrounding environment. In some embodiments, the shift in acidity (pK_a) of about 10 orders of magnitude is corresponds to only an energy change of <14 kcal/mol, which supports the conclusion that suitable light absorbing moiety for the photoacid compounds herein described can absorb a very long wavelength light (e.g. from about 900 to about 1100 nm) and that various moiety that can be excited at long wavelength are expected to be able to initiate photoacid chemistry. For example, light at 1010 nm has an energy of 28 kcal/mol, twice what is needed to produce the desired pK_a shift.

FIG. 1D shows a proof of concept establishing viability of the essential photochemical reaction proposed (see also Example 5 showing that irradiation produces the carboxylic acid shown). FIG. 1E shows how the light-absorbing feature of the molecule—the chromophore—can be varied while leaving the essential chemistry intact. As the chromophore gets larger, it can absorb longer wavelength light such as, for example, long wavelength visible light and/or NIR light. Even at wavelengths far out into the NIR, enough energy can be present to enhance the pK_a of the OH. For example, light at 1010 nm (commonly used in optical coherence tomography) has an energy of 28 kcal/mol, twice what is needed or a factor of 10 orders of magnitude.

The light absorbing moieties described herein can be selected to absorb longer wavelengths of light. In some instances, known dyes and NIR absorbers, can permit empirical determination which systems are most effective (see, for example, [Ref 1]). FIG. 1F shows a retinal/carotene-type compound that can be continuously tuned by just increasing the number of double bonds. In this approach, the molecule left after uncaging resembles carotene or vitamin E, and can exert non-toxic activity. FIG. 1G shows a merocyanine dye strategy. These are very common, highly tunable structures that have seen extensive biological use in the form of the common Cy and Alexa dyes ([Ref 7]) and possess arene and heteroarene moieties suitable to the preparation reactions of Examples 1-4 and Examples 7-8.

The photochemistry illustrated by the exemplary illustration of FIG. 1 can uncage compounds other than carboxylates. FIG. 1H shows uncaging of an amine, in this particular case producing the inhibitory neurotransmitter γ-aminobutyric acid (GABA). This strategy can be used to uncage many compounds including, for example, neurotransmitters, anti-cancer agents, sedatives, antibodies, protein therapeutics, imaging markers, and others. By way of example, a compound such as etomidate can be caged in several ways. The unfunctionalized N of the imidazole ring of etomidate can be acylated to produce a structure that can be acid cleaved. Alternative, carboxyl derivatives at C2 of etomidate (between the two nitrogens) decarboxylate when hydrolyzed, feeding naturally into the t-butyl ester strategy herein described. From the structure shown above, the unfunctionalized N of the imidazole ring of etomidate provides a handle for attaching a photocage.

The generality of the uncaging process herein described can permit the develop other probes and ways to monitor the efficiency of the system. For example, fluorescein is a common dye that is often used in biological imaging. It exists in two forms that can interconvert (FIG. 2). Either the carboxylic acid or the OH of the fluorescein could be caged within the photoacid compounds described herein. The caged compound would not be fluorescent. Photonic uncaging would liberate fluorescein, allowing an array of imaging strategies to evaluate the efficiency and localization of the photonic uncaging. Of course, many other dyes and imaging agents could be manipulated in the same way.

In embodiments of the photoacid compounds herein described, the photochemical excited state can increase the acidity of appropriate groups by as many as 10 orders of magnitude ([Ref 5] and [Ref 6]). In those embodiments, such an increase in acidity is intramolecular and hence does not alter the pH of the surrounding environment.

In some embodiments, a suitable wavelength provides an energy change of <14 kcal/mol and results in shifting an acid-base equilibrium (pK_a) by 10 orders of magnitude. In particular in some embodiments, such a shift is associated to a wavelength of from about 900 to about 1100 nm). For example, light at 1010 nm has an energy of 28 kcal/mol, twice what is needed to produce the desired pK_a shift. Additional embodiments will be identifiable to a skilled person upon reading of the present disclosure.

In some embodiments, the photoacids are expected to be tunable with regard to lifetime and absorption spectrum. Often, the excited-state lifetimes of these molecules are short, which could limit the efficiency of the proton-transfer reaction. However, several strategies for enhancing excited state lifetimes are known, including adding heavy atoms to facilitate conversion to the longer-lived triplet excited state. Additionally, the addition of electron-withdrawing substituents at key points in the extended π system can create “super photoacids” which deprotonate very efficiently in aqueous solutions upon excitation. In some embodiments, photoacidic molecules can be based on 2-naphthols, which display the desired photoacid effect, have a good safety profile, and can be easily modified to control water-solubility and to the tune the optical properties (see e.g. schematized in FIG. 1C and FIG. 1D).

In some embodiments, the long wavelength light used to uncage the payload is infrared light. In particular, in some embodiments, the infrared light is of a wavelength between 750 nm and 1400 nm corresponding to near infrared light. In other embodiments the near infrared light used to uncage the payload compounds can be between 900 and 1100 nm.

The method for and uncaging the caged compound by irradiating the photoacid compound of Formula (I) with light at a wavelength suitable to promote the photoacid compound of Formula (I) to an excited state wherein the hydrogen substituted heteroatom presented on the light absorbing moiety of the photoacid compound has an excited state pK_a lower than the ground state pK_a.

Irradiating can be performed through various procedures and techniques identifiable by a skilled person. In particular, a long wavelength light can be delivered by any of a number of means such as via microscope, endoscope, LCD panel or LED display as handheld or non-portable devices or worn as glasses or other such attachment to the body. Image intensifiers can be used to further increase the emitted power from such devices in order to activate the preparation of molecules.

Other approaches can use high intensity short wavelength light and are suitable for applications in which use of the short length is desired. For example in a biological environment, use of a high intensity short wavelength can be used in application wherein production of reactive oxygen species or genetic manipulation of host cells is desired.

Photoacid compounds described herein can be provided as a part of systems to deliver compounds, identifiable by a skilled person upon reading of the present disclosure. In some embodiments, the systems for delivery of the caged compounds herein described can be provided in the form of combinations of photoacid compounds and/or related compositions, in which the system can comprise one or more photoacid compounds, and a suitable vehicle identifiable by a skilled person.

In some embodiments, the systems herein described can be provided in the form of kits of parts. In a kit of parts, one or more photoacid compounds herein described, and suitable light source and other reagents to perform the reactions can be comprised in the kit independently. The photoacid compounds can be included in one or more compositions, and each photoacid compounds can be in a composition together with a suitable vehicle.

The term “vehicle” as used herein indicates any of various media acting usually as solvents, carriers, binders or diluents for the caged compounds that are comprised in the composition as an active ingredient.

Further characteristics of the present disclosure will become more apparent hereinafter from the following detailed disclosure by way or illustration only with reference to an experimental section.

EXAMPLES

The photoacid compounds, compositions methods and systems herein described are further illustrated in the following examples, which are provided by way of illustration and are not intended to be limiting.

In particular, the following examples illustrate exemplary photoacid in which the light absorbing moiety is formed by naphthol, and cyanine, X¹ is an 0 or a C, R¹ and R² are either methyl or are linked to form a cycloalkyl moiety and the payload hydrocinnamic acid and related methods and systems. A person skilled in the art will appreciate the applicability and the necessary modifications to adapt the features described in detail in the present section, to additional photoacid compounds, methods and systems according to embodiments of the present disclosure.

A skilled person will realize, upon a reading of the present disclosure, that compounds similar to those exemplified below can be made using the synthetic methods herein described. A skilled person can select suitable starting material based on the starting materials exemplified below by utilizing databases such as SCIFINDER® and REAXYS®. A skilled person would also be able to use purification methods in addition to those exemplified below such as, for example, recrystallization, preparatory thin-layer chromatograph, preparatory high-pressure liquid chromatography, and others known in the art. A skilled person will also realize, that where appropriate, protecting groups for functional groups can be used according to methods known in the art (see, e.g. [Ref 8] and [Ref 9])

Example 1

Synthesis of Exemplary Naphthalene-Based Photoacid Compounds

Described below is the synthesis of compound 1, as seen in FIG. 3.

Synthesis of Compound 3

To a 0.1 M solution of 3,4-dihydroxynaphthalene (2) in dry dichloromethane (DCM) under argon is added at 0° C. 2.8 eq triethylamine (TEA) followed by chloroacetyl chloride (1.1 eq). The solution is allowed to warm to room temperature over one hour, then refluxed four hours. Upon completion, the reaction is diluted with water, and extracted with DCM. The combined organics are washed with brine, dried, filtered and concentrated in-vacuo to afford the product (3).

A skilled person will realize that other chloroacyl chlorides can be selected to increase the ring size of the lactone thereby being able to produce different values of n in the photoacid compounds of Formula (I). By way of example, 3-chloropropionyl chloride and 4-chlorobutyryl chloride can be used in place of chloroacetyl chloride to provide photoacid compounds of Formula (I) with values of n of 2 and 3, respectively.

A skilled person will also realize that the above reaction is not limited to 3,4-dihydroxynaphthalene and that the above strategy can be applied to other ortho dihydroxyaryl and heteroaryl molecules to provide light absorbing moieties with different functional groups on the light absorbing moiety.

A skilled person will also realize that hydroxyl groups can be placed on an arene or heteroarene using methods known to a skilled person (e.g. aromatic substitution reactions). By way of example, an aryl or heteroaryl ring can be subjected to nitration/reduction reactions to afford ortho diamino aryl or heteroaryl rings which can then be subjected to the Sandmeyer reaction (see, e.g. [Ref 10]) using water to convert the amino groups into hydroxyl groups to afford ortho dihydroxy aryl and heteroaryl molecules.

Synthesis of Compound 4

Lactone 3 is dissolved in dry tetrahydrofuran (THF; 0.2 M) under argon and cooled to 0° C. Methylmagnesium bromide (MeMgBr; 2.2 eq, 3.0 M in diethyl ether) is added dropwise and the reaction is allowed to warm to room temperature. After one hour, a solution of hydrocinnamoyl chloride (2.2 eq) in dichloromethane is added dropwise, and the mixture is stirred overnight. Upon completion, the reaction is quenched with saturated aqueous sodium bicarbonate, and extracted with dichloromethane. The combined organics are dried over MgSO₄, filtered and concentrated in-vacuo. The crude is flashed on silica-gel eluting with 10% ethyl acetate (EtOAc) in hexane to yield the product (4) as a crude oil.

A skilled person would recognize that additional Grignard reagents can be chosen such that groups other than methyl can be substituted in the positions corresponding to R¹ and R² in Formulas (I)-(II) described herein. A skilled person would also recognize that a bis-Grignard reagent could be used to synthesize a compound in which R¹ and R² are they are linked together to form a cyclic moiety. Such an exemplary reaction is:

and an exemplary procedure would be as follows [Ref 11]: to a solution of magnesium turnings (10 eq) in dry THF, 1,4-dibromobutane (2.2 eq, 0.2 M) is added and the solution is gently heated until reaction is initiated. After 1 hour, the solution is transferred via cannula into a stirred solution of 25 (1.0 eq, 0.2 M) in dry THF under Ar at 0° C. The reaction is allowed to warm to room temperature over 1 hour. To the solution is then added the acid chloride (2.2 eq, 0.2 M) as a solution in DCM. The mixture is stirred at room temperature overnight, then quenched with water. The mixture is extracted with DCM, and the combined organics are dried with MgSO4, filtered and concentrated in-vacuo. The resulting residue is taken up in 1:1 THF-MeOH, and cooled to 0° C. Aqueous LiOH (3 eq, 1 M) is added dropwise, and the reaction is warmed to room temperature. After stirring 1 hour, the reaction is quenched with aq. citric acid, extracted DCM, dried MgSO4, filtered, and concentrated in-vacuo. The residue is purified by silica gel chromatography.

Additionally a skilled person would recognize that the acid chloride used in the reaction can comprise the payload compound (R³) and that payload compounds other than the phenylethyl payload of compound 4a can be incorporated by choice of the appropriate acid chloride. A skilled person will also recognize that acid anhydrides, activated esters, and other activated carboxylic acid derivatives can be used instead of an acid chloride.

Synthesis of Photoacid Compound 1

Diester 4 (0.1 M) is dissolved in 1:1 THF-methanol (MeOH) and cooled to 0° C. An aqueous solution of LiOH (3.0 eq, 1.0 M) is added dropwise and the reaction is warmed to room temperature. After 2.5 hours, the reaction is quenched with aqueous citric acid, and extracted with dichloromethane. The combined organics are dried over MgSO₄, filtered and concentrated in-vacuo. The crude is flashed on silica-gel eluting with 20% EtOAc in hexane to yield the product (1) as a clear oil.

Example 2

Possible Synthesis of Acene-Based Photoacid Compounds

A skilled person would recognize that the synthesis of the naphthalene-based photoacid compound 1 in Example 1 can be modified to synthesize acene-based photoacid compounds with more than two fused aryl rings. For example, a skilled person could apply the methods of Lin et al. (“Iterative synthesis of acenes via homo-elongation” Chem. Commun. 2009(7): 803-805) to perform the reaction:

to provide an acene of desired length analogous to compound 2 in Example 1, which could then be carried through the synthetic steps of Example 1. A skilled person would also recognize that the aldehyde and/or nitrile groups (R) in compound c can be converted to other functional groups (e.g. alcohols, esters, amines, and others identifiable to a skilled person) for use in functionalizing the final photoacid compound product though standard reaction conditions known to a skilled person (e.g. reduction with lithium aluminum hydride, diisobutyl aluminum hydride, and others identifiable to a skilled person).

A skilled person will also realize that the aldehyde groups (R) can be further converted into amines (e.g., by reductive amination; see, e.g., [Ref 12]). The amines can further be functionalized by standard peptide coupling techniques (see e.g. [Ref 13]) with sulfonate peptides such as, for example:

to, for example, increase water solubility (see e.g., [Ref 14] and [Ref 15]).

In in some embodiments, the substituent of compound 49 can be added to a pendent functional group (e.g. an amine) on the light absorbing moiety (see Examples 1-4). In particular, such a substituent can provide, for example, a compound according to Formula (XX):

wherein R is CH₂NH₂ or another moiety according such as 49, and n is between 0 and 5; or a compound according to Formula (XXI):

Example 3

Synthesis of Cyanine (Cy5)-Based Photoacid Compound 5

Described below is the synthesis of photoacid compound 5 as shown in FIG. 5. Synthesis of compound 7

3,4-dimethoxyaniline (6; 0.1 M) is dissolved in 1:1 HCl—H₂O and cooled to −10° C. under argon. A chilled aqueous solution of NaNO₂ (1.1 eq) is added slowly via syringe, ensuring that the reaction maintains a temperature below 0° C. After stirring 30 minutes, a chilled solution of 5 nCl₂ (3 eq, 2.0 M) in concentrated HCl followed by 3-methyl-2-butanone (3 eq) is added. The mixture is stirred 30 minutes, then quenched into a vigorously stirred solution of aqueous sodium bicarbonate and EtOAc. After extraction with EtOAc, the combined organics are dried with MgSO₄, filtered, and concentrated in-vacuo. The residue is taken up in AcOH (0.1 M), and additional 3-methyl-2-butanone (3 eq) is added. The reaction is stirred overnight at room temperature, then concentrated in-vacuo. The crude is flashed directly on silica-gel eluting with 75% EtOAc in hexane to obtain the product (7) as a brown oil.

Synthesis of Compound 8

Dimethoxyindolenine 7 (0.1 M) is dissolved in dry DCM under argon, and cooled to 0° C. BBr₃ (2.2 eq) is added dropwise, and the mixture is allowed to warm to r.t. After stirring 3 hours, the reaction is diluted in water, and adjusted to pH 5 using solid sodium acetate. The mixture is extracted with DCM, and the combined organics are dried over Na₂SO₄, filtered, and concentrated in-vacuo. The residue is flashed on 5% MeOH in DCM with 1% acetic acid to obtain the desired product (8) as a brown solid.

Synthesis of Compound 9

To a solution of 8 in dry DCM (1 eq, 0.1 M) under argon is added at 0° C. triethylamine (2.2 eq) followed by chloroacetylchloride (1.1 eq). The solution is allowed to warm to room temperature over one hour, then refluxed for four hours. Upon completion, the reaction is diluted with water, and extracted with DCM. The combined organics are washed with brine, dried over Na₂SO₄, filtered and concentrated in-vacuo (See also synthesis of compound 3 in Example 1 and [Ref 16]).

Synthesis of Compound 10

Compound 9 is dissolved in dry THF (1 eq, 0.2 M) under argon and cooled to 0° C. MeMgBr (2.2 eq, 3.0 M in Et₂O) is added dropwise and the reaction is allowed to warm to room temperature. After one hour, a solution of hydrocinnamoyl chloride in DCM (2.2 eq, 0.2 M) is added dropwise, and the mixture is stirred overnight. The reaction is then quenched with saturated aqueous sodium bicarbonate, and extracted with DCM. The combined organics are dried over MgSO₄, filtered and concentrated in-vacuo. The crude is flashed on silica gel eluting with 10% EtOAc:Hexane to yield the product as a clear oil. See also synthesis of compound 4 in Example 1.

Synthesis of Compound 11

Compound 10 (1 eq, 0.1 M) and iodomethane (3 eq) are dissolved in dry DCM and stirred at reflux overnight. The mixture is then cooled to room temperature, concentrated in-vacuo, and used directly in the next step (see also [Ref 17]).

Synthesis of Compound 12

Compound 11 (1 eq, 0.2 M) and malondialdehyde bis(phenylimine).HCl (1.1 eq) are dissolved in acetic anhydride and heated to 100° C. for 30 minutes. The solution is cooled to room temperature, then a solution of 23 (1 eq, 0.2 M) in pyridine is added. The reaction is stirred overnight, then concentrated in-vacuo. The residue is purified by silica gel chromatography (see also [Ref 18]).

Synthesis of Photoacid Compound 5

Compound 12 (1 eq, 0.1 M) is dissolved in 1:1 THF.MeOH. At 0° C., an aqueous solution of LiOH (3 eq, 1.0 M) is added dropwise and the reaction is warmed to room temperature. After 2.5 hours, the reaction is quenched with aqueous citric acid, and extracted with DCM. The combined organics are dried over MgSO₄, filtered and concentrated in-vacuo. The product is purified by silica gel chromatography. See also synthesis of compound 1 in Example 1.

A skilled person will realize that additional functional groups can be placed on the indole rings of the cyanine by choosing the appropriate aniline derivative similar to compound 6 above. Such different functional groups can be selected, for example, to modulate the wavelength of light absorbed by the light absorbing molecule (see e.g. [Ref 1] and [Ref 19]), to attach groups for increasing water solubility (see e.g., Example 2), or to attach heavy atoms for increasing excited state lifetimes (see e.g., Example 4). A skilled person will also realize that different alkyl iodides can be selected as in the synthesis of compound 11 above to place different alkyl substituents on the indole nitrogens in the final cyanine, for example, to modulate the wavelength of light absorbed by the light absorbing molecule (see e.g. [Ref 1] and [Ref 19]).

Example 4

Synthesis of Cyanine (Cy5)-Based Photoacids 13 and 14

Described below is the synthesis of photoacids 13 and 14 as shown in FIG. 5.

Synthesis of Compound 16

Compound 15 (1 eq, 1.0 M) is dissolved in 3:2 AcoH—H₂O and cooled to 0° C. Concentrated HNO₃ (1.1 eq) is added and the solution is heated to 65° C. for 10 minutes. After cooling to room temperature, the mixture is allowed to precipitate at 0° C. overnight. The crystalline product is collected on a sintered glass funnel and washed with ice-cold water. The solid is then dissolved in an ice-cold solution of KOH (1.1 eq, 0.5 M in 1:4 H₂O—MeOH) and allowed to warm to 50° C. for 15 minutes. Cooling to 0° C. then affords a crystalline product that is filtered, washed with ice water, and dried in-vacuo.

Synthesis of Compound 17

Compound 16 (1 eq) is dissolved in acetic acid (0.3 M) and added to a solution of NaNO₂ (1.1 eq, 2.0 M) in concentrated H₂SO₄, keeping the temperature between 15-20° C. with an ice-bath. The resulting solution is added over 5 minutes to a solution of CuBr (1.1 eq, 0.05 M in 1:1 HBr—H₂O) heated at 80° C. After addition, the reaction mixture is allowed to cool to room temperature and extracted with DCM. The combined organics are dried over MgSO₄, filtered, and concentrated in-vacuo.

Synthesis of Compound 18

Compound 17 (1 eq, 0.1 M), iron powder (3 eq), and conc. HCl (5 eq) are dissolved in EtOH and heated to reflux. After stirring 5 hours, the mixture is cooled to room temperature, made basic by addition of Na₂CO₃, and extracted with Et₂O. The combined organics are washed with water, dried over MgSO4, filtered, passed through a plug of silica gel, and concentrated in-vacuo.

Synthesis of Compound 19

A suspension of 18 (1 eq, 0.2 M) in 1:1 conc. HCl—H₂O is cooled to −10° C. under Ar. A chilled solution of NaNO₂ (1.1 eq, 2.0 M) in H₂O is slowly added, keeping the temperature below 0° C. The solution is stirred at the temperature for 30 minutes, then a chilled solution of 5 nCl₂ (3 eq, 2.0 M) in conc. HCl is added slowly. After addition, the mixture is diluted in H₂O, and extracted Et₂O. The remaining organic is made basic with NaOH, then extracted with Et2O. The combined organics are dried over MgSO₄, filtered, and concentrated in-vacuo. The residue is taken up in AcOH, and 3-methyl-2-butanone (2.2 eq) is added. The mixture is refluxed overnight, then concentrated in-vacuo. The crude is flashed on silica gel eluting with 25% EtOAc, Hexane to obtain the product as a reddish oil.

Synthesis of Compound 20

Compound 19 (1 eq, 0.1 M) is dissolved in dry DCM under Ar and cooled to 0° C. BBr₃ (1.1 eq) is added dropwise, and reaction stirred at the temperature for 5 hours. The reaction is then diluted in H2O, extracted DCM, dried over MgSO4, and concentrated in-vacuo. The crude is flashed on 25% EtOAc:Hex to yield the product as a colorless oil.

Synthesis of Compound 21

Compound 20 is dissolved in iodomethane and refluxed overnight. After cooling to room temperature, the excess iodomethane is removed in-vacuo. The resulting residue is used without further purification.

Synthesis of Compounds 13 and 14

Compound 21 (1 eq, 0.2 M) and malondialdehyde bis(phenylimine.HCl (1.1 eq) are dissolved in acetic anhydride and heated to 100° C. for 30 minutes. The solution is cooled to room temperature, then a solution of 23 (1 eq, 0.2 M) in pyridine is added. The reaction is stirred overnight, then concentrated in-vacuo. The residue is purified by silica gel chromatography to afford compound 14 with the phenoxy group as an acetate ester. The acetate ester of 14 (1 eq, 0.1 M) is dissolved in 1:1 THF—MeOH. At 0° C., an aqueous solution of LiOH (3 eq, 1.0 M) is added dropwise and the reaction is warmed to room temperature. After 2.5 hours, the reaction is quenched with aqueous citric acid, and extracted with DCM. The combined organics are dried over MgSO4, filtered and concentrated in-vacuo. The product is purified by silica gel chromatography to afford compound 14. Compound 13 is made in the same manner except using indolium 24 instead of 23.

Example 5

Decaging of Payload Compound

Compound 1a (see Example 1) was decaged using the following procedure. In a quartz cuvette, 1a (0.001 M) is dissolved in spectroscopic-grade acetonitrile and irradiated at 300 nm using a 1-kW xenon arc lamp at room temperature for 15 minutes. Aliquots are removed and analyzed by analytical LC-MS utilizing a gradient elution of 10-100% acetonitrile-water over 10 minutes. The data shown represents t=0 minutes in the lower LC-MS trace, t=15 minutes in the upper LC-MS trace.

Example 6

Synthesis of Photoacid Compound with X¹═C (Compound 31)

The linker with X¹ in Formulas (I) and (II) being C can be synthesized according to the synthesis scheme of FIG. 7 (see, e.g., [Ref 20]). A skilled person will realize that the reactions below are not limited and can be applied to molecules similar to compound 27.

Synthesis of Compound 28

3-hydroxy-2-naphthaldehyde (27; 1 eq, 0.1 M) is dissolved in dry DCM under Ar and cooled to 0° C. A solution of AlCl₃ (1 eq, 1.0 M) in dry DCM is added, and the mixture is warmed to room temperature. Upon completion, the reaction is quenched with water, extracted with DCM, dried MgSO₄, filtered and concentrated.

A skilled person will realize that molecules similar to compound 27 can be used. By way of example, in some molecules, the aldehyde may be a precursor such as an alcohol or ester which may be oxidized or reduced, respectively, to afford an aldehyde.

Synthesis of Compound 29

The aldehyde (1 eq, 0.1 M) and (carbethoxymethylene)triphenylphosphorane (1.1 eq) are dissolved in dry xylene under Ar and refluxed 13 hours. The solution is diluted in water, and extracted EtOAc, dried MgSO₄, filtered and concentrated in-vacuo.

Synthesis of Compound 30

Compound 29 (1 eq, 0.1 M) and Raney Nickel (20%) are stirred in aqueous NaOH (1 M) at 90° C. for 1 hour. After cooling to r.t., the reaction is quenched with 1M HCl, and extracted with DCM. The combined organics are dried over MgSO₄, filtered and concentrated in-vacuo. The residue is taken up in dry benzene and refluxed with PTSA (1 eq) for 1 hour. The mixture is cooled, extracted with EtOAc, dried with MgSO₄, filtered and concentrated in-vacuo.

Synthesis of Compound 31

Compound 30 (1 eq, 0.2 M) is dissolved in dry THF under Ar and cooled to 0° C. A solution of MeMgBr (2.2 eq, 3.0 M in Et₂O) is added dropwise, and the reaction is allowed to warm to room temperature over 1 hour. To the solution is then added hydrocinnamoyl chloride (2.2 eq, 0.2 M) as a solution in DCM. The mixture is stirred at room temperature overnight, then quenched with water. The mixture is extracted with DCM, and the combined organics are dried with MgSO4, filtered and concentrated in-vacuo. The resulting residue is taken up in 1:1 THF-MeOH, and cooled to 0° C. Aqueous LiOH (3 eq, 1 M) is added dropwise, and the reaction is warmed to room temperature. After stirring 1 hour, the reaction is quenched with aq. citric acid, extracted DCM, dried MgSO₄, filtered, and concentrated in-vacuo. The residue is purified by silica gel chromatography.

Example 7

General Synthesis of Cyanine-Based Photoacid Compounds

A skilled person will realize that cyanine-based [Ref 1, 19] photoacid compounds in addition to those above can be synthesized using general methods. These general reaction methods are shown in FIG. 8A-F.

FIG. 8A shows a general synthetic strategy to synthesize photoacid compounds of Formula (I) using a common precursor (ortho dihydroxyarene; 32). In FIG. 8A, X′ and Y′ are linked together to form part of an arene or heteroarene. Compound 32 is then carried through the steps of Example 1 and/or Example 3 to provide compound 34, shown in FIG. 8A with an optional protecting group (PG; see [Ref 9] and [Ref 8]).

FIG. 8B shows a general synthetic scheme for the synthesis of closed chain cyanines with a variable-length polyene and variable heteroaryl groups. In FIG. 8B, commercially available precursors are converted to compounds 36 and 35 (which can be converted into compound 36), and compound 26 is converted into compound 37 (see, e.g. [Ref 21]). In compounds 35, 36, and 37, X is nitrogen and Y is a heteroatom such as, for example, N, O, or S. Groups R^a and R^b in compounds 35, 36, and 37 can be H, alkyl, or O-alkyl. In the alternative, R^a and R^b can be linked together to form part of an arene or heteroarene. In some cases, when R^a and R^b are linked together to form part of an arene or heteroarene, the arene or heteroarene can be of the form of compound 32 and can be carried through the steps of FIG. 8A. Similarly, when R^a and R^b are O-alkyl, they may be subjected to Deprotection conditions (see, e.g., synthesis of compound 8 in Example 3) to afford a dihydroxylated arene or heteroarene can be of the form of compound 32.

FIG. 8C shows an exemplary application of the synthesis shown in FIG. 8B to the general synthesis of photoacid compounds with cyanine light absorbing moieties. In FIG. 8C, compound 34 from FIG. 8A is carried through the synthetic steps of FIG. 8B (with a deprotection step; see [Ref 9] and [Ref 8]) to afford a photoacidic compound (29) as herein described with payload moiety R³.

FIG. 8D shows a photoactive molecule with a particular desired absorbance wavelength (compound 40) and an analogous photoactive compound as herein described (compound 41) incorporating compound 40 as the light absorbing moiety. Compound 40 can be synthesized using the quinolinium 44 (analogous to compound 36) using the methods of FIG. 8B. The synthesis of quinolinium 44 can be accomplished using the reactions of FIG. 8E.

FIG. 8F shows the synthesis of photoacid compound 41 according to the methods of FIG. 8A, FIG. 8B, and FIG. 8E. Compound 45, which can be synthesized in one step from a commercially available compound, is converted to dihydroxyquinoline 43 via the first reaction of FIG. 8E. Dihydroxyquinoline 43 can then be converted to compound 47 via the reactions of FIG. 8A. Compound 47 can then be converted to quinolinium 48 via the second reaction of FIG. 8E. Quinolinium 48 can in turn be converted to photoacid compound 41 via the last reaction of FIG. 8B similar to what is done in FIG. 8C.

The examples set forth above are provided to give those of ordinary skill in the art a complete disclosure and description of how to make and use the embodiments photoacid compounds and related compositions, methods, and systems of the disclosure, and are not intended to limit the scope of what the Applicants regard as their disclosure. Modifications of the above-described modes for carrying out the disclosure can be used by persons of skill in the art, and are intended to be within the scope of the following claims.

The entire disclosure of each document cited (including patents, patent applications, journal articles including related supplemental and/or supporting information sections, abstracts, laboratory manuals, books, or other disclosures) in the Background, Summary, Detailed Description, and Examples is hereby incorporated herein by reference. All references cited in this disclosure are incorporated by reference to the same extent as if each reference had been incorporated by reference in its entirety individually. However, if any inconsistency arises between a cited reference and the present disclosure, the present disclosure takes precedence.

The terms and expressions which have been employed herein are used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the disclosure claimed. Thus, it should be understood that although the disclosure has been specifically disclosed by preferred embodiments, exemplary embodiments and optional features, modification and variation of the concepts herein disclosed can be resorted to by those skilled in the art, and that such modifications and variations are considered to be within the scope of this disclosure as defined by the appended claims.

It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting. As used in this specification and the appended claims, the singular forms “a,” an and the include plural referents unless the content clearly dictates otherwise. The term “plurality” includes two or more referents unless the content clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the disclosure pertains.

The term “alkyl” as used herein refers to a linear, branched, or cyclic saturated hydrocarbon group typically although not necessarily containing 1 to about 15 carbon atoms, or 1 to about 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, octyl, decyl, and the like, as well as cycloalkyl groups such as cyclopentyl, cyclohexyl and the like. Generally, although again not necessarily, alkyl groups herein contain 1 to about 15 carbon atoms. The term “cycloalkyl” intends a cyclic alkyl group, typically having 4 to 8, or 5 to 7, carbon atoms. The term “substituted alkyl” refers to alkyl substituted with one or more substituent groups, and the terms “heteroatom-containing alkyl” and “heteroalkyl” refer to alkyl in which at least one carbon atom is replaced with a heteroatom. If not otherwise indicated, the terms “alkyl” and “lower alkyl” include linear, branched, cyclic, unsubstituted, substituted, and/or heteroatom-containing alkyl and lower alkyl, respectively.

The term “hydrocarbyl” as used herein refers to any univalent radical, derived from a hydrocarbon, such as, for example, methyl or phenyl. The term “hydrocarbylene” refers to divalent groups formed by removing two hydrogen atoms from a hydrocarbon, the free valencies of which may or may not be engaged in a double bond, typically but not necessarily containing 1 to 20 carbon atoms, in particular 1 to 12 carbon atoms and more particularly 1 to 6 carbon atoms which includes but is not limited to linear cyclic, branched, saturated and unsaturated species, such as alkylene, alkenylene alkynylene and divalent aryl groups, e.g., 1,3-phenylene, —CH₂CH₂CH₂-propane-1,3-diyl, —CH₂-methylene, —CH═CH—CH═CH—. The term “hydrocarbyl” as used herein refers to univalent groups formed by removing a hydrogen atom from a hydrocarbon, typically but not necessarily containing 1 to 20 carbon atoms, in particular 1 to 12 carbon atoms and more particularly 1 to 6 carbon atoms, including but not limited to linear cyclic, branched, saturated and unsaturated species, such as univalent alkyl, alkenyl, alkynyl and aryl groups e.g. ethyl and phenyl groups.

The term “heteroatom-containing” as in a “heteroatom-containing alky group” refers to a alkyl group in which one or more carbon atoms is replaced with an atom other than carbon, e.g., nitrogen, oxygen, sulfur, phosphorus or silicon, typically nitrogen, oxygen or sulfur. Similarly, the term “heteroalkyl” refers to an alkyl substituent that is heteroatom-containing, the term “heterocyclic” refers to a cyclic substituent that is heteroatom-containing, the terms “heteroaryl” and “heteroaromatic” respectively refer to “aryl” and “aromatic” substituents that are heteroatom-containing, and the like. It should be noted that a “heterocyclic” group or compound may or may not be aromatic, and further that “heterocycles” may be monocyclic, bicyclic, or polycyclic as described above with respect to the term “aryl.” Examples of heteroalkyl groups include alkoxyaryl, alkylsulfanyl-substituted alkyl, N-alkylated amino alkyl, and the like. Examples of heteroaryl substituents include pyrrolyl, pyrrolidinyl, pyridinyl, quinolinyl, indolyl, pyrimidinyl, imidazolyl, 1,2,4-triazolyl, tetrazolyl, and others known to a skilled person, and examples of heteroatom-containing alicyclic groups are pyrrolidino, morpholino, piperazino, piperidino, and other known to a skilled person.

The term “alkoxy” as used herein intends an alkyl group bound through a single, terminal ether linkage; that is, an “alkoxy” group may be represented as —O-alkyl where alkyl is as defined above. A “lower alkoxy” group intends an alkoxy group containing 1 to 6 carbon atoms. Analogously, “alkenyloxy” and “lower alkenyloxy” respectively refer to an alkenyl and lower alkenyl group bound through a single, terminal ether linkage, and “alkynyloxy” and “lower alkynyloxy” respectively refer to an alkynyl and lower alkynyl group bound through a single, terminal ether linkage.

The term “alkylamino” as used herein intends an alkyl group bound through a single terminal amine linkage; that is, an “alkylamino” may be represented as —NH-alkyl where alkyl is as defined above. A “lower alkylamino” intends a alkylamino group containing 1 to 6 carbon atoms. The term “dialkylamino” as used herein intends two identical or different bound through a common amine linkage; that is, a “dialkylamino” may be represented as —N(alkyl)₂ where alkyl is as defined above. A “lower dialkylamino” intends a alkylamino wherein each alkyl group contains 1 to 6 carbon atoms. Analogously, “alkenylamino”, “lower alkenylamino”, “alkynylamino”, and “lower alkynylamino” respectively refer to an alkenyl, lower alkenyl, alkynyl and lower alkynyl bound through a single terminal amine linkage; and “dialkenylamino”, “lower dialkenylamino”, “dialkynylamino”, “lower dialkynylamino” respectively refer to two identical alkenyl, lower alkenyl, alkynyl and lower alkynyl bound through a common amine linkage. Similarly, “alkenylalkynylamino”, “alkenylalkylamino”, and “alkynylalkylamino” respectively refer to alkenyl and alkynyl, alkenyl and alkyl, and alkynyl and alkyl groups bound through a common amine linkage.

The term “aryl” as used herein, and unless otherwise specified, refers to an aromatic substituent containing a single aromatic ring or multiple aromatic rings that are fused together, directly linked, or indirectly linked (such that the different aromatic rings are bound to a common group such as a methylene or ethylene moiety). Aryl groups can contain 5 to 24 carbon atoms, or aryl groups contain 5 to 14 carbon atoms. Exemplary aryl groups contain one aromatic ring or two fused or linked aromatic rings, e.g., phenyl, naphthyl, biphenyl, diphenylether, diphenylamine, benzophenone, and the like. “Substituted aryl” refers to an aryl moiety substituted with one or more substituent groups, and the terms “heteroatom-containing aryl” and “heteroaryl” refer to aryl substituents in which at least one carbon atom is replaced with a heteroatom, as will be described in further detail infra.

The term “arene”, as used herein, refers to an aromatic ring or multiple aromatic rings that are fused together. Exemplary arenes include, for example, benzene, naphthalene, anthracene, and the like. The term “heteroarene”, as used herein, refers to an arene in which one or more of the carbon atoms has been replaced by a heteroatom (e.g. O, N, or S). Exemplary heteroarenes include, for example, indole, benzimidazole, thiophene, benzthiazole, and the like. The terms “substituted arene” and “substituted heteroarene”, as used herein, refer to arene and heteroarene molecules in which one or more of the carbons and/or heteroatoms are substituted with substituent groups.

The terms “cyclic”, “cyclo-”, and “ring” refer to alicyclic or aromatic groups that may or may not be substituted and/or heteroatom containing, and that may be monocyclic, bicyclic, or polycyclic. The term “alicyclic” is used in the conventional sense to refer to an aliphatic cyclic moiety, as opposed to an aromatic cyclic moiety, and may be monocyclic, bicyclic or polycyclic.

The terms “halo”, “halogen”, and “halide” are used in the conventional sense to refer to a chloro, bromo, fluoro or iodo substituent or ligand.

The term “substituted” as in “substituted alkyl,” “substituted aryl,” and the like, is meant that in the, alkyl, aryl, or other moiety, at least one hydrogen atom bound to a carbon (or other) atom is replaced with one or more non-hydrogen substituents.

Examples of such substituents include, without limitation: functional groups such as halo, hydroxyl, sulfhydryl, C1-C24 alkoxy, C2-C24 alkenyloxy, C2-C24 alkynyloxy, C5-C24 aryloxy, C6-C24 aralkyloxy, C6-C24 alkaryloxy, acyl (including C2-C24 alkylcarbonyl (—CO-alkyl) and C6-C24 arylcarbonyl (—CO-aryl)), acyloxy (—O-acyl, including C2-C24 alkylcarbonyloxy (—O—CO-alkyl) and C6-C24 arylcarbonyloxy (—O—CO-aryl)), C2-C24 alkoxycarbonyl (—(CO)—O-alkyl), C6-C24 aryloxycarbonyl (—(CO)—O-aryl), halocarbonyl (—CO)—X where X is halo), C2-C24 alkylcarbonato (—O—(CO)-β-alkyl), C6-C24 arylcarbonato (—O—(CO)—O-aryl), carboxy (—COOH), carboxylato (COO⁻), carbamoyl (—(CO)—NH2), mono-(C1-C24 alkyl)-substituted carbamoyl (—(CO)—NH(C1-C24 alkyl)), di-(C1-C24 alkyl)-substituted carbamoyl (—(CO)—N(C1-C24 alkyl)2), mono-(C5-C24 aryl)-substituted carbamoyl (—(CO)—NH-aryl), di-(C5-C24 aryl)-substituted carbamoyl (—(CO)—N(C5-C24 aryl)2), di-N—(C1-C24 alkyl),N—(C5-C24 aryl)-substituted carbamoyl, thiocarbamoyl (—(C5-NH2), mono-(C1-C24 alkyl)-substituted thiocarbamoyl (—(CO)—NH(C1-C24 alkyl)), di-(C1-C24 alkyl)-substituted thiocarbamoyl (—(CO)—N(C1-C24 alkyl)2), mono-(C5-C24 aryl)-substituted thiocarbamoyl (—(CO)—NH-aryl), di-(C5-C24 aryl)-substituted thiocarbamoyl (—(CO)—N(C₅-C₂₄ aryl)₂), di-N—(C₁-C₂₄ alkyl),N—(C5-C24 aryl)-substituted thiocarbamoyl, carbamido (—NH—(CO)—NH₂), cyano(—C≡N), cyanato (—O—C≡H), thiocyanato (—S—C≡N), formyl (—(CO)—H), thioformyl ((CS)—H), amino (—NH2), mono-(C1-C24 alkyl)-substituted amino, di-(C1-C24 alkyl)-substituted amino, mono-(C5-C24 aryl)-substituted amino, di-(C5-C24 aryl)-substituted amino, C2-C24 alkylamido (—NH—(CO)-alkyl), C6-C24 arylamido (—NH—(CO)-aryl), imino (—CR═NH where R=hydrogen, C1-C24 alkyl, C5-C24 aryl, C6-C24 alkaryl, C6-C24 aralkyl, and others known to a skilled person), C2-C20 alkylimino (CR═N(alkyl), where R=hydrogen, C1-C24 alkyl, C5-C24 aryl, C6-C24 alkaryl, C6-C24 aralkyl, and others known to a skilled person), arylimino (—CR═N(aryl), where R=hydrogen, C1-C20 alkyl, C5-C24 aryl, C6-C24 alkaryl, C6-C24 aralkyl, and others known to a skilled person), nitro (—NO2), nitroso (—NO), sulfo (—SO2-OH), sulfonato (—SO2-O⁻), C1-C24 alkylsulfanyl (—S-alkyl; also termed “alkylthio”), C5-C24 arylsulfanyl (—S-aryl; also termed “arylthio”), C1-C24 alkylsulfinyl (—(SO)-alkyl), C5-C24 arylsulfinyl (—(SO)-aryl), C1-C24 alkylsulfonyl (—SO2-alkyl), C5-C24 arylsulfonyl (—SO2-aryl), boryl (—BH2), borono (—B(OH)₂), boronato (—B(OR)₂ where R is alkyl or other hydrocarbyl), phosphono (—P(O)(OH)2), phosphonato (—P(O)(O⁻)2), phosphinato (—P(O)(O⁻), phospho (—PO2), phosphino (—PH2), silyl (—SiR3 wherein R is hydrogen or hydrocarbyl), and silyloxy (—O-silyl); and the hydrocarbyl moieties C1-C24 alkyl (e.g. C1-C12 alkyl and C1-C6 alkyl), C2-C24 alkenyl (e.g. C2-C12 alkenyl and C2-C6 alkenyl), C2-C24 alkynyl (e.g. C2-C12 alkynyl and C2-C6 alkynyl), C5-C24 aryl (e.g. C5-C14 aryl), C6-C24 alkaryl (e.g. C6-C16 alkaryl), and C6-C24 aralkyl (e.g. C6-C16 aralkyl).

The term “acyl” refers to substituents having the formula —(CO)-alkyl, —(CO)-aryl, or —(CO)-aralkyl, and the term “acyloxy” refers to substituents having the formula —O(CO)-alkyl, —O(CO)-aryl, or —O(CO)-aralkyl, wherein “alkyl,” “aryl, and “aralkyl” are as defined above.

The term “alkaryl” refers to an aryl group with an alkyl substituent, and the term “aralkyl” refers to an alkyl group with an aryl substituent, wherein “aryl” and “alkyl” are as defined above. In some embodiments, alkaryl and aralkyl groups contain 6 to 24 carbon atoms, and particularly alkaryl and aralkyl groups contain 6 to 16 carbon atoms. Alkaryl groups include, for example, p-methylphenyl, 2,4-dimethylphenyl, p-cyclohexylphenyl, 2,7-dimethylnaphthyl, 7-cyclooctylnaphthyl, 3-ethyl-cyclopenta-1,4-diene, and the like. Examples of aralkyl groups include, without limitation, benzyl, 2-phenyl-ethyl, 3-phenyl-propyl, 4-phenyl-butyl, 5-phenyl-pentyl, 4-phenylcyclohexyl, 4-benzylcyclohexyl, 4-phenylcyclohexylmethyl, 4-benzylcyclohexylmethyl, and the like. The terms “alkaryloxy” and “aralkyloxy” refer to substituents of the formula —OR wherein R is alkaryl or aralkyl, respectively, as just defined.

When a Markush group or other grouping is used herein, all individual members of the group and all combinations and possible subcombinations of the group are intended to be individually included in the disclosure. Every combination of components or materials described or exemplified herein can be used to practice the disclosure, unless otherwise stated. One of ordinary skill in the art will appreciate that methods, device elements, and materials other than those specifically exemplified can be employed in the practice of the disclosure without resort to undue experimentation. All art-known functional equivalents, of any such methods, device elements, and materials are intended to be included in this disclosure.

Whenever a range is given in the specification, for example, a temperature range, a frequency range, a time range, or a composition range, all intermediate ranges and all subranges, as well as, all individual values included in the ranges given are intended to be included in the disclosure. Any one or more individual members of a range or group disclosed herein can be excluded from a claim of this disclosure. The disclosure illustratively described herein suitably can be practiced in the absence of any element or elements, limitation or limitations, which is not specifically disclosed herein.

“Optional” or “optionally” means that the subsequently described circumstance may or may not occur, so that the description includes instances where the circumstance occurs and instances where it does not according to the guidance provided in the present disclosure. For example, the phrase “optionally substituted” means that a non-hydrogen substituent may or may not be present on a given atom, and, thus, the description includes structures wherein a non-hydrogen substituent is present and structures wherein a non-hydrogen substituent is not present. It will be appreciated that the phrase “optionally substituted” is used interchangeably with the phrase “substituted or unsubstituted.” Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned can be identified in view of the desired features of the compound in view of the present disclosure, and in view of the features that result in the formation of stable or chemically feasible compounds. The term “stable”, as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

A number of embodiments of the disclosure have been described. The specific embodiments provided herein are examples of useful embodiments of the disclosure and it will be apparent to one skilled in the art that the disclosure can be carried out using a large number of variations of the devices, device components, methods steps set forth in the present description. As will be obvious to one of skill in the art, methods and devices useful for the present methods can include a large number of optional composition and processing elements and steps.

In particular, it will be understood that various modifications may be made without departing from the spirit and scope of the present disclosure. Accordingly, other embodiments are within the scope of the following claims.

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Claims

1. A photoacid compound comprising

a light absorbing moiety attaching an payload moiety through a linker moiety

wherein the linker moiety is an organic moiety comprising a geminal dialkyl moiety linked to an ester group having a carbonyl oxygen, the carbonyl group of the ester attaching the payload moiety; the light absorbing moiety is an organic moiety attaching the linker moiety in ortho position to a hydroxyl group; and the linker is configured to present the carbonyl oxygen for reaction with the hydroxyl group.

2. The photoacid compound of claim 1 wherein the light-absorbing moiety is a substituted or unsubstituted polycyclic aromatic hydrocarbon, a substituted or unsubstituted closed chain cyanine, or a substituted or unsubstituted hemicyanine.

3. The photoacid compound of claim 1, wherein the light absorbing moiety is able to absorb light at a wavelength of from about 900 nm to about 1100 nm.

4. The photoacid compound of claim 1, wherein the geminal dialkyl moiety can be joined together to form a cyclic moiety.

5. The photoacid compound of claim 1, wherein the linker moiety is a monoalkoxy or a dialkoxy moiety in which an oxy group forms part of the ester group having the carbonyl oxygen.

6. The photoacid compound of claim 1, wherein the payload moiety is a substituted or unsubstituted alkyl, aryl, heteroaryl, alkoxy, alkylamino, or dialkylamino moiety.

7. A photoacid compound according to formula (I):

wherein: R4 is a light-absorbing moiety presenting a hydroxyl group for interaction with the carbonyl oxygen of the R3(CO)O group, wherein the light-absorbing moiety is a substituted or unsubstituted polycyclic aromatic hydrocarbon, a substituted or unsubstituted closed chain cyanine, or a substituted or unsubstituted hemicyanine, and wherein the hydroxyl group is covalently bonded to the polycyclic aromatic hydrocarbon, the closed chain cyanine, or the hemicyanine, and the hydroxyl group is in a position ortho to X1; R3 is a payload moiety, wherein the payload moiety is a substituted or unsubstituted alkyl, aryl, heteroaryl, alkoxy, alkylamino, or dialkylamino moiety; X1 is independently selected from the group consisting of C and O; m is between 0 and 3; and R1 and R2 are independently C1-C6 alkyl groups, cycloalkyl, or substituted or unsubstituted hydrocarbylene groups wherein when R1 and R2 are substituted or unsubstituted hydrocarbylene groups, R1 and R2 are linked together to form a cyclic moiety.

8. The photoacidic compound according to claim 7, wherein X1 is O and R1 and R2 are methyl, ethyl, or are linked together to form a cyclopentyl or cyclohexyl moiety.

9. The photoacidic compound according to claim 7, wherein X1 is C and R1 and R2 are methyl, ethyl, or are linked together to form a cyclopentyl or cyclohexyl moiety.

10. The photoacid compound of claim 7, wherein R4 has formula (II):

wherein n is between 0 and 5.

11. The photoacidic compound according to claim 10, wherein n is O.

12. The photoacid compound of claim 7, wherein R4 has formula (III):

where n is between 0 and 5, and m is between 1 and 3.

13. The photoacid of claim 12, wherein m is 2 and n is 0.

14. The photoacid compound of claim 7, wherein R4 has formula (IV):

wherein Ra and Rb are independently H, alkyl, or O-alkyl; Y is N, O, or S; and p is between 1 and 4.

15. The photoacid compound of claim 14, wherein p is 2.

16. The photoacid compound of claim 7, wherein R4 has formula (V):

wherein Rc and Rd are alkyl substituents and q is between 1 and 4.

17. The photoacid compound of claim 16, wherein q is 2.

18. The photoacid compound of claim 7, wherein R4 has formula (VI):

wherein r is between 1 and 4.

19. The photoacid compound of claim 18, wherein r is 2.

20. The photoacid of claim 7, wherein R3 has the structure of formula (VII):

wherein q is between 0 and 5; Rα is H, or substituted or unsubstituted alkyl, alkylamino, alkoxy, aryl, arylamino, aryloxy, heteroaryl, hetroarylamino, and heteroaryloxy group;

X is C or N;

and wherein when q is greater than 1, each Rα is independent of the other Rα substituents.

21. The photoacid of claim 7, wherein R3 has the structure of formula (VIII):

wherein: n is between 1 and 5; Rα, Rβ, and Rγ are independently H, or substituted or unsubstituted alkyl, alkylamino, alkoxy, aryl, arylamino, aryloxy, heteroaryl, hetroarylamino, and heteroaryloxy; and

wherein when n is greater than 1, the Rα and Rβ of each C(Rα)(Rβ) unit are independent of the Rα and Rβ of the other units.

22. The photoacid of claim 7, wherein R3 has the structure of formula (IX):

wherein: p is between 1 and 5; Rα, Rβ, and Rγ are independently H, or substituted or unsubstituted alkyl, alkylamino, alkoxy, aryl, arylamino, aryloxy, heteroaryl, hetroarylamino, and heteroaryloxy, wherein Rδ is H, substituted or unsubstituted alkyl, acyl, aryl; and

wherein when p is greater than 1, the Rα and Rβ of each C(Rα)(Rβ) unit are independent of the Rα and Rβ of the other units.

23. The photoacid of claim 7, wherein R3 has the structure of formula (X):

wherein m is between 1 and 5; Rα, Rβ, and Rγ are independently H, or substituted or unsubstituted alkyl, alkylamino, alkoxy, aryl, arylamino, aryloxy, heteroaryl, hetroarylamino, and heteroaryloxy; and

wherein when m is greater than 1, the Rα and Rβ of each C(Rα)(Rβ) unit are independent of the Rα and Rβ of the other units.

24. The photoacid of claim 7, wherein R3 has the structure of formula (XI):

wherein q is between 0 and 4; Rα is H, or substituted or unsubstituted alkyl, alkylamino, alkoxy, aryl, arylamino, aryloxy, heteroaryl, hetroarylamino, and heteroaryloxy; ε is a substituted or unsubstituted hydrocarbylene, X is C or N; and

wherein when q is greater than 1, each Rα is independent of the other Rα substituents.

25. The photoacid compound of claim 7, wherein R3 has a structure selected from the group consisting of formulas (XII)-(XVII):

26. A method to deliver a compound, comprising

providing a caged compound, the caged compound being caged as a payload moiety within the photoacid compound of claim 1, the photoacid compound being in a ground state in which the hydrogen substituted heteroatom presented on the light absorbing moiety of the photoacid compound has a ground state pKa; and

uncaging the caged compound by irradiating the photoacid compound with light at a wavelength suitable to promote the photoacid compound to an excited state wherein the hydrogen substituted heteroatom presented on the light absorbing moiety of the photoacid compound has an excited state pKa lower than the ground state pKa.

27. The method according to claim 26, wherein the wavelength of the light is greater than 750 nm.

28. The method according to claim 26, wherein irradiating the photoacid compound is performed with light at a wavelength between about 750 and about 1400 nm.

29. The method according to claim 26, wherein irradiating the photoacid compound is performed with light at a wavelength between about between about 900 and about 1100 nm.

30. The method according to claim 26, wherein irradiating the photoacid compound is performed with light at a wavelength less than about 750 nm.

31. A system to deliver a compound, the system comprising at least two of:

one photoacid compound of claim 1; and

a light source suitable to irradiate light at a suitable wavelength, for simultaneous, combined or sequential use in a method to deliver a compound, comprising

providing a caged compound, the caged compound being caged as a payload moiety within a photoacid compound of claim 1, the photoacid compound being in a ground state in which the hydrogen substituted heteroatom presented on the light absorbing moiety of the photoacid compound has a ground state pKa; and

uncaging the caged compound by irradiating the photoacid compound with light at a wavelength suitable to promote the photoacid compound to an excited state wherein the hydrogen substituted heteroatom presented on the light absorbing moiety of the photoacid compound has an excited state pKa lower than the ground state pKa.