TUMOR INHIBITORS AND RELATED SUBSTANCES

本提案侧重于抗肿瘤药物的全合成。 Quassinoid。具体目标包括准马菌素、布鲁替丁和 银杏红素。此外，我们还计划制备多种C(15)酯 与A-降冰片素相关，以检查结构要求 用于生物活动。膜胆固醇积聚的假说 构成了肿瘤发生的早期阶段，使我们专注于 开发一种有效的途径来合成紧凑型蛋白，这已经被证明是一种 3-羟基-3-甲基戊二酰辅酶A的有效竞争性抑制剂 还原酶，胆固醇生物合成中的速率控制酶。作为一种 扩展使用双环[2.2.1]庚烷化学的早期研究，我们 计划以立体定向、光学活性的形式制备硫那霉素 和三个C(10)类似物[10Beta-氟，10Beta-甲基，和 10甲氧基硫代阿霉素组。

This proposal focuses on the total synthesis of antineoplastic quassinoids. Specific targets include quasimarin, bruceantin, and glaucarubinone. In addition, we plan to prepare a variety of C(15) esters related to A-norquasimarin in order to examine the structural requirements for biological activity. The hypothesis that membrane cholesterol build up constitutes an early phase in tumorigenesis, led us to concentrate on developing an efficient route to compactin, which has been shown to be a potent competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, the rate-controlling enzyme in cholesterol biosynthesis. As an extension of earlier studies employing bicyclo[2.2.1]heptane chemistry, we plan to prepare stereospecifically, in optically active form, thienamycin and three C(10) analogs [10Beta-fluoro, 10Beta-methyl, and 10Beta-methoxythienamycin.