ABSTRACT
A structure-based drug design strategy was used to optimize a novel benzolactam series of HSP90α/ß inhibitors to achieve >1000-fold selectivity versus the HSP90 endoplasmic reticulum and mitochondrial isoforms (GRP94 and TRAP1, respectively). Selective HSP90α/ß inhibitors were found to be equipotent to pan-HSP90 inhibitors in promoting the clearance of mutant huntingtin protein (mHtt) in vitro, however with less cellular toxicity. Improved tolerability profiles may enable the use of HSP90α/ß selective inhibitors in treating chronic neurodegenerative indications such as Huntington's disease (HD). A potent, selective, orally available HSP90α/ß inhibitor was identified (compound 31) that crosses the blood-brain barrier. Compound 31 demonstrated proof of concept by successfully reducing brain Htt levels following oral dosing in rats.
Subject(s)
HSP90 Heat-Shock Proteins/antagonists & inhibitors , Huntington Disease/drug therapy , Animals , Drug Design , HSP90 Heat-Shock Proteins/chemistry , Humans , Male , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
A wide variety of novel small-molecule natural products has recently been reported. These compounds were isolated from marine and terrestrial sources, and from a variety of animals, plants and microorganisms. With the breadth of diversity represented in these bioactive small molecules, the future of natural product drug discovery looks bright.
Subject(s)
Drug Design , Actinobacteria/chemistry , Animals , Anura , Fungi/chemistry , Myxococcales/chemistry , Plants/chemistry , Urochordata/chemistryABSTRACT
Two new 1,2,3,4-tetrahydroanthraquinones, auxarthrol A (compound 1) and auxarthrol B (2), along with three known pyrrolyloctatetraenyl-alpha-pyrone pigments, auxarconjugatin A (3), auxarconjugatin B (4) and rumbrin (5), were isolated from the fungus Auxarthron umbrinum. Structure elucidation of new compounds 1 and 2 was accomplished by spectroscopic data analysis while identification of the known pigments (3-5) was achieved by LC-MS-photodiode array detection.
Subject(s)
Anthraquinones/chemistry , Anthraquinones/metabolism , Fungi/metabolism , Biotechnology , Fermentation , Fungal Proteins/chemistry , Fungal Proteins/metabolism , Magnetic Resonance Spectroscopy , Pigments, Biological/chemistry , Pigments, Biological/metabolism , Pyrones/chemistry , Pyrones/metabolism , Pyrroles/chemistry , Pyrroles/metabolismABSTRACT
Two new trichothecenes, 14'-hydroxymytoxin B (1) and 16-hydroxyroridin E (3), were isolated from a fermentation extract of Myrothecium roridum. The structures of 1 and 3 were determined by spectral data interpretation. Both compounds showed potent cytotoxic activity against primary soft-tissue sarcoma cells.
Subject(s)
Antineoplastic Agents/isolation & purification , Fungi/chemistry , Trichothecenes/isolation & purification , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Boston , Cells, Cultured/drug effects , Chromatography, High Pressure Liquid , Drug Screening Assays, Antitumor , Humans , Inhibitory Concentration 50 , Molecular Structure , Nuclear Magnetic Resonance, Biomolecular , Sarcoma , Trichothecenes/chemistry , Trichothecenes/pharmacology , Tumor Cells, Cultured/drug effectsABSTRACT
Three novel cytochalasans, phomacins A, B and C, were isolated from a fermentation broth of the fungus Phoma sp. and purified by HSCCC (high speed countercurrent chromatography) followed by HPLC. The structures were determined by 1D and 2D NMR techniques. All three compounds have shown potent inhibitory activity against the HT29 colonic adenocarcinoma cell line.
