RESUMO
A new group of thiazolyl peptide antibiotics, the nocathiacins, was isolated from cultured broth of Nocardia sp. The major analogs nocathiacins I-III (1-3) were purified using silica gel and Sephadex LH-20 chromatography techniques. The structures of nocathiacins I-III were determined by spectroscopic (2D-NMR, MSn) methods, and share structural similarities to glycothiohexide-alpha (4).
Assuntos
Antibacterianos/química , Antibacterianos/isolamento & purificação , Nocardia/química , Peptídeos , Cromatografia em Gel , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Espectrometria de Massas por Ionização por Electrospray , Espectrofotometria UltravioletaRESUMO
A C-8 keto pleuromutilin derivative has been synthesized from the biotransformation product 8-hydroxy mutilin. A key step in the process was the selective oxidation at C-8 of 8-hydroxy mutilin using tetrapropylammonium perruthenate. The presence of the C-8 keto group precipitated interesting intramolecular chemistry to afford a compound (10) with a novel pleuromutilin-derived ring system.
Assuntos
Diterpenos/síntese química , Biotransformação , Cetonas/química , Oxirredução , Compostos Policíclicos/química , PleuromutilinasRESUMO
PURPOSE: Stretch activated nonselective cationic channels (SACs) are present in urinary bladder myocytes and thought to be activated during bladder filling. We investigated the relationship of stretch induced calcium signaling inhibition in bladder myocytes and bladder compliance modulation in an in vitro whole bladder model. MATERIALS AND METHODS: Grammostola spatulata venom (SpiderPharm, Yarnell, Arizona) was purified by preparative high performance liquid chromatography. The resulting fractions were examined for their ability to inhibit the swelling activated intracellular free Ca2+ signal in cultured bladder myocytes. An in vitro rat whole bladder model was used to examine the effect of venom fractions on compliance, emptying and spontaneous contractions during bladder filling. RESULTS: The gadolinium ion, a SAC inhibitor, and venom fractions caused concentration dependent inhibition of the swelling activated intracellular free Ca2+ signal in bladder myocytes. When tested in a rat isolated whole bladder model, 0.1 and 0.2 mg./ml. partially purified venom produced a significant improvement in compliance (p <0.05), caused significant inhibition of the frequency of spontaneous bladder contractions (mean +/- SEM 35.8% +/- 3.7% and 62.3% +/- 4.4%, respectively, p =0.001) and significantly reduced spontaneous bladder emptying, that is emptying in the absence of exogenous stimulation (38.8% +/- 5.6% and 43.9% +/- 2.5%, respectively, p =0.0008). However, it produced little or no inhibition of carbachol induced bladder emptying. CONCLUSIONS: Our data suggest that the activation of stretch induced signaling in bladder myocytes may have an important role in myogenic regulation of bladder contractility during bladder filling. Inhibition of SACs may improve bladder compliance.
Assuntos
Bloqueadores dos Canais de Cálcio/farmacologia , Sinalização do Cálcio/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Venenos de Aranha/farmacologia , Bexiga Urinária/citologia , Bexiga Urinária/efeitos dos fármacos , Animais , Células Cultivadas , Complacência (Medida de Distensibilidade)/efeitos dos fármacos , Feminino , Técnicas In Vitro , Miócitos de Músculo Liso/metabolismo , Ratos , Ratos Sprague-Dawley , Venenos de Aranha/isolamento & purificação , Bexiga Urinária/metabolismo , Bexiga Urinária/fisiologiaRESUMO
Core-modified sordaricin derivatives were prepared via biotransformation followed by chemical modification and tested for antifungal activity. The antifungal activity proved to be very sensitive to modifications in the sterics and/or lipophilicity of the diterpene skeleton. Introduction of polar groups such as hydroxyl in the diterpene core results in loss of potency while small and lipophilic groups such as fluorine and the 7,8-olefin are well tolerated.
Assuntos
Antifúngicos/metabolismo , Antifúngicos/farmacologia , Antifúngicos/química , Biotransformação , Candida albicans/efeitos dos fármacos , Candida glabrata/efeitos dos fármacos , Diterpenos , Interações Hidrofóbicas e Hidrofílicas , Testes de Sensibilidade Microbiana , Nocardia/metabolismo , EstereoisomerismoRESUMO
The synthesis and biological activity of sordarin oxazepine derivatives are described. The key step features a regioselective oxidation of an unprotected triol followed by double reductive amination to afford the ring-closed products. The spectrum of antifungal activity for these novel derivatives includes coverage of Candida albicans, Candida glabrata, and Cryptococcus neoformans.
Assuntos
Antifúngicos/síntese química , Antifúngicos/farmacologia , Fungos/efeitos dos fármacos , Oxazepinas/síntese química , Oxazepinas/farmacologia , Candida albicans/efeitos dos fármacos , Candida glabrata/efeitos dos fármacos , Cryptococcus neoformans/efeitos dos fármacos , Ligação de Hidrogênio , Indenos , Testes de Sensibilidade Microbiana , Relação Estrutura-AtividadeRESUMO
A fermentation directed product search for potential anticancer drugs conducted by Bristol-Myers in the 1970s and early 1980s resulted in the identification of a novel indolocarbazole (IC) rebeccamycin (RBM) as a potential drug development candidate. Subsequently, an analog program designed to impart distal site in vivo antitumor activity resulted in the discovery of diethylaminoethyl analog of RBM (DEAE-RBM), which is presently undergoing clinical evaluation as NSC 655649 and BMY-27557. Strong DNA intercalation is the primary mechanism of action of DEAE-RBM resulting in the potent catalytic inhibition of both topoisomerases I and II. Precursor feeding fermentation experiments with fluorine-substituted tryptophans yielded novel fluoroindolocarbazoles (FICs). These FICs were identified as targeting topoisomerase (topo) I in a mechanism-based screen and their action on topo I was confirmed by production of topo I-mediated single-strand breaks in DNA at sites essentially identical to those induced by camptothecin. Topo I dependent cytotoxicity was demonstrated for specific FICs using a P388 and camptothecin-resistant P388/CPT45 pair of cell lines, the latter expresses little or no functional topo I. For example, topo I selectivity was greatest with 3,9-difluoro substituted FIC and was least significant and least cytotoxic with 4,8-difluoro substituted FIC. The review focuses on the discovery of the rebeccamycin class of compounds and their structure-activity relationships leading to the development of the clinical candidate BMY-27557 (NSC 655649), as well as the lead identification of the fluoroindolocarbazole class of compounds.