SYNTHESIS OF BIOLOGICALLY ACTIVE NATURAL PRODUCTS

生物活性天然产物的合成

• 批准号: 2838610
• 负责人: BARRY B. SNIDER
• 金额: $ 17.58万
• 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/2838610
• 关键词: Diels Alder reaction; alkaloids; analgesics; antiAIDS agent; antiinflammatory agents; antineoplastic antibiotics; chemical synthesis; cytotoxicity; drug design /synthesis /production; immunosuppressive; quinazolines; sesquiterpenes; 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：该提案由六个无关的合成项目组成 设计用于制备结构新颖的生物活性天然产品 作为药物的潜在感兴趣。 在第一个项目中，PI计划 对含三环类鸟嘌呤的完整合成研究 巴兹拉丁。 Batzelladines与Crambines和 ptilomycalin A，先前提案的主题，并显示抗AIDS 抑制HIV GP 120人类CD4结合的活性。 在第二个项目中，PI计划准备马丁内林（112）和 Martinellic Acid（113），结构新颖的吡咯喹啉在结构上是新颖的， 拥有两个或三个鸟齿也很不寻常。 马丁内林是一个 几种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中发挥作用 炎。 在第三个项目中，PI计划合成犀牛A（143）A 相当简单或固定苯丙烯具有相当大的兴趣，因为它 针对髓样K-562细胞，人Molt-4白血病细胞和 鼠L1210白血病细胞在40-100 nm范围内。 由于只有3.1毫克 该化合物是从海绵中分离出来的，总合成将是必要的 为了进一步研究生物学活性。 PI最近已经完成了ent-氟尼唑啉G的合成（162）。 在第四个项目中，他计划扩展这项工作以准备 烟氮唑啉B（147）和C（151）和螺旋喹唑啉（152）。 这些 化合物是中等的细胞毒性，152抑制了物质的结合 p对人U-373 mg完整细胞，因此可能是一种新型的镇痛药或 抗炎药。 FR901483（186）是一个不寻常的酪氨酸二聚体，带有Azabicyclo（3.3.1） 在体外施加有效的免疫抑制活性的非骨架 在大鼠皮肤同种异体移植模型中，显着延长了生存时间。 在 初步研究，PI已开发了两步途径，通往179 包含适当功能化的完整碳骨架，为186。 在第六个项目中，PI计划准备Penostatins A（188），B（189）， C（187）去年被孤立，显示为p388 白血病为0.8-1.1 mg/ml。 此综合的关键步骤是 三烯基甘酰基192的分子内双向alder alder alder alder反应为191 和立体异构体。