抗肿瘤药442. 二氧抑素的合成及生物活性

Antineoplastic agents 442. Synthesis and biological activities of dioxostatin.

作者信息

Pettit G R, Lippert J W, Boyd M R, Verdier-Pinard P, Hamel E

机构信息

Department of Chemistry and Biochemistry, Arizona State University, Tempe 85287-2404, USA.

出版信息

Anticancer Drug Des. 2000 Oct;15(5):361-71.

PMID:11354312

Abstract

A high-yield regioselective synthesis of (E)-combretastatin A-1 2b was completed using methoxymethyl (MOM) protection and a Wadsworth-Emmons reaction as key steps. In turn, (E)-stilbene 11 was converted by convenient syntheses to both (S,S)- and (R,R)-1,3-dioxolanes 5a and 6a. A Sharpless asymmetric dihydroxylation reaction was employed for preparation of intermediates (S,S)-12 and (R,R)-13. The (4S,5S)-4-(2',3'-dihydroxy4'-methoxyphenyl)-5-(3",4",5"-trimethoxyphenyl)-1, 3-dioxolane 5a was found to be a highly potent inhibitor of microtubule assembly (IC50 = 0.59 microM) and was designated dioxostatin. Conversion to sodium phosphate 17 (P388 lymphocytic leukemia cell line: ED50 = 0.2 microg/ml) provided a very useful water-soluble prodrug.

摘要

使用甲氧基甲基（MOM）保护和沃兹沃思 - 埃蒙斯反应作为关键步骤，完成了（E）-康普他汀A - 1 2b的高产率区域选择性合成。反过来，（E）-二苯乙烯11通过简便的合成方法转化为（S，S）-和（R，R）-1,3 - 二氧戊环5a和6a。采用夏普莱斯不对称双羟基化反应制备中间体（S，S）-12和（R，R）-13。发现（4S，5S）-4-（2'，3'-二羟基-4'-甲氧基苯基）-5-（3“，4”，5“-三甲氧基苯基）-1,3 - 二氧戊环5a是微管组装的高效抑制剂（IC50 = 0.59 microM），并被命名为二氧他汀。转化为磷酸钠17（P388淋巴细胞白血病细胞系：ED50 = 0.2 microg/ml）提供了一种非常有用的水溶性前药。