ONCOGENE-DIRECTED SYNTHESIS OF CEPHALOSTATIN CANCER DRUG

这项提议寻求：利用一种新的不对称吡嗪偶联来 完成C-C-的全合成及生物活性测定 14‘，15’二氢脑抑素-1；开发新的手性化学 用β-硝基-丙酮阴离子来制备和检测反式 头孢他丁/利特拉津杂交种“头孢氨酸阿尔法”；进一步探索 合成6/6螺酮结构域的硝基丙酮方法学 非常有效的抗癌药物Altohyrtins A-C。如果是C-14‘，15’ 二氢脑抑素1不具有亚纳摩尔活性，总 将利用开发的化学方法合成头孢菌素1 结合头孢洛嗪α的合成。一个 将使用伪组合方法来快速评估 三十个新的三环吡嗪的活性；一系列乙烯基醚 将生成并测试以评估氧中间体 作为头孢他汀类抗癌活性的负责物种， 利特拉津，以及新的类固醇抗肿瘤药物OSW-1。这个 类固醇生物合成抑制因子活性与激素代谢的关系 将探索头孢菌素7的抗癌活性。 脑抑素1和/或7的光亲和标记类似物 将准备好，以尝试确定生物目标的 头孢他汀类药物。最佳试剂的克量将合成为 毒理学和人体I期临床试验的前奏。

This proposal seeks: to utilize a new unsymmetrical pyrazine coupling to complete the total synthesis and determine the biological activity of C- 14',15' dihydrocephalostatin 1; to develop new chemistry of symchiral Beta-nitroacetonide anions in order to prepare and test the unnatural cephalostatin/ritterazine hybrid "cephalozine alpha"; to further explore the nitroacetonide methodology to synthesize the 6/6 spiroketal domain of the extremely potent anticancer agents altohyrtins A-C. If C-14',15' dihydrocephalostatin 1 does not have subnanomolar activity, the total synthesis of cephalostatin 1 will be undertaken using chemistry developed in conjunction with the synthesis of cephalozine alpha. A pseudocombinatorial approach will be employed to rapidly assess the activity of thirty new trisdecacyclic pyrazines; a series of vinyl ethers will be generated and tested in order to evaluate oxonium intermediates as the species responsible for anticancer activity of the cephalostatins, ritterazines, and the new steroidal antineoplastic OSW-1. The relationship between steroid biosynthesis inhibitor activity and anticancer activity will be explored for cephalostatin 7. Several photoaffinity-labeled analogs of cephalostatin 1 and/or cephalostatin 7 will be prepared in order to try to identify the biological target of the cephalostatins. Gram quantities of the best agent will be synthesized as a prelude to toxicological and human Phase I clinical trials.