SYNTHESIS OF BIOLOGICALLY ACTIVE NATURAL PRODUCTS

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、具有生物活性的天然产品 与毒品一样具有潜在的吸引力。在第一个项目中，PI计划 三环胍类化合物的完整合成研究 巴泽拉丁。巴泽拉丁与螃蟹类关系密切， 上一份提案的主题是青霉素A，并显示出抗艾滋病的作用 抑制HIV gp 120与人CD4结合的活性。 在第二个项目中，PI计划制备马丁内林(112)和 马丁酸(113)，结构新颖的还原的吡咯喹啉， 也不同寻常地拥有两到三个鸟嘌呤。马提内林是一种 几种G蛋白偶联受体系统(IC50)的有效抑制剂 60-250 nm)，因此可能在镇痛和减少 发炎。 在第三个项目中，PI计划合成轮叶草酸A(143)a 相当简单的二十七碳二烯，引起人们的极大兴趣，因为它 对髓系K-562细胞、人Molt-4白血病细胞和 40-100 nm范围内的小鼠L1210白血病细胞。因为只有3.1毫克的 这种化合物是从海绵中分离出来的，需要进行全合成 用于进一步研究生物活性。 PI最近完成了对甲基呋喃喹唑啉G(162)的合成。 在第四个项目中，他计划将这项工作延长到准备阶段 氟喹唑啉B(147)和C(151)，以及螺喹唑啉(152)。这些 化合物具有中等的细胞毒性，152抑制物质的结合 P对人U-373 MG完整细胞的作用，因此可能是一种新的止痛药。 抗炎剂。 FR901483(186)是一种罕见的含氮杂双环(3.3.1)的酪氨酸二聚体 在体外具有强大的免疫抑制活性的壬烷骨架和 显著延长大鼠同种异体皮肤移植模型的存活时间。在……里面 初步研究，PI已经制定了两步走到179的路线，其中 含有适当官能化的186的完整碳骨架。 在第六个项目中，PI计划制备Penostins A(188)，B(189)， 和C(187)是去年分离到的，对P388有细胞毒性 白血病浓度为0.8-1.1 mg/m L。这一合成的关键一步是 乙二酸三烯酯192的分子内Diels-Alder反应合成191 和立体异构体。

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.