Novel combretastatin analogues effective against murine solid tumors: Design and structure-activity relationships
Novel combretastatin analogues effective against murine solid tumors: Design and structure-activity relationships
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DOI：
10.1021/jm980101w
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发表时间：
1998-07-30
影响因子：
7.3
通讯作者：
Tsuji, T
中科院分区：
文献类型：
--
作者：
Ohsumi, K;Nakagawa, R;Tsuji, T
合成了一系列考布他汀A-4（CA-4）类似物，并评价了它们对小鼠结肠26腺癌的细胞毒作用和对微管蛋白聚合的抑制作用。由于CA-4具有有限的水溶性，因此目标化合物被设计为通过引入含氮基团来改善溶解度。在合成的化合物中，那些用氨基取代CA-4的酚羟基的化合物在体外对小鼠结肠26腺癌显示出有效的抗微管蛋白活性和细胞毒性。在小鼠肿瘤模型Colon 26中在体内评价了一些在体外有效的化合物。其中，13 bHCl、21 aHCl和21 bHCl在动物模型中显示出显著的抗肿瘤活性，而CA-4无效。在两种鼠肿瘤模型（结肠38和3LL）和人异种移植物HCT-15中进一步评价了13 bHCl和21 aHCl。这些化合物显示出与CDDP相当或上级的有效抗肿瘤活性。并对该类化合物的构效关系进行了讨论。
A series of combretastatin A-4 (CA-4) analogues were synthesized, and their cytotoxic effects against murine Colon 26 adenocarcinoma and inhibitory activity on tubulin polymerization were evaluated. Since CA-4 has limited aqueous solubility, the target compounds were designed to improve solubility by introduction of a nitrogen-containing group. Among the compounds synthesized, those with an amino moiety in place of the phenolic OH of CA-4 showed potent antitubulin activity and cytotoxicity against murine Colon 26 adenocarcinoma in vitro. Some of the compounds which were potent in vitro were evaluated in the murine tumor model Colon 26 in vivo. Among these, 13bHCl, 21aHCl, and 21bHCl showed significant antitumor activity in the animal model, while CA-4 was ineffective. 13bHCl and 21aHCl were further evaluated in two murine tumor models (Colon 38 and 3LL) and human xenografts HCT-15. These compounds showed potent antitumor activity comparable or superior to that of CDDP. The structure-activity relationships of this series of compounds are also discussed.