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首页> 外文期刊>The Journal of Antibiotics: An International Journal >Generation of Novel Epothilone Analogs with Cytotoxic Activity by Biotransformation
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Generation of Novel Epothilone Analogs with Cytotoxic Activity by Biotransformation

机译：通过生物转化产生具有细胞毒活性的新型埃博霉素类似物

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摘要

The epothilones reprsent a new class of bacterial natural products with broad spectrum of antiproliferative acativity various types of human tumors and tumor cell lines. The attractive preclinical profile of epothilones has made them promising lead compounds for novel anticancer agents and has spurred a strong interest in obtaining different derivatives to fully evaluate their therapeutic potentials. We have generated a number of novel epothione D and 10,11-dehydroepothilone D (Epo490) analogs via biotransformation using Amycolata autotrophica to alter the oxidation state of the parental compounds. The bioconverted compounds displayed different degrees of potency in cytotoxicity assays against a panel of human tumor cell lines, with 11-hydroxyepothilone D, 14-hydroxyepothilone D, and 21-hydroxyepothilone D showing comparable activity to that of epothilone D, and 21-hyroxy Epo490 being comparable to Epo490. The addition of hydroxyl group(s) seems to cause a decrease in cytotoxic activity against multiple drug resistant cell lines (with overexpressed P-glycoprotein). The compounds generated by biotransformation exert differential effects on tublin polymerization, which correlate with their biological activities.
机译：埃博霉素代表一类新型的细菌天然产物，具有广泛的抗增殖能力，适用于各种类型的人类肿瘤和肿瘤细胞系。埃博霉素的有吸引力的临床前特征使它们成为新型抗癌药的有希望的先导化合物，并引起了人们对获得不同衍生物以充分评估其治疗潜力的强烈兴趣。我们已经通过使用木霉淀粉自养菌改变亲本化合物的氧化态，通过生物转化产生了许多新型的埃坡霉素D和10,11-脱氢埃坡霉素D（Epo490）类似物。经过生物转化的化合物在针对一组人类肿瘤细胞系的细胞毒性试验中显示出不同程度的效力，其中11-羟基埃博霉素D，14-羟基埃博霉素D和21-羟基埃博霉素D的活性与埃博霉素D和21-羟基Epo490相当与Epo490相当。羟基的添加似乎导致针对多种耐药细胞系（P-糖蛋白过表达）的细胞毒性活性降低。通过生物转化产生的化合物对微管蛋白聚合产生不同的影响，这与其生物活性相关。

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