Synthesis and antitumor activity of CBI-bearing ester and carbamate prodrugs of CC-1065 analogue.
Synthesis and antitumor activity of CBI-bearing ester and carbamate prodrugs of CC-1065 analogue.
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CC-1065 类似物的 CBI 酯和氨基甲酸酯前药的合成和抗肿瘤活性。
DOI：
10.1016/j.bmc.2006.07.062
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发表时间：
2006
影响因子：
3.5
通讯作者：
Larrick,JamesW
中科院分区：
文献类型：
--
作者：
Wang,Yuqiang;Li,Lianfa;Tian,Zhiming;Jiang,Wei;Larrick,JamesW
合成了带有CBI的CC-1065类似物的前药。在体外和小鼠肿瘤模型中评价化合物对肿瘤细胞的抗肿瘤活性。分别带有甲基哌嗪和DHA部分的化合物1和7在L1210白血病和刘易斯肺癌小鼠肿瘤模型中显示出显著的抗肿瘤活性。对于氨基甲酸酯前药1-4和6，药物在体外和动物肿瘤模型中的效力之间存在良好的相关性;然而，前药的抗肿瘤活性与连接游离药物的键的类型之间不存在相关性。在生理pH下可以或不能质子化的那些的抗肿瘤活性之间没有显著差异。与其他携带DHA部分的前药相比，各自携带DHA部分的化合物6和7没有显示出显著改善的抗肿瘤活性，这表明DHA可能不能普遍用于显著改善药物的抗肿瘤功效。
Prodrugs of a CBI-bearing CC-1065 analogue were synthesized. Antitumor activity of the compounds was evaluated against tumor cells in vitro and in mouse tumor models. Compounds 1 and 7, bearing methylpiperazine and DHA moieties, respectively, showed significant antitumor activity in both the L1210 leukemia and Lewis lung carcinoma mouse tumor models. For the carbamate prodrugs 1–4 and 6, there is a good correlation between the drug’s potency both in vitro and in animal tumor models; however, there is no correlation between the prodrug’s antitumor activity and the type of bonds linking the free drug. There are no significant differences between the antitumor activities of those that can or cannot be protonated at physiological pH. Compounds 6 and 7, each bearing a DHA moiety, did not show significantly improved antitumor activity compared to other prodrugs bearing DHA moieties, suggesting that DHA may not be used universally to significantly improve a drug’s antitumor efficacy.