ONCOGENE-DIRECTED SYNTHESIS OF CEPHALOSTATIN CANCER DRUG

该提案寻求：利用新的不对称吡嗪偶联， 完成了C-的全合成，并测定了C-的生物活性。 14 '，15'-二氢头孢菌素1;开发新的同手性化合物 β-硝基丙酮阴离子，以制备和测试非天然的 头孢菌素/利特拉嗪杂合物“头孢嗪α”;进一步探讨 合成6/6螺缩酮结构域的硝基丙酮方法 一种非常有效的抗癌药物altohyrtins A-C。如果C-14 '，15' 二氢头孢菌素1不具有亚纳摩尔活性， 头孢菌素1的合成将使用开发的化学方法进行， 结合头孢嗪α的合成。一 伪组合的方法将被用来快速评估 三十个新十三环吡嗪的活性;一系列乙烯基醚 将生成并测试，以评估氧鎓中间体 作为负责头孢菌素抗癌活性的种类， 利特拉嗪和新的甾体化合物CYTOSW-1。的 类固醇生物合成抑制剂活性与 将探索头孢菌素7的抗癌活性。 几 光亲和标记的头孢菌素1和/或头孢菌素7的类似物 将准备，以试图确定生物目标的 头孢菌素。克数量的最佳药剂将被合成为 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.