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Alterations in protein folding and the regulation of conformational states have become increasingly important to the functionality of key molecules in signaling, cell growth, and cell death. Molecular chaperones, because of their properties in protein quality control, afford conformational flexibility to proteins and serve to integrate stress-signaling(More)
Suberoylanilide hydroxamic acid (SAHA), an inhibitor of histone deacetylase, is used in clinical trials for a variety of advanced cancers. Twelve new analogs of SAHA were synthesized and tested as in vitro inhibitors of isolated histone deacetylases (HDACS) and in vivo inhibitors of interferon regulated transcriptional responses (a marker for HDAC(More)
Sansalvamide A, a cyclic depsipeptide isolated from a marine fungus of the genus Fusarium, is composed of four hydrophobic amino acids (Phe, two Leu, Val) and one hydroxy acid ((S)-2-hydroxy-4-methylpentanoic acid; O-Leu) with five stereogenic centers all having S-stereochemistry. We have recently synthesized the corresponding cyclic peptide (Gu, W.; Liu,(More)
In our effort to develop agents for the treatment of influenza, a phenotypic screening approach utilizing a cell protection assay identified a series of azaindole based inhibitors of the cap-snatching function of the PB2 subunit of the influenza A viral polymerase complex. Using a bDNA viral replication assay (Wagaman, P. C., Leong, M. A., and Simmen, K. A.(More)
A series of 4-amino-pyrido[2,3-d]pyrimidin-5(8H)-ones were designed and synthesized as a novel class of inhibitors of NAD(+)-dependent DNA ligase that possess potency against Gram-positive bacteria.
2-(((3R,4R)-4-(Allyloxy)-1-benzylpyrrolidin-3-yl)methyl)-6-(2,5-dimethyl-1H-pyrrol-1-yl)-4-methylpyridine (2), a key intermediate for the preparation of novel neuronal nitric oxide synthase (nNOS) inhibitors, is synthesized using diisopropyl (R)-(+)-malate as the starting material. The key steps involve a Frater-Seebach diastereoselective alkylation and a(More)
VX-787 is a first in class, orally bioavailable compound that offers unparalleled potential for the treatment of pandemic and seasonal influenza. As a part of our routine SAR exploration, carboxylic acid isosteres of VX-787 were prepared and tested against influenza A. It was found that the negative charge is important for maintaining potency and(More)
Omuralide, a transformation product of the microbial metabolite lactacystin, was the first molecule discovered as a specific inhibitor of the proteasome and is unique in that it specifically inhibits the proteolytic activity of the 20S subunit of the proteasome without inhibiting any other protease activities of the cell. The total syntheses of omuralide(More)
Mitochondrial monoamine oxidase was inactivated by o-mercaptobenzylamine (1) and o- (2) and p-methylthiobenzylamine (5). Experiments were carried out to provide evidence for possible mechanisms of inactivation. The corresponding o- (3) and p-hydroxybenzylamine (4) are not inactivators. Four radiolabeled analogues of 2 and 5, having radioactivity at either(More)
Patients with pancreatic cancer have little hope for cure because no effective therapies are available. Sansalvamide A is a cyclic depsipeptide produced by a marine fungus. We investigated the effect of a novel sansalvamide A analogue on growth, cell-cycle phases, and induction of apoptosis in human pancreatic cancer cells in vitro. The sansalvamide(More)