Dowell R I, Springer C J, Davies D H, Hadley E M, Burke P J, Boyle F T, Melton R G, Connors T A, Blakey D C, Mauger A B
Cancer Research Department, Zeneca Pharmaceutical, Cheshire, U.K.
J Med Chem. 1996 Mar 1;39(5):1100-5. doi: 10.1021/jm950671l.
Antibody-directed enzyme prodrug therapy (ADEPT) is a two-step approach for the treatment of cancer which seeks to generate a potent cytotoxic agent selectively at a tumor site. In this work described the cytotoxic agent is generated by the action of an enzyme CPG2 on a relatively nontoxic prodrug. The prodrug 1 currently on clinical trial is a benzamide and is cleaved by CPG2 to a benzoic acid mustard drug 1a. We have synthesized a series of new prodrugs 3-8 where the benzamide link has been replaced by, for example, carbamate or ureido. Some of these alternative links have been shown to be good substrates for CPG2 and therefore new candidates for ADEPT. The active drugs 3a and 4a derived from the best of these prodrugs are potent cytotoxic agents (1-2 microM) some 100 times more than 1a. The prodrugs 3 and 4 are some 100-200-fold less cytotoxic, in a proliferating cell assay, than their corresponding active drugs 3a and 4a.
抗体导向酶前药疗法（ADEPT）是一种治疗癌症的两步法，旨在在肿瘤部位选择性地产生一种强效细胞毒性剂。在这项所述的研究中，细胞毒性剂是由酶CPG2作用于一种相对无毒的前药产生的。目前正在临床试验的前药1是一种苯甲酰胺，被CPG2切割成苯甲酸芥子气药物1a。我们合成了一系列新的前药3 - 8，其中苯甲酰胺连接键已被例如氨基甲酸酯或脲基取代。这些替代连接键中的一些已被证明是CPG2的良好底物，因此是ADEPT的新候选物。从这些最佳前药衍生而来的活性药物3a和4a是强效细胞毒性剂（1 - 2 microM），比1a强约100倍。在前体细胞试验中，前药3和4的细胞毒性比其相应的活性药物3a和4a低约100 - 200倍。
