Chloroethylating and methylating dual function antineoplastic agents display superior cytotoxicity against repair proficient tumor cells

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:23

Article

Baumann, Raymond P.¹ 

[1] Yale Univ, Sch Med, Dept Pharmacol, Yale Comprehens Canc Ctr, New Haven, CT 06520 USA

关键词: Chloroethylating;    O-6-Alkylguanine-DNA alkyltransferase;    1,2-Bis(sulfonyl)hydrazines;    Methylating;    Laromustine;    Dual function;    MGMT;    AGT;   

DOI  :  10.1016/j.bmcl.2013.01.016

来源: Elsevier

【 摘 要 】

Two new agents based upon the structure of the clinically active prodrug laromustine were synthesized. These agents, 2-(2-chloroethyl)-N-methyl-1,2-bis(methylsulfonyl)-N-nitrosohydrazinecarboxamide (1) and N-(2-chloroethyl)-2-methyl-1,2-bis(methylsulfonyl)-N-nitrosohydrazinecarboxamide (2), were designed to retain the potent chloroethylating and DNA cross-linking functions of laromustine, and gain the ability to methylate DNA at the O-6 position of guanine, while lacking the carbamoylating activity of laromustine. The methylating arm was introduced with the intent of depleting the DNA repair protein O-6-alkylguanine-DNA alkyltransferase (AGT). Compound 1 is markedly more cytotoxic than laromustine in both AGT minus EMT6 mouse mammary carcinoma cells and high AGT expressing DU145 human prostate carcinoma cells. DNA cross-linking studies indicated that its cross-linking efficiency is nearly identical to its predicted active decomposition product, 1,2-bis(methylsulfonyl)-1-(2-chloroethyl) hydrazine (90CE), which is also produced by laromustine. AGT ablation studies in DU145 cells demonstrated that 1 can efficiently deplete AGT. Studies assaying methanol and 2-chloroethanol production as a consequence of the methylation and chloroethylation of water by 1 and 2 confirmed their ability to function as methylating and chloroethylating agents and provided insights into the superior activity of 1. (C) 2013 Elsevier Ltd. All rights reserved.

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