SYNTHESIS AND ANTITUMOR ACTIVITY OF TERPENOIDS

我们建议做的工作分为四个独立的研究 项目，虽然有三个是针对一个共同的目标： 生物活性生物碱 （a）继续进行研究 不对称加成反应的区域选择性和机理 手性亚磺酰基烯丙基阴离子和烯丙基膦酰基阴离子与烯酮，和 随后环化以产生手性吲嗪， 吡咯烷类、（+）-三蒽酮、（-）泽喃酮、（-）-二氢石蒜碱和 萜类;（B）α-氨基碳负离子的不对称烷基化反应 以及随后的闭环反应，以及retronecine的合成 和山靛碱N-氧化物;（c）手性短小毒素生物碱的合成;和 (d)继续测定抗肿瘤活性 二萜类化合物，合成中间体和生物碱。 前三个项目主要针对生物活性的合成 生物碱和化学是相关的。 我们的长期目标是 将这些工作延伸到手性的、天然存在的 inolizidine，pyrrolizidine，lycopodine，ibophyllidine，quinolizidine，和 石蒜烷生物碱 这些生物碱骨架的合成已被 提出了 合成的天然产物及其合成中间体， 将使用体外组织培养来测试类似物的抗肿瘤活性 系统. 一旦确定了活性化合物，将在 Matthew Suffness博士实验室癌症部门的体内动物模型 治疗，NCI或Dr. Dolores Takemoto（合作研究者）实验室。

The work which we propose to do divides into four separate research projects, although three are aimed at a common goal: synthesis of biologically active alkaloids. These are: (a) continuation in the studies of the regioselectivity and mechanism of the asymmetric addition reactions of chiral sulfinylallyl anions and allylphosphonyl anions with enones, and the subsequent cyclizations to produce chiral indolizidines, pyrrolizidines, (+)-trianthine, (-)zephyranthine, (-)-dihydrolycorine, and terpenoids; (b) asymmetric alkylation reactions of alpha-amino carbanions and the subsequent ring closure reactions, and the syntheses of retronecine and indicine N-oxide; (c) synthesis of chiral pumiliotoxin alkaloids; and (d) continuation in the determination of antitumor activities of trichothecenes, synthetic intermediates and alkaloids. The first three projects aim mainly at the synthesis of biologically active alkaloids, and the chemistry are related. Our long term goals will be the extension of these works into the syntheses of chiral, naturally occurring inolizidine, pyrrolizidine, lycopodine, ibophyllidine, quinolizidine, and lycorane alkaloids. The syntheses of these alkaloids' skeletons have been proposed. The synthesized natural products and their synthetic intermediates and analogs will be tested for antitumor activity using in vitro tissue culture systems. Once the active compounds are identified, they will be tested in vivo animal models at Dr. Matthew Suffness's laboratory, Division of Cancer Treatment, NCI or Dr. Dolores Takemoto's (Co-investigator) laboratory.