Abstract: Substituted nitrobenzothiazinones (BTZs) are potent antituberculosis prodrugs that are reductively activated to produce nitroso moieties that form covalent adducts with a cysteine residue of decaprenylphosphoryl-?-D-ribose-2?-oxi-dase (DprE1) of Mycobacterium tuberculosis (Mtb). The resulting cell wall synthesis inhibition is lethal to Mtb, leading to consideration of development of BTZs for clinical use. The hydride-induced reduction of the nitroaromatic proceeds by reversible formation of the corresponding Meisenheimer complex. Herein we demonstrate that chemical reduction of BTZ043 with NaBD4 followed by reoxidation incorporates deuterium into the core nitro aromatic warhead. Subsequent reduction of the deuterated species is not affected, but, as expected, reoxidation is slowed by the deuterium isotope effect, thus prolonging the lifetime of the active nitroso oxidation state.

Abstract: Substituted nitrobenzothiazinones (BTZs) are potent antituberculosis prodrugs that are reductively activated to produce nitroso moieties that form covalent adducts with a cysteine residue of decaprenylphospholyl-?-D-ribose-2?-oxi-dase (DprE1) of Mycobacterium tuberculosis (Mtb). The resulting cell wall synthesis inhibition is lethal to Mtb, leading to consideration of development of BTZs for clinical use. The hydride-induced reduction of the nitroaromatic proceeds by reversible formation of the corresponding Meisenheimer complex. Herein we demonstrate that chemical reduction of BTZ043 with NaBD4 followed by reoxidation incorporates deuterium into the core nitro aromatic warhead. Subsequent reduction of the deuterated species is not affected, but, as expected, reoxidation is slowed by the deuterium isotope effect, thus prolonging the lifetime of the active nitroso oxidation state.

Abstract: The present invention relates to novel dihydroisoquinolinone (DHQ) derivative compounds of the following formula: wherein R1 to R7, X, Y, Z, b, c and d have the meanings provided herein. The invention further relates to combinatorial libraries containing two or more such compounds, as well as methods of preparing DHQ derivative compounds.

Abstract: The invention relates to an inventive method for tracking the identity of chemicals or compounds attached to individual solid phase particles during combinatorial synthesis. A particularly preferred coding method, termed “ENCORE” for short, involves Encoding by a Necklace, Color, and Reaction vessel. The Encore technique preferably combines three different coding methods: sequential position on a necklace for the first combinatorial step, color coding of individual necklaces for the second combinatorial step, and reaction vessel coding as the indication of the identity of the last building block. Two novel techniques for integrated assembly of necklaces also are described, as are novel dedicated tools for manual or automatic necklace assembly and manipulation.

Abstract: In a first embodiment, this invention includes an integrated robot apparatus for performing combinatorial chemistry synthesis protocols and having interchangeable work-stations, robot arm tools, and reaction vessels and reaction vessel arrays. The work-stations and tools are specialized to perform tasks necessary for the synthesis in a plurality of the reaction vessels grouped in a plurality of the reaction vessel arrays. Preferably, these elements function interchangeably because they have standardized sizes and conformation. The work-stations and tools include those for fluid dispensing or aspirating from individual reaction vessels or from all the reaction vessels in an array simultaneously. The reaction vessels can include, alternatively, stackable, ball-sealed reaction vessels, microtitre-like reaction vessel arrays, arrays of independent reaction vessels, valve-sealed reaction vessels, septum-sealed reaction vessels, and syringe reaction vessels.

Abstract: The present invention is directed to linkers based on ester bond linkages, especially iminodiacetic acid ester bond linkages, for use in solid phase peptide synthesis. In particular, the invention is directed to cleavable linkers that can release peptide from the solid phase support under relatively mild conditions by formation of a diketopiperazine or other cyclic structure, such that the cyclic structure remains on the solid phase support, and, in a second cleavage, under more stringent conditions of high pH. The invention is further directed to solid phase supports prepared with multiple cleavable linkers, including a linker that is cleaved by formation of a cyclic product. One such second linker is an ester of hydroxymethylbenzoic acid, or esters formed by carboxy groups of aspartic or glutamic acid.

Abstract: A solid phase synthesis system is provided by employing a fully automated robot that operates with a novel timing protocol for handling multiple synthetic tasks efficiently. The novel timing protocol is realized by performing steps in the synthesis cycles for different compounds, such as peptides, concurrently rather than on a sequential basis.

Abstract: The present invention relates to methods for determining the amino acid composition, and more preferably the sequence, of a peptide using mass spectrometric techniques. The method is particularly useful for sequencing peptides isolated from natural sources or from libraries of peptides that have been prepared synthetically, and for peptides that are not amenable to Edman degradation sequencing. In one embodiment, the method for determining the amino acid composition or sequence of a peptide comprises determining the difference of the mass of the peptide from the mass of a deuterium-hydrogen exchanged peptide, and from this difference determining the number of exchangeable (labile) hydrogen atoms (protons). Candidate peptides having amino acid compositions or sequences that do not contain the observed number of exchangeable protons are eliminated.

Abstract: The present invention relates to antigenic peptides of the formulaH--Val--X--Y FORMULA Iwherein X is a polypeptide residue selected from the group consisting of:Val-Pro-Arg-Arg-Lys-Ala-Lys-Ile;Ser-Gly-Lys-Ala-Arg-Gly-Trp-Phe;Tyr-Tyr-Arg-Asp-Ser-Arg-Ash-Pro-Leu;Phe-Ile-His-Asn-Phe-Lys-Arg-Lys-Gly;Ser-Ile-Glu-Trp-Arg-Lys-Lys-Arg-Tyr-Ser; andLeu-His-Thr-Gly-Glu-Arg-Asp-Trp-His-Leu-Gly,and Y is a hydroxyl group or an amino group. The invention also relates to a method of preparing these peptides.These novel peptides exhibit useful antigenic properties, with respect to Human Immunodeficiency Virus (HIV), formerly known as Human T-cell Lymphotropic Type-III Virus (HTLV-III). Human Immunodeficiency Virus is associated with the diseases known as Acquired Immune Deficiency Syndrome (AIDS) and Aids Related Complex (ARC). The present antigenic peptides are useful for the detection of antibodies active against HIV and are suitable for use as diagnostic agents.