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

从海绵Halichondria okadai中分离得到的生物碱Halichondria okadai被证明能抑制血管细胞黏附分子-1(VCAM-1)的表达，VCAM-1是治疗冠心病和炎症的潜在靶点。拉索内酯A是从海绵Forcepia sp.中分离出来的一种多烯大环内酯类化合物，在一项新开发的全细胞试验中也被发现具有抑制细胞黏附的作用。我们计划合成这两种天然产物，并开发一种治疗动脉硬化的新的有效药物。卤化氯的合成研究：以串联分子内Michael加成-[3+2]环加成反应为关键反应步骤，成功地合成了外消旋三环卤化氯核。对于不对称合成，有效地构建了具有光学活性的氮杂螺环部分。拉索内酯A的合成研究：对两个关键结构单元C_1-C_&lt；16&gt；和C_&lt；18&gt；-C_&lt；25&gt；的结构进行了研究。采用不对称环氧化和烷基化技术，有效地完成了C_1-C_1-C_(16)&gt；链段的合成。另一方面，利用我们开发的自由基环化反应作为关键步骤合成了C_&lt；18&C_&lt；25&gt；链段。然而，合成的产物是非对映异构体，这是由于在转化过程中C_&lt；21&gt；发生了意想不到的异构化。卤化氯合成中间体的生物学评价：为了探索对新药开发有用的先导化合物，用正常细胞和一些癌细胞对几种卤化氯合成中间体进行了生物测定。因此，有趣的是，卤代氯的三环核心显示出类似于细胞凋亡的活性。

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.