SYNTHESIS OF ANTIMITOTIC NATURAL PRODUCTS

抗有丝分裂天然产物的合成

基本信息

批准号：
08672414
负责人：
SHIRAI Ryuichi
金额：
$ 1.41万
依托单位：
UNIVERSITY OF TOKYO
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1996
资助国家：
日本
起止时间：
1996 至 1997
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-08672414/
关键词：
CURACIN USTILOXIN TUBULIN MICROTUBULES ANTIMITOTIC AGENT ASYMMETRIC SYNTHESIS TOTAL SYNTHESIS キュラシンA ウスチロキシンD

项目摘要

There are number of natural and synthetic compounds that interfere with microtubule function by binding to tubulim. Curacin A,isolated from a Caribbean cyanobacterium Lyngbya majuscula, was found to be a novel antimitotic agent. Asymmetric total synthesis of curacin A was performed in a highly stereo-controlled manner. The key steps were (1) an asymmetric allylation using a chiral allyltitanium reagent and a double-asymmetric Simmons-Smith cyclopropanation to introduce three chiral centers, (2) Wittig and Wittig-Horner reactions to construct the C(3-4) and C(7-10) alkenes, and (3) a direct conversion of the thiazolidine to thiazoline. The four stereoisomers of a partial structure at the thiazoline moiety were also synthesized to elucidate the absolute configurations of three chiral centers in curacin A.In addition, A series of side chain analogs of curacin A were synthesized and the effect to in vitro micritubule polymerization was examined. These side chain analogs showed weak or no anti-tubulin activity suggesting that the side chain of curacin A was restrictly recognized by microtubule proteins. Ustiloxin D,isolated as the minor component of ustiloxins from the water extract of false smut balls, exhibits potent anti-tubulin activity. The common structure found in these class of compounds is 13-membered core structure, which seems to be responsible substructure for anti-tubulin activity. Reductive removal of sulfoxide side chain of ustiloxin A gave ustiloxin D,an important intermediate for the symthesis of its analogs. Methylation of phenolic hydroxyl group or methylamino geoup resulted in disappearance of the antitubulin activity. The 13-membered cyclic peptides, novel analogs of phomopsin-ustiloxin class of antibiotics without glycine residue, were also synthesized.

有许多天然和合成化合物通过与微管结合来干扰微管功能。从加勒比蓝细菌lyngbya majuscula分离出的素蛋白A被发现是一种新型的抗魔法剂。以高度立体控制的方式进行素素A的不对称总合成。关键步骤是（1）使用手性烯丙基试剂和双重的Simmons-Smith-Smith Cylopropanation介绍三个手性中心，（2）Wittig和Wittig-Horner反应构建C（3-4）和C（7-10）Alkenes和（3）Aniquion，（2）噻唑啉。还合成了噻唑啉部分处的部分结构的四个立体异构体，以阐明库糖蛋白A.In中三个手性中心的绝对构型，合成了一系列库拉辛A的侧链类似物，并检查了对体外微蛋白化合物的效果。这些侧链类似物显示出弱或没有抗细胞纤维蛋白活性，这表明库拉蛋白A的侧链被微管蛋白限制。乌斯利毒素D（从假斑点球的水提取物中被分离为乌斯利洛氧蛋白的次要成分）表现出有效的抗微管蛋白活性。这些化合物中发现的共同结构是13元的核心结构，这似乎是抗微管蛋白活性的负责子结构。紫氧蛋白A的硫氧化磺酰侧链的还原性去除给出了Ustiloxin d，这是其类似物符号的重要中间体。酚类羟基或甲基氨基旋藻的甲基化导致抗蛋白活性消失。还合成了13元的循环肽，即没有甘氨酸残基的phomopsin- ulosiloxin类的新型类似物。