Springer C J, Antoniw P, Bagshawe K D, Searle F, Bisset G M, Jarman M
Department of Medical Oncology, Charing Cross Hospital, London, England.
J Med Chem. 1990 Feb;33(2):677-81. doi: 10.1021/jm00164a034.
The synthesis of three novel prodrugs, 4-[bis[2-(mesyloxy)ethyl]amino]benzoyl-L-glutamic acid (7), 4-[(2-chloroethyl)[2-(mesyloxy)ethyl]amino]benzoyl-L-glutamic acid (8), and 4-[bis(2-chloroethyl)amino]benzoyl-L-glutamic acid (9), for use as anticancer agents, is described here. Each is a bifunctional alkylating agent in which the activating effect of the ionized carboxyl function is masked through an amide bond to the glutamic acid residue. These relatively inactive prodrugs are designed to be activated to their corresponding nitrogen alkylating agents (10, 11, and 12, respectively) at a tumor site by prior administration of a monoclonal antibody conjugated to the bacterial enzyme carboxypeptidase G2 (CPG2). The viability of two different tumor cell lines was monitored with each prodrug in the presence of CPG2. All three compounds showed substantial prodrug activity--with conversion to the corresponding active drug leading to greatly increased cytotoxicity.
本文描述了三种新型前药4-[双[2-(甲磺酰氧基)乙基]氨基]苯甲酰-L-谷氨酸(7)、4-[(2-氯乙基)[2-(甲磺酰氧基)乙基]氨基]苯甲酰-L-谷氨酸(8)和4-[双(2-氯乙基)氨基]苯甲酰-L-谷氨酸(9)的合成，它们用作抗癌剂。每一种都是双功能烷基化剂，其中离子化羧基功能的活化作用通过与谷氨酸残基的酰胺键被掩盖。这些相对无活性的前药被设计成通过预先给予与细菌酶羧肽酶G2(CPG2)偶联的单克隆抗体，在肿瘤部位被活化成它们相应的氮烷基化剂(分别为10、11和12)。在CPG2存在的情况下，用每种前药监测两种不同肿瘤细胞系的活力。所有三种化合物都显示出显著的前药活性——转化为相应的活性药物导致细胞毒性大大增加。
