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Studies on the development of drugs for arteriosclerosis based on the inhibition of cell adhesion molecules' induction

基于抑制细胞粘附分子诱导的动脉硬化药物开发研究

基本信息

批准号：
11557172
负责人：
SHISHIDO Kozo
金额：
$ 8.64万
依托单位：
The University of Tokushima
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B).
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2000
项目状态：
已结题

项目摘要

Alkaloid halichlorine, which was isolated from the sponge Halichondria okadai, was shown to inhibit the expression of VCAM-1 (vascular cell adhesion molecule-1), a potential target for the treatment of coronary heart disease and inflammation. Lasonolide A, which is polyene macrolide isolated from the sponge Forcepia sp., was discovered also to inhibit cell adhesion in a newly developed whole cell assay. We planned to synthesize both natural products and to develop a new and efficient drug for the treatment of arteriosclerosis.1. Synthetic studies on halichlorine : The racemic tricyclic core of halichlorine was successfully synthesized by using the tandem intramolecular Michael addition-[3+2] cycloaddition as a key reacton step. For the enantioselective synthesis, the optically active aza-spirocyclic moiety was efficiently constructed.2. Synthetic studies on lasonolide A : Constuctions of the two key structural units, C_1-C_<16> and the C_<18>-C_<25> segments, were investigated. The synthesis of the C_1-C_<16> segment was efficiently accomplished employing the asymmetric epoxidation and alkylation tecniques. On the other hand, the C_<18>-C_<25> segment was synthesized by using a radical cyclization, which was developed by us, as a key step. The synthesized product, however, was the diastereoisomer due to an unexpected epimerization at C_<21> during the conversion.3. Biological evaluations of the synthetic intermediates of halichlorine : To explore the useful lead compounds for the development of new drugs, the biological assay for some kinds of synthetic intermediates of halichlorine was investigated by using normal cell and some cancer cells. As a result, interestingly, the tricyclic core of halichlorine exhibited apoptosis-like activity.

从海绵Halichondria okadai中分离的生物碱halichlorine显示出抑制VCAM-1（血管细胞粘附分子-1）的表达，VCAM-1是治疗冠心病和炎症的潜在靶点。Lasonsulfate A是从海绵Forcepia sp.中分离的多烯大环内酯，在新开发的全细胞测定中也发现其抑制细胞粘附。我们计划合成这两种天然产物，并开发一种新的有效的治疗动脉粥样硬化的药物。卤氯灵的合成研究：以分子内Michael加成-[3+2]环加成为关键步骤，成功地合成了卤氯灵的外消旋三环核。在对映选择性合成中，有效地构建了光学活性的氮杂螺环部分.拉松素A的合成研究：研究了C_1-C_2和C_1-C_2两个关键结构单元的结构<16><18><25>。采用<16>不对称环氧化和烷基化技术，有效地完成了C_1-C_2链段的合成。另一方面，采用自由基环化法合成了C_<18>-C_<25>链段。然而，由于在转化过程中在C_处发生了意想不到的差向异构化，合成的产物为非对映异构<21>体.卤氯碱合成中间体的生物学评价：为了寻找对新药开发有用的先导化合物，本文采用正常细胞和癌细胞对卤氯碱合成中间体的生物活性进行了研究。结果，有趣的是，卤氯的三环核心表现出类似前列腺增生的活性。