SYNTHESIS OF BIOLOGICALLY ACTIVE NATURAL PRODUCTS

生物活性天然产物的合成

基本信息

批准号：
6699049
负责人：
BARRY B. SNIDER
金额：
$ 27.31万
依托单位：
BRANDEIS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-12-01 至 2005-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6699049
关键词：
Porifera Tunicata antibiotics biological products cyclization cyclopentane cytotoxicity diterpenes drug design /synthesis /production guanidines macrolide antibiotics quinazolines quinoline receptor sensitivity vitamin D

项目摘要

This proposal consists of seven unrelated projects designed to prepare structurally novel, biologically active natural products of potential interest as drugs and to explore new synthetic methods of general interest. (1) The first synthesis of the novel pyrroloquinolines martinellic acid and martinelline will be completed. These alkaloids inhibit several G-protein coupled receptors. (2) New methods have been developed and used for the first syntheses of fumiquinazolines A, B, G, and I and asperlicin. This project will be completed by the synthesis of the more highly oxidized fumiquinazolines C, D, E, and H, fiscalins A and B, and citreoindole. (3) The novel diterpene antibiotic guanacastepene that appears to function by disruption of membranes will be prepared using a novel route to the hydroazulene ring system. This chemistry will be used for a short synthesis of the CD ring system of vitamin D. (4) Haterumalide B and haterumalide NA (oocydin A) are novel macrolides isolated from a sponge, ascidian and phytopathogen that are cytotoxic and show selective toxicity to breast cancer cells. An efficient route to these compounds using a Stille coupling of an allylic bromide or acetate with a vinylstannane to construct the skipped chlorodiene unit will be developed. (5) Cytoskyrin A, graciliformin, and rugulosin are unusual bisanthraquinoid natural products that have potent biological activity and structural novelty. They will be synthesized by a biogenetic route using a phenyldimethylsilyl group as a latent hydroxy group. (6) Phloeodictine A and Al-A7 area family of guanidine containing amidinium salt natural products that are cytotoxic and antibacterial. In model studies, a general new route to these compounds has been developed by adding Grignard reagents to the acyl group of an N-acylamidine and then alkylating the amidine. This will be extended to the natural products and analogues. (7) Mn(III)-based oxidative cyclization of Meldrum's acid derivatives occurs almost instantaneously at 25 degrees celcius to give predominantly cyclohexene products. The mechanism and synthetic utility of these cyclizations will be developed.

该提案由七个不相关的项目组成，旨在制备具有潜在药物用途的结构新颖、具有生物活性的天然产物，并探索具有普遍意义的新合成方法。（1）完成新型吡咯喹啉马丁内利酸和马丁内林的首次合成。这些生物碱抑制多种 G 蛋白偶联受体。 (2)开发并使用了新方法首次合成了文喹唑啉A、B、G、I和曲霉素。该项目将通过合成氧化程度更高的夫米喹唑啉 C、D、E 和 H、财政菌素 A 和 B 以及柠檬吲哚来完成。 (3) 新型二萜抗生素胍那卡斯特烯 (guanacasstepene) 似乎通过破坏膜发挥作用，将使用氢甘菊环系统的新途径来制备。该化学将用于维生素 D CD 环系统的短合成。 (4) Haterumalide B 和 haterumalide NA (oocydin A) 是从海绵、海鞘和植物病原体中分离出来的新型大环内酯，具有细胞毒性，对乳腺具有选择性毒性癌细胞。将开发一种生产这些化合物的有效途径，使用烯丙基溴或乙酸酯与乙烯基锡烷的 Stille 偶联来构建跳过的氯二烯单元。 (5) Cytoskyrin A、graciliformin 和 rugulosin 是不寻常的双蒽醌类天然产物，具有有效的生物活性和结构新颖性。它们将使用苯基二甲基甲硅烷基作为潜在羟基通过生物合成途径合成。 (6)Phloeodictine A和Al-A7是含有脒盐的胍天然产物家族，具有细胞毒性和抗菌性。在模型研究中，通过将格氏试剂添加到 N-酰基脒的酰基上，然后将脒烷基化，开发了这些化合物的通用新途径。这将扩展到天然产物和类似物。 (7) Meldrum 酸衍生物的基于 Mn(III) 的氧化环化几乎在 25 摄氏度下立即发生，主要产生环己烯产物。将开发这些环化的机制和合成用途。