Epothilone Analogs by Partial Chemical Synthesis

描述(申请人提供)：本项目的长期目标是 产生抑制癌细胞增殖的新型细胞毒剂。 Epothilone D是一种16元聚酮类大内酯，具有广阔的应用前景 活性，但由本地生物体Sorangium以低效价产生 纤维素，仅极少量地溶于水。化学合成法 埃博西酮类药物已经实现，但方法复杂且成本高昂。 最近，kosan开发了针对异源细菌的发酵工艺。 大批量生产依维酮D。此软件的现成版本 化合物为部分化学合成新化合物提供了一个独特的机会 类比。在第一阶段，将使用化学方法产生一些 Epothilone D的类似物和类似物将进行效力和水分测试 溶解度。最有希望的候选人(S)，他们的实力至少与， 比亲本更易溶于水的物质将进入第二阶段 开发商业上可行的生产方法。 建议的商业应用： 埃普西隆被广泛认为是紫杉醇(TaxolTM)的继任者，对多药耐药肿瘤更有效。拟议中的溶解度更高的埃普西隆类似物将在每年20亿美元的乳腺癌、肺癌和卵巢癌治疗市场上具有潜在的竞争优势。

DESCRIPTION (provided by applicant): The long term objective of this project is to generate novel cytotoxic agents that inhibit cancer cell proliferation. Epothilone D, a 16-membered polyketide-derived macrolactone, has promising activity but is produced in low titers by the native organism, Sorangium cellulosum, and is only sparingly soluble in water. Chemical synthesis of epothilones has been achieved but the methods are elaborate and costly. Recently, Kosan has developed fermentation processes for the heterologous production of Epothilone D in large quantities. The ready availability of this compound offers a unique opportunity for partial chemical synthesis of new analogs. In Phase I, chemical methods will be used to generate a number of analogs of Epothilone D and the analogs will be tested for potency and water solubility. The most promising candidate(s) which are at least as potent as, and more water soluble than the parent will be carried forward into Phase II to develop commercially feasible production methods. PROPOSED COMMERCIAL APPLICATION: Epothilone is widely acclaimed as a successor to paclitaxel (TaxolTM) and is more effective against multiple drug resistant tumors. The proposed epothilone analogs with increased solubility will have a potentially competitive advantage for a $2 billion per year market for the treatment of breast, lung and ovarian cancers.