新型抗癌药物的先导结构——药理学、发酵及构效关系。

Karl-Heinz Altmann, Klaus Memmert
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引用次数: 11

摘要

Epo's A和B是天然存在的微管稳定剂,在体外低纳米或亚纳米浓度下抑制人类癌细胞的生长。与紫杉醇(紫杉醇、紫杉醇)不同,在体外对不同类型的多药耐药癌细胞系和体内对多药耐药肿瘤也有活性。Epo B (EPO906, patupilone)目前正在进行III期临床试验。自1996年年中首次公开埃泊霉素的绝对立体化学性质以来,已经制备了许多合成和半合成类似物,并确定了它们的体外生物活性。除了产生丰富的SAR信息外,这些努力还鉴定了至少六种化合物(除了促红细胞生成素B),目前正处于人体临床评估的不同阶段。这些化合物中最先进的Epo B内酰胺BMS-247550 (ixabepilone)最近已获得FDA批准用于治疗转移性和晚期乳腺癌。本章将首先概述促红细胞生成素B在体外和体内的基本生物学特征。接下来,我们将对Epo b的发酵生产过程进行回顾。本章的主要部分将集中在epthilone SAR最相关的方面,包括对微管蛋白聚合的影响、体外抗增殖活性和体内抗肿瘤活性。将特别强调在作者自己的实验室进行的工作,但是也将包括来自其他小组的数据。在最后一节中,将简要讨论正在进行临床开发的那些埃泊霉素类似物的现状。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Epothilones as lead structures for new anticancer drugs--pharmacology, fermentation, and structure-activity-relationships.

Epothilones (Epo's) A and B are naturally occurring microtubule-stabilizers, which inhibit the growth of human cancer cells in vitro at low nM or sub-nM concentrations. In contrast to taxol (paclitaxel, Taxol) epothilones are also active against different types of multidrug-resistant cancer cell lines in vitro and against multidrug-resistant tumors in vivo. Their attractive preclinical profile has made epothilones important lead structures in the search for improved cytotoxic anticancer drugs and Epo B (EPO906, patupilone) is currently undergoing Phase III clinical trials. Numerous synthetic and semisynthetic analogs have been prepared since the absolute stereochemistry of epothilones was first disclosed in mid-1996 and their in vitro biological activity has been determined. Apart from generating a wealth of SAR information, these efforts have led to the identification of at least six compounds (in addition to Epo B), which are currently at various stages of clinical evaluation in humans. The most advanced of these compounds, Epo B lactam BMS-247550 (ixabepilone), has recently obtained FDA approval for the treatment of metastatic and advanced breast cancer. This chapter will first provide a summary of the basic features of the biological profile of Epo B in vitro and in vivo. This will be followed by a review of the processes that have been developed for the fermentative production of Epo B. The main part of the chapter will focus on the most relevant aspects of the epothilone SAR with regard to effects on tubulin polymerization, in vitro antiproliferative activity, and in vivo antitumor activity. Particular emphasis will be placed on work conducted in the authors' own laboratories, but data from other groups will also be included. In a final section, the current status of those epothilone analogs undergoing clinical development will be briefly discussed.

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