SYNTHESIS OF BIOLOGICALLY ACTIVE NATURAL PRODUCTS

生物活性天然产物的合成

• 批准号: 6329749
• 负责人: BARRY B. SNIDER
• 金额: $ 18.63万
• 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 2001-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6329749
• 关键词: Diels Alder reaction; alkaloids; analgesics; antiAIDS agent; antiinflammatory agents; antineoplastic antibiotics; chemical synthesis; cytotoxicity; drug design /synthesis /production; immunosuppressive; quinazolines; sesquiterpenes

DESCRIPTION: This proposal consists of six unrelated synthetic projects designed to prepare structurally novel, biologically active natural products of potential interest as drugs. In the first project the PI plans to complete synthetic studies of the tricyclic guanidine containing batzelladines. The batzelladines are closely related to the crambines and ptilomycalin A, the subject of the previous proposal, and show anti-AIDS activity inhibiting HIV gp 120-Human CD4 binding. In the second project the PI plans to prepare martinelline (112) and martinellic acid (113), structurally novel reduced pyrroloquinolines that are also unusual in possessing two or three guanidines. Martinelline is an effective inhibitor at several G-protein coupled receptor systems (IC50 60-250nM) and may therefore play a role in analgesia and reduction of inflammation. In the third project the PI plans to synthesize rhopaloic acid A (143) a fairly simple nor-sesterterpene which is of considerable interest because it is cytotoxic against myeloid K-562 cells, human Molt-4 leukemia cells and murine L1210 leukemia cells in the 40-100 nM range. Since only 3.1 mg of this compound was isolated from a sponge, total synthesis will be necessary for further investigation of biological activity. The PI has recently completed a synthesis of ent-fumiquinazoline G (162). In the fourth project, he plans to extend this work to prepare fumiquinazoline B (147) and C (151), and spiroquinazoline (152). These compounds are moderately cytotoxic and 152 inhibits the binding of substance P to human U-373 MG intact cells and therefore might be a novel analgesic or antiinflammatory agent. FR901483 (186) is an unusual tyrosine dimer with an azabicyclo (3.3.1) nonane skeleton that exerts potent immunosuppressive activity in vitro and significantly prolongs survival time in the rat skin allograft model. In preliminary studies, the PI has developed a two step route to 179, which contains the suitably functionalized complete carbon skeleton of 186. In the sixth project the PI plans to prepare penostatins A (188), B (189), and C (187) which were isolated last year and shown to be cytotoxic to P388 leukemia at 0.8-1.1 mg/mL. The key step in this synthesis is the intramolecular Diels-Alder reaction of trienyl glyoxylate 192 to give 191 and stereoisomers.

描述：该提案由六个不相关的综合项目组成 旨在制备结构新颖、具有生物活性的天然产物 作为药物具有潜在的兴趣。 在第一个项目中，PI 计划 含三环胍的完整合成研究 巴特泽拉迪斯。 Batzelladines 与 Chambines 密切相关， ptilomycalin A，先前提案的主题，并显示抗艾滋病作用 抑制 HIV gp 120-人类 CD4 结合的活性。 在第二个项目中，PI 计划制备 martinelline (112) 和 马丁内利酸 (113)，一种结构新颖的还原吡咯喹啉， 拥有两个或三个胍也很不寻常。 马丁内琳是一个 多种 G 蛋白偶联受体系统的有效抑制剂（IC50 60-250nM），因此可能在镇痛和减少 炎。 在第三个项目中，PI计划合成箭叶酸A（143）a 相当简单的正二倍半萜烯，它引起了很大的兴趣，因为它 对骨髓 K-562 细胞、人 Molt-4 白血病细胞和 小鼠 L1210 白血病细胞在 40-100 nM 范围内。 因为只有 3.1 毫克 该化合物是从海绵中分离出来的，需要全合成 以便进一步研究生物活性。 PI 最近完成了 ent-fumiquinazoline G (162) 的合成。 在第四个项目中，他计划扩展这项工作以准备 文喹唑啉 B (147) 和 C (151)，以及螺喹唑啉 (152)。 这些 化合物具有中等细胞毒性，并且 152 抑制物质的结合 P 为人 U-373 MG 完整细胞，因此可能是一种新型镇痛药或 抗炎剂。 FR901483 (186) 是一种不寻常的酪氨酸二聚体，具有氮杂双环 (3.3.1) 壬烷骨架在体外发挥有效的免疫抑制活性 显着延长大鼠皮肤同种异体移植模型的存活时间。 在 初步研究后，PI 制定了一条通往 179 的两步路线，其中 含有适当功能化的完整碳骨架186。 在第六个项目中，PI计划制备penostatin A (188)、B (189)、 和 C (187)，去年分离并显示对 P388 具有细胞毒性 0.8-1.1 mg/mL 的白血病。 该合成的关键步骤是 乙醛酸三烯酯 192 的分子内 Diels-Alder 反应得到 191 和立体异构体。