SYNTHESIS OF BIOLOGICALLY ACTIVE NATURAL PRODUCTS

描述：该提案由六个不相关的合成项目组成 设计用于制备结构新颖、具有生物活性的天然产物， 作为药物具有潜在的兴趣。 在第一个项目中，PI计划 三环胍的全合成研究 大杂烩。 巴策尔人与克拉宾斯人关系密切， ptilomycalin A，是前面提出的课题，并显示出抗艾滋病 抑制HIV gp 120-人CD 4结合的活性。 在第二个项目中，PI计划制备马丁奈林（112）和 马丁内拉酸（113），结构新颖的还原吡咯并喹啉， 也不寻常的拥有两个或三个胍。 Martinelline是一种 对几种G蛋白偶联受体系统有效的抑制剂（IC 50 60- 250 nM），因此可能在镇痛和减少 炎症 在第三个项目中，PI计划合成rhopaloic acid A（143）a 相当简单的去甲二倍半萜烯，这是相当令人感兴趣的，因为它 对髓样K-562细胞、人Molt-4白血病细胞具有细胞毒性， 小鼠L1210白血病细胞在40-100 nM范围内。 因为只有3.1毫克的 该化合物是从海绵中分离出来的，需要进行全合成 进一步研究生物活性 PI最近完成了对映富米喹唑啉G（162）的合成。 在第四个项目中，他计划扩展这项工作， 烟喹唑啉B（147）和C（151），以及螺喹唑啉（152）。 这些 化合物具有中度细胞毒性，152抑制物质结合 P对人U-373 MG完整细胞的作用，因此可能是一种新的镇痛剂或 间谍。 FR 901483（186）是一种不常见的酪氨酸二聚体，具有氮杂双环（3.3.1） 在体外发挥有效的免疫抑制活性的壬烷骨架， 显著延长大鼠皮肤移植模型的存活时间。 在 初步研究，PI已经制定了一个两步路线179， 含有186的适当官能化的完整碳骨架。 在第六个项目中，PI计划制备penostatin A（188）、B（189）、 和C（187），它们是去年分离的，并显示对P388具有细胞毒性 0.8-1.1 mg/mL。 合成的关键步骤是 乙醛酸三烯酯192分子内Diels-Alder反应，得到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.