Asymmetric Synthesis of Antitumor Agents

抗肿瘤药物的不对称合成

• 批准号: 6878756
• 负责人: MICHAEL T. CRIMMINS
• 金额: $ 6.12万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-02-08 至 2006-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6878756
• 关键词: alkylation; antifungal agents; antineoplastic antibiotics; apoptosis; biological products; cytotoxicity; drug design /synthesis /production; growth inhibitors; pyrones; stereochemistry; tubulin

The specific objectives of the proposed research are to execute a synthesis of the potent antitumor agents laulimalide, apoptolidin and leucascandrolide A. Ultimately, perhaps less complex derivatives of these potent antitumor agents with similar or better biological profiles can be prepared. During the course of the investigation, general methodology for the asymmetric synthesis of polyacetate and and polypropionate natural products will be developed. The asymmetric approaches to polyacetate and polypropionate fragments described herein should also find application in the synthesis of a variety of other biologically important compounds. Leucasandrolide A was isolated from the calcareous sponge Leucasandra caveolata. The gross structure and relative stereochemistry was assigned based on extensive two dimensional NMR experiments. The absolute configuration was assigned by Mosher's method using the Mosher's ester of the C5 hydroxyl. Leucasandrolide displayed significant cytotoxicity in vitro (IC50 = 0.05 and 0.25 mug/ml with KB and P388 cells, respectively) as well as very strong inhibition of Candida albicans, a pathogenic yeast that attacks AIDS patients.3 Apoptolidin, from Norcardiopsis sp. induced apoptotic cell death in rat glia cells transformed with the adenovirus E1A oncogene (IC50 11ng/mL) but not in normal glia cells or normal fibroblasts (IC50 greater than 100 mug/mL). Laulimalide is a potent inhibitor of cell growth with low, nanomolar IC50 values which was isolated from an Okinawan sponge Fasciospongia rimosa. Laulimalide shows paclitaxel-like microtubule stabilization, however, in contrast to paclitaxel, laulimalide inhibits proliferation of SKVLB-1 cells, a multidrug resistant cell line. Laulimalide stimulates tubulin polymerization more effectively than paclitaxel. Laulimalide is a representative of a new class of microtubule stabilizing agents with promise for therapeutic potential.

拟议的研究的具体目标是执行有效的抗肿瘤剂Laulimalide，apoptolidin和leucascandrolide A的合成。最终，可以准备这些有效抗肿瘤药物具有相似或更好的生物学特征的这些有效抗肿瘤药物的复杂衍生物。 在调查过程中，将开发出多乙酸和多丙酸天然产物的不对称合成的一般方法。 本文所述的多乙酸和聚丙酸碎片的不对称方法也应在合成各种其他重要重要性化合物的合成中找到应用。从钙质海绵leucasandra caveolata中分离出leucasandrolide a。 基于广泛的二维NMR实验分配了总结构和相对立体化学。 使用C5羟基的Mosher酯通过Mosher的方法分配了绝对构型。 Leucasandrolide在体外表现出明显的细胞毒性（IC50 = 0.05和0.25 mug/ml，分别用Kb和P388细胞）以及非常强的糖果白色念珠菌，一种致病的酵母，一种攻击的致病性酵母菌。用腺病毒E1A癌基因（IC50 11NG/mL）转化的大鼠胶质细胞中诱导的凋亡细胞死亡，但在正常胶质细胞或正常成纤维细胞（IC50大于100 mug/ml）中诱导的凋亡细胞死亡。 Laulimalide是一种有效的细胞生长抑制剂，其低纳摩尔IC50值是从冲绳海绵fasciospongongia rimosa分离出来的。 Laulimalide显示出类似紫杉醇的微管稳定化，但是，与紫杉醇相比，Laulimalide抑制了SKVLB-1细胞的增殖，SKVLB-1细胞（一种多药抗性细胞系）。 比紫杉醇比紫杉醇更有效地刺激小管蛋白聚合。 Laulimalide是一类新的微管稳定剂的代表，具有治疗潜力的希望。