Epothilone Analogs by Partial Chemical Synthesis

描述（由申请人提供）：本项目的长期目标是 以产生抑制癌细胞增殖的新型细胞毒性剂。 埃博霉素D是一种16元聚酮衍生的大环内酯， 活性，但由天然生物堆囊菌以低滴度产生 纤维素，并且仅微溶于水。的化学合成 已经实现了埃博霉素，但是方法复杂且昂贵。 最近，Kosan已经开发了用于异源微生物的发酵方法。 大量生产埃坡霉素D。这种现成的可用性 化合物为部分化学合成新化合物提供了独特的机会 类似物在第一阶段，将使用化学方法产生一些 将测试埃坡霉素D的类似物和类似物的效力和水分 溶解度最有希望的候选人，至少与， 并且比母体更易溶于水，将带入第二阶段， 开发商业上可行的生产方法。 拟定商业应用： 埃博霉素被广泛认为是紫杉醇（TaxolTM）的继任者，对多种耐药肿瘤更有效。 所提出的具有增加的溶解度的埃博霉素类似物将具有潜在的竞争优势，用于治疗乳腺癌、肺癌和卵巢癌，市场每年为20亿美元。

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.