SYNTHESIS OF BIOLOGICALLY ACTIVE NATURAL PRODUCTS

生物活性天然产物的合成

• 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
• 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

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.

该提案由七个无关的项目组成，旨在制备具有药物潜在兴趣的结构新颖，生物活性的天然产物，并探索新的一般兴趣的合成方法。 （1）新型吡咯喹啉的马铃薯酸和马丁林的第一个合成将完成。 这些生物碱抑制了几种G蛋白偶联受体。 （2）已开发并使用了新方法，并将其用于烟氮唑啉A，B，G和I和绿心蛋白的第一批合成。 该项目将通过合成更高度氧化的富灵烟酸酯C，D，E和H，Fiscalins A和B和Citreoindole来完成。 （3）新型的二萜抗生素鸟脉苯丙胺似乎通过膜的破坏起作用，将使用通往氢氮环系统的新型途径制备。 该化学物质将用于对维生素D的CD环系统的短合成。（4）Haterumalide B和Haterumalide Na（卵母素A）是从海绵，腹侧和植物病原体中分离出的新型大花环，它们具有细胞毒性，并显示出对乳腺癌细胞的选择性毒性。 将开发使用烯丙基溴或乙酸盐与乙烯烷烷构建跳过的叶绿素单元的蒸汽偶联到这些化合物的有效途径。 （5）细胞甲蛋白A，graciliformin和rugulosin是具有强大生物学活性和结构新颖性的异常双甘心喹啉天然产物。 它们将通过使用苯二甲基甲硅烷基群体作为潜在羟基的生物遗传学途径合成。 （6）含有细胞毒性和抗菌性的硫酸盐属植物A和Al-A7区域家族。 在模型研究中，通过将grignard试剂添加到N-酰胺定氨酸的酰基基团，然后将烷基化氨基烷基化来开发到这些化合物的一般新途径。 这将扩展到天然产品和类似物。 （7）基于Mn（III）的氧化氧化环化的Meldrum酸衍生物几乎立即发生在25摄氏度下，以产生主要的环己烯产物。 这些自动化的机制和合成效用将开发出来。