Abstract: The invention relates to epothilone analog represented by the formula I wherein (i) R2 is absent or oxygen; “a” can be either a single or double bond; “b” can be either absent or a single bond; and “c” can be either absent or a single bond, with the proviso that if R2 is oxygen then “b” and “c” are both a single bond and “a” is a single bond; if R2 is absent then “b” and “c” are absent and “a” is a double bond; and if “a” is a double bond, then R2, “b” and “c” are absent; R3 is a radical selected from the group consisting of hydrogen; lower alkyl; —CH?CH2; —C?CH; —CH2F; —CH2Cl; —CH2—OH; —CH2—O—(C1-C6-alkyl); and —CH2—S—(C1-C6-alkyl); R4 and R5 are independently selected from hydrogen, methyl or a protecting group; and R1 is as defined in the specification, or a salt of a compound of the formula I where a salt-forming group is present. A further aspect of the invention is related to the synthesis of epothilone E.

Abstract: Proteins of moderate size having native peptide backbones are produced by a method of native chemical ligation. Native chemical ligation employs a chemoselective reaction of two unprotected peptide segments to produce a transient thioester-linked intermediate. The transient thioester-linked intermediate then spontaneously undergoes a rearrangement to provide the full length ligation product having a native peptide bond at the ligation site. Full length ligation products are chemically identical to proteins produced by cell free synthesis. Full length ligation products may be refolded and/or oxidized, as allowed, to form native disulfide-containing protein molecules. The technique of native chemical ligation is employable for chemically synthesizing full length proteins.

Abstract: A metal catalyzed click chemistry ligation process is employed to bind azides and terminal acetylenes to give triazoles. In many instances, the reaction sequence regiospecifically ligates azides and terminal acetylenes to give only 1,4-disubstituted [1,2,3]-triazoles.

Abstract: The invention relates to cis- and trans-12, 13-cyclopropyl and 12,13-cyclobutyl epothilones of formula I to IV wherein Ar is a radical represented by the following structure: and the other radicals and symbols have the meanings as defined herein; to their chemical synthesis and biological evaluation; their use in the treatment of neoplastic diseases and to pharmaceutical preparations containing such compounds. The compounds described herein are potent tubulin polymerization promoters and cytotoxic agents.

Abstract: Certain oxadiazole ketone compounds are useful as FAAH inhibitors. Such compounds may be used in pharmaceutical compositions and methods for the treatment of disease states, disorders, and conditions mediated by fatty acid amide hydrolase (FAAH) activity. Thus, the compounds may be administered to treat anxiety, pain, inflammation, sleep disorders, eating disorders, or movement disorders (such as MS).

Abstract: Bisaryloxime ethers and bisarylhydroazones are shown to be effective for inhibiting formation of amyloid fibrils of transthyretin.

Abstract: Cyclic homodetic peptides having a repeating D-L-chirality motif are shown to have a stable disk conformation with the amino acid side chains extending radially outward and the carbonyl and amino groups extending axially upward or downward. Such cyclic peptides can be employed as subunits in the assembly of molecular tubes. Cyclic peptides having a repeating D-L-chirality motif and lacking mutually repulsive side-chains are shown to stack atop one another in an anti-parallel fashion and are shown to be held together by the formation of ?-sheet hydrogen bonding. The stacked cyclic peptides form a molecular tube having a central channel. The diameter of the channel is determined by the size cyclic peptide. If the cyclic peptide includes ionizable amino acid residues, e.g. glutamic acid or lysine, assembly and disassembly of the molecular tubes can be controlled by varying the pH. If the cyclic peptide includes hydrophobic amino acid residues, the molecular tube will insert into a lipid membrane.

Abstract: Anlogs of ningalin B lacking inherent cytotoxic activity may be employed to reverse multi-drug resistant (MDR) phenotype and to resensitize transformed cells, including a human colon cancer cell line (HCT116/VM46), with respect to a variety of cytotoxic agents, e.g., vinblastine and doxorubicin. In many instances, resensitization is achieved at lower doses than the prototypical agent verapamil. Total synthesis of ningalin B and its analogs was achieved using a concise, efficient approach based on a heterocyclic azadiene Diels-Alder strategy (1,2,4,5-tetrazine?1,2-diazine?pyrrole) ideally suited for construction of the densely functionalized pyrrole core found in the natural product is detailed.

Abstract: Epothilone A, epothilone B, analogs of epothilone and libraries of epothilone analogs are synthesized. Epothilone A and B are known anticancers agents that derive their anticancer activity by the prevention of mitosis through the induction and stabilization of microtubulin assembly. The analogs of epothilone are novel. Several of the analogs are demonstrated to have a superior cytotoxic activity as compared to epothilone A or epothilone B as demonstrated by their enhanced ability to induce the polymerization and stabilization of microtubules.

Abstract: Designed epoxide and cyclopropane epothilone analogs with substituted side-chains are disclosed and characterized with respect to their biological activities against a series of human cancer cell lines. Among the several bioactive analogs, the epothilone B analog with a thiomethyl thiazole ring stands out as the most potent.

Abstract: D-enzyme compositions are described comprising an amino acid residue sequence that defines an polypeptide able to catalyze an enzymatic reaction.

Abstract: Designed imminocyclitols have potent inhibition activity with respect to hexoaminidases and glycosidases.

Abstract: The present invention provides novel glycoluril derivatives for use as core molecules in combinatorial chemistry. Core molecules of the present invention can contain from one to six building blocks. Preferred building blocks are substituted amine radicals. Combinatorial libraries containing such core molecules are also provided.

Abstract: D-enzyme compositions are described comprising an amino acid residue sequence that defines an polypeptide able to catalyze an enzymatic reaction. The D-enzyme has an amino acid residue sequence consisting essentially of D-amino acids.

Abstract: The reactivity of a number of p-methylphenyl thioglycoside (STol) donors which are either fully protected or have one hydroxyl group exposed has been quantitatively determined by HPLC in conjunction with the development of a broadly applicable approach for a facile one-pot synthesis of oligosaccharides. The influence on reactivity of the structural effects of different monosaccharide cores and different protecting groups on each glycoside donor is characterized and quantified. In addition, a correlation between glycosyl donor reactivity and the chemical shift of the anomeric proton by 1 H NMR has been established. A database of thioglycosides as glycosyl donors has been created using this reactivity data. The utility is demonstrated by the easy and rapid one-pot assembly of various linear and branched oligosaccharide structures.

Abstract: A practical and high-yielding method for the efficient, one-step synthesis of diverse classes of N,N?-differentiated sulfamides employs a wide range of amino alcohols and simple amines using Burgess-type reagents. This methodology extends the application and availability of sulfamides within the fields of chemical biology, medicinal chemistry, asymmetric synthesis, and supramolecular chemistry.

Abstract: Bifunctional antibiotics that target both bacterial RNA and resistance-causing enzymes are disclosed. The A-site of bacterial 16S rRNA serves as the target site for most aminoglycoside antibiotics. Resistance to this class of antibiotics is frequently developed by microbial enzymatic acetylation, phosphorylation or ribosylation of aminoglycosides, modifications that weaken their interactions with the target RNA. Using surface plasmon resonance (SPR), the binding affinity and stoichiometry of various amino-glycosides have been investigated and it was found that neamine, the key pharmacophore of the deoxystreptamine class of amino-glycosides, binds to the A-site in a two to one stoichiometry with a Kd of 10 ?M for each binding site. A library of neamine dimers was prepared and their affinities to 16S rRNA A-site were determined by SPR, with Kd=40 nM for the best dimer (an ˜103-fold increase in affinity). Antibiotic activities of the dimers were determined for several bacterial strains by the Kirby-Bauer method.

Abstract: Combinatorial libraries of HIV and FIV protease inhibitors are characterized by ?-keto amide or hydroxyethylamine core structures flanked by on one side by substituted pyrrolidines, piperidines, or azasugars and on the other side by phenylalanine, tyrosine, or substituted tyrosines. The libraries are synthesized via a one step coupling reaction. Highly efficacious drug candidates are identified by screening the libraries for binding and inhibitory activity against both HIV and FIV protease. Drug candidates displaying clinically useful activity against both HIV and FIV protease are identified as being potentially resistive against a loss of inhibitory activity due to development of resistant strains of HIV.

Abstract: Potent inhibitors of fatty acid amide hydrolase (FAAH) are constructed having K1's below 200 pM and activities 102-103 times more potent than the corresponding trifluoromethyl ketones. The potent inhibitors combine several features, viz.: 1.) an ?-keto heterocylic head group; 2.) a hydrocarbon linkage unit employing an optimal C12-C8 chain length; and 3.) a phenyl or other ?-unsaturation corresponding to the arachidonyl ?8,9/?11,12 and/or oleyl ?9,10 positions. A preferred ?-keto heterocylic head group is ?-keto N4 oxazolopyridine, with incorporation of a second weakly basic nitrogen. Fatty acid amide hydrolase is an enzyme responsible for the degradation of oleamide (an endogenous sleep-inducing lipid) and anandamide (an endogenous ligand for cannabinoid receptors).

Abstract: The selective potentiation and/or inhibition of the 5-HT2A and/or 5-HT1A response to serotonin (5-HT) is achieved using analogs of oleamide. Selective potentiation and/or inhibition of the 5-HT2A and/or 5-HT1A leads to a modulation of serotonergic signal transduction of cells having various receptor subtypes. A subset of analogs is identified that inhibits rather than potentiates the 5-HT2A, but not the 5-HT1A, receptor response. These analogs enable the selective modulation of serotonin receptor subtypes and even have opposing effects on the different subtypes. An analysis of the activity of the oleamide analogs discloses that the structural features required for activity are highly selective. In particular, the presence, position, and stereochemistry of the 9-cis double bond is required and even subtle structural variations reduce or eliminate activity.