Novel prodrugs which are activated to cytotoxic alkylating agents by carboxypeptidase G2

• DOI: 10.1021/jm00164a034
• Publication Date: 2005-03-18T11:09:09Z
• Authors: Caroline J. Springer; Pari Antoniw; Bagshawe; Frances Searle; Graham M. F. Bisset; Michael Jarman
• Keywords: Carboxypeptidase A

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 (8), and 4-[bis(2-chloroethyl)amino]benzoyl-L-glutamic (9), for use as anticancer agents, is described here. Each a bifunctional alkylating agent in which the activating effect ionized carboxyl function masked through an amide bond to glutamic residue. These relatively inactive prodrugs are designed be activated their corresponding nitrogen agents (10, 11, 12, respectively) at tumor site by prior administration monoclonal antibody conjugated bacterial enzyme carboxypeptidase G2 (CPG2). viability two different cell lines was monitored with each prodrug presence CPG2. All compounds showed substantial activity--with conversion active drug leading greatly increased cytotoxicity.