Synthesis and biological evaluation of indole-based, anti-cancer agents inspired by the vascular disrupting agent 2-(3'-hydroxy-4'-methoxyphenyl)-3-(3″,4″,5″-trimethoxybenzoyl)-6-methoxyindole (OXi8006).
Synthesis and biological evaluation of indole-based, anti-cancer agents inspired by the vascular disrupting agent 2-(3'-hydroxy-4'-methoxyphenyl)-3-(3″,4″,5″-trimethoxybenzoyl)-6-methoxyindole (OXi8006).
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DOI：
10.1016/j.bmc.2013.07.028
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发表时间：
2013-11-01
影响因子：
3.5
通讯作者：
Pinney KG
中科院分区：
文献类型：
--
作者：
Macdonough MT;Strecker TE;Hamel E;Hall JJ;Chaplin DJ;Trawick ML;Pinney KG
基于2-芳基-3-芳酰基吲哚的微管蛋白组装的小分子抑制剂（称为OXi 8006）的发现启发了一系列二氢吲哚官能化类似物的设计、合成和生物学评价。在大多数实施例中，侧接的2-芳基环含有3-羟基-4-甲氧基取代模式，并且稠合的芳基环以6-甲氧基为特征。大部分可变性在3-芳酰基部分，其被修饰以引入甲氧基（33-36）、硝基（25-27）、卤素（28-29）、三氟甲基（30）或三氟甲氧基（31-32）官能团。在两种类似物（34和36）中，稠合芳环中的甲氧基取代模式不同，而在另一种衍生物（35）中，酚部分从侧基2-芳环移位到稠合芳环的-7位。评价每种化合物对SK-0 V-3（卵巢癌）、NCI-H460（肺癌）和DU-145（前列腺癌）人癌细胞系的细胞毒性（体外）以及它们抑制微管蛋白组装的能力。其中四种化合物（30、31、35、36）被证明是微管蛋白组装的有效抑制剂（IC 50 < 5 µM），其中三种化合物（31、35、36）对三种癌细胞系具有强烈的细胞毒性。在该系列中最具活性的化合物（36），其在7位引入甲氧基，在抑制微管蛋白组装和细胞毒性方面与先导化合物OXi 8006相当。
The discovery of a 2-aryl-3-aroyl indole-based small-molecule inhibitor of tubulin assembly (referred to as OXi8006) inspired the design, synthesis, and biological evaluation of a series of diversely functionalized analogues. In the majority of examples, the pendant 2-aryl ring contained a 3-hydroxy-4-methoxy substitution pattern, and the fused aryl ring featured a 6-methoxy group. Most of the variability was in the 3-aroyl moiety, which was modified to incorporate methoxy (33–36), nitro (25–27), halogen (28–29), trifluoromethyl (30), or trifluoromethoxy (31–32) functionalities. In two analogues (34 and 36), the methoxy substitution pattern in the fused aryl ring varied, while in another derivative (35) the phenolic moiety was translocated from the pendant 2-aryl ring to position-7 of the fused aryl ring. Each of the compounds were evaluated for their cytotoxicity (in vitro) against the SK-OV-3 (ovarian), NCI-H460 (lung), and DU-145 (prostate) human cancer cell lines and for their ability to inhibit tubulin assembly. Four of the compounds (30, 31, 35, 36) proved to be potent inhibitors of tubulin assembly (IC50 < 5 µM), and three of these compounds (31, 35, 36) were strongly cytotoxic against the three cancer cell lines. The most active compound (36) in this series, which incorporated a methoxy group at position-7, was comparable in terms of inhibition of tubulin assembly and cytotoxicity to the lead compound OXi8006.
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DOI：
10.1093/jnci/83.11.757
发表时间：
1991-06-05
期刊：
JOURNAL OF THE NATIONAL CANCER INSTITUTE
影响因子：
--
作者：
MONKS, A;SCUDIERO, D;BOYD, M
通讯作者：
BOYD, M
DOI：
10.1016/0304-4165(81)90231-2
发表时间：
1981-01-01
期刊：
BIOCHIMICA ET BIOPHYSICA ACTA
影响因子：
--
作者：
HAMEL, E;LIN, CM
通讯作者：
LIN, CM
影响因子：
2.7
作者：
Hall, John J.;Sriram, Madhavi;Pinney, Kevin G.
通讯作者：
Pinney, Kevin G.
影响因子：
2.3
作者：
ELZAYAT, AAE;DEGEN, D;VONHOFF, DD
通讯作者：
VONHOFF, DD
DOI：
10.1007/978-1-4419-6609-4_1
发表时间：
2010-01-01
期刊：
VASCULAR DISRUPTIVE AGENTS FOR THE TREATMENT OF CANCER
影响因子：
--
作者：
Dougherty, Graeme J.;Chaplin, David J.
通讯作者：
Chaplin, David J.