RESUMEN
Epothilone is a kind of macrolide compound, which has anticancer activity and strong inhibitory effect on breast cancer and rectal cancer cells. Herein, the chemical and biological synthesis of epothilones and how to improve fermentation yield and separation methods were summarized and discussed.
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/aislamiento & purificación , Epotilonas/biosíntesis , Epotilonas/síntesis química , Epotilonas/aislamiento & purificación , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cerámica/química , Ensayos de Selección de Medicamentos Antitumorales , Epotilonas/farmacología , Fermentación , Glicosilación , Humanos , Mutación , Porosidad , Metabolismo Secundario , Streptomyces/genética , Streptomyces/metabolismo , Relación Estructura-Actividad , Propiedades de SuperficieRESUMEN
As a continuous work to find more epothilone congeners produced by the epothilones A and B producing Sorangium cellulosum strain So0157-2 in the large-scale fermentation (5000 L), we reinvestigated the chemical compositions of the fermentation broth. Consequently, two new epothilone variants (1-2) and one new natural epothilone derivative (3) were isolated from the fermentation broth. Their structures were established as 16-ethyl epothilone B (1), 6-desmethyl-16-hydroxymethyl epothilone C (2) and 20-ethyl epothilone A (3), respectively, by an extensive NMR analysis.
Asunto(s)
Epotilonas/aislamiento & purificación , Myxococcales/química , Cromatografía Líquida de Alta Presión , Epotilonas/química , Fermentación , Espectroscopía de Resonancia Magnética , Estructura MolecularAsunto(s)
Antineoplásicos/farmacología , Epotilonas/farmacología , Microtúbulos/metabolismo , Resonancia Magnética Nuclear Biomolecular/métodos , Moduladores de Tubulina/farmacología , Antineoplásicos/aislamiento & purificación , Epotilonas/aislamiento & purificación , Humanos , Microtúbulos/ultraestructura , Modelos Moleculares , Myxococcales/química , Neoplasias/tratamiento farmacológico , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/aislamiento & purificaciónAsunto(s)
Antineoplásicos/aislamiento & purificación , Antineoplásicos/metabolismo , Epotilonas/aislamiento & purificación , Epotilonas/metabolismo , Myxococcales/metabolismo , Antineoplásicos/química , Epotilonas/química , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Estructura MolecularAsunto(s)
Antineoplásicos/farmacología , Epotilonas/farmacología , Animales , Antineoplásicos/química , Antineoplásicos/clasificación , Antineoplásicos/aislamiento & purificación , Productos Biológicos/química , Productos Biológicos/clasificación , Productos Biológicos/aislamiento & purificación , Productos Biológicos/farmacología , Cromatografía Líquida de Alta Presión , Evaluación Preclínica de Medicamentos , Epotilonas/química , Epotilonas/clasificación , Epotilonas/aislamiento & purificaciónRESUMEN
Since the late 1990s and the rapid expansion of monoclonal antibodies and synthetic protein kinase inhibitors in oncology, anticancer natural products fell out of fashion with the pharmaceutical industry. But in 2007 with the approval of three new drugs derived from natural products, the emergence of promising antitumor compounds from microorganisms (e.g. alvespimycin, salinosporamide) and the growing importance of new formulations of known natural product-derived drugs (nanoparticle formulations, oral forms), we are witnessing a new wave for natural products in oncology. The recent approval of the microtubule-targeted epothilone derivative ixabepilone (Ixempra), the DNA-alkylating marine alkaloid trabectedin (Yondelis) and the inhibitor of mTOR protein kinase temsirolimus (Torisel) is emblematic of the evolution of the field which combines the long established finding of conventional cytotoxic agents and the emergence of molecularly targeted therapeutics. These three examples also illustrate the increasing importance of microbial sources for the discovery of medically useful natural products. The contribution of innovative biological targets is also highlighted here, with references to proteasome inhibitors and novel approaches such as manipulation of mRNA splicing. Altogether, these observations plead for the return of natural products in oncology.
Asunto(s)
Antineoplásicos/uso terapéutico , Productos Biológicos/uso terapéutico , Neoplasias/tratamiento farmacológico , Antineoplásicos/aislamiento & purificación , Antineoplásicos/farmacología , Productos Biológicos/aislamiento & purificación , Productos Biológicos/farmacología , Dioxoles/aislamiento & purificación , Dioxoles/farmacología , Dioxoles/uso terapéutico , Epotilonas/aislamiento & purificación , Epotilonas/farmacología , Epotilonas/uso terapéutico , Humanos , Sirolimus/análogos & derivados , Sirolimus/aislamiento & purificación , Sirolimus/farmacología , Sirolimus/uso terapéutico , Tetrahidroisoquinolinas/aislamiento & purificación , Tetrahidroisoquinolinas/farmacología , Tetrahidroisoquinolinas/uso terapéutico , TrabectedinaRESUMEN
The epothilones are a novel class of antineoplastic agents possessing antitubulin activity. The compounds were originally identified as secondary metabolites produced by the soil-dwelling myxobacterium Sorangium cellulosum. Two major compounds, epothilone A and epothilone B, were purified from the S. cellulosum strain So ce90 and their structures were identified as 16-member macrolides. Initial screening with these compounds revealed a very narrow and selective antifungal activity against the zygomycete, Mucor hiemalis. In addition, strong cytotoxic activity against eukaryotic cells, mouse L929 fibroblasts and human T-24 bladder carcinoma cells was observed. Subsequent studies revealed that epothilones induce tubulin polymerization and enhance microtubule stability. Epothilone-induced stabilisation of microtubules was shown to cause arrest at the G2/M transition of the cell cycle and apoptosis. The compounds are active against cancer cells that have developed resistance to taxanes as a result of acquisition of beta-tubulin overexpression or mutations and against multidrug-resistant cells that overexpress P-glycoprotein or multidrug resistance-associated protein. Thus, epothilones represent a new class of antimicrotubule agents with low susceptibility to key tumour resistance mechanisms. More recently, a range of synthetic and semisynthetic epothilone analogues have been produced to further improve the adverse effect profile (or therapeutic window) and to maximize pharmacokinetic and antitumour properties. Various epothilone analogues have demonstrated activity against many tumour types in preclinical studies and several compounds have been and still are being evaluated in clinical trials. This article reviews the identification and early molecular characterization of the epothilones, which has provided insight into the mode of action of these novel antitumour agents in vivo.
Asunto(s)
Antineoplásicos/farmacología , Epotilonas/farmacología , Moduladores de Tubulina/farmacología , Animales , Diseño de Fármacos , Resistencia a Múltiples Medicamentos , Resistencia a Antineoplásicos , Epotilonas/aislamiento & purificación , Epotilonas/farmacocinética , Humanos , Myxococcales/metabolismoRESUMEN
A myxobacterium strain AHB125 belonging to genus Sorangium cellulosum was isolated from Anhui area in China and identified with morphological analysis by electron microscopy and phase contrast microscope according to Bergey's manual of systematic bacteriology (8th Ed.). Its high-antitumor bioactivity metabolites was evaluated by bioassay-directed screening technique with B16 tumor cell line etc. Research results showed that it exhibited not only strong antitumor ability bioactivities and broad-spectrum antitumor abilities to B16, Bel7402, H446, SGC7901 cell lines, but also has selectivity and pertinence to B16 and SGC7901 cell lines. The compound was confirmed as epothilone B by HPLC and LC/MS analysis, compared to the epothilone B standard sample. Bioassay indicated that there were other high-bioactive substances in the metabolites.
Asunto(s)
Antineoplásicos/farmacología , Epotilonas/farmacología , Myxococcales/metabolismo , Animales , Antineoplásicos/química , Antineoplásicos/aislamiento & purificación , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Cromatografía Liquida , Epotilonas/química , Epotilonas/aislamiento & purificación , Humanos , Ratones , Estructura Molecular , Myxococcales/química , Espectrometría de Masa por Ionización de ElectrosprayRESUMEN
Natural products have been used as medicinal agents for many years. In addition, these compounds have served as the starting points for semisynthetic analogs with improved properties. This review highlights work on several classes of natural products and their derivatives, including both well established and emerging structural classes that are in, or nearing, clinical use for a variety of important indications.
Asunto(s)
Epotilonas/química , Eritromicina/química , Bacterias Grampositivas/química , Taxoides/química , Alcanos/química , Alcanos/aislamiento & purificación , Antifúngicos/química , Antifúngicos/aislamiento & purificación , Carbamatos/química , Carbamatos/aislamiento & purificación , Epotilonas/aislamiento & purificación , Eritromicina/aislamiento & purificación , Furanos , Lactonas/química , Lactonas/aislamiento & purificación , Lípidos , Macrólidos/química , Macrólidos/aislamiento & purificación , Modelos Químicos , Pironas , Relación Estructura-Actividad , Taxoides/aislamiento & purificaciónRESUMEN
Nine new epothilone analogues (6-8, 10, 11a, 11b, 12, 13, and 15) were isolated from fermentations of Myxococcus xanthus strains engineered with modified polyketide synthase genes. The epothilone structures were elucidated primarily through interpretation of 1D and 2D NMR data. 4-Desmethyl-10,11-didehydroepothilone D (6) displayed activity against several tumor cell lines, including a multi-drug-resistant cell line.