Synthesis Of A Novel Prodrug For ADEPT And Its Cytotoxic Evaluation

Antibody directed enzyme prodrug therapy (ADEPT) uses the specificity of antibody-antigen and enzyme-substrate to selectively kill tumor cells. The enzyme for ADEPT should be nonimmunogenic and efficient. The prodrug for ADEPT should has low toxicity, the required characteristic of a high rate of being turned over by related enzyme, and a linear dose-related cell kill. Thus, according to the specificity of a mutation β-lactamase with low immunogenicity to its substrate, we linked an alkylating agent-melphalan with cephalosporins which is a good substrate for β-lactamase to synthesize the target compound-cephalosporin melphalan, and evaluated its antitumor activity.We chose GCLE as a raw material, which was converted to GIE by iodination, then GIE coupled with esterified melphalan, and then the conjugate was oxidated and hydrolysised to synthesize cephalosporin melphalan. The structure of target compound was identified by1H NMR and mass spectrometry. Its anti-tumor activity in vitro was evaluated by the MTT method. We determinated the inhibition rate (%) and IC50(μmol/l) of prodrug and original drug in the setting range of concentration. It showed that:The group of single prodrug does not exist significant differences with the blank group; The prodrug is non-toxic in vitro; Both the activated prodrug and melphalan can significantly kill the tumor cells; Their IC50was101.97±1.70μmol/1and66.69±0.37umol/1; The activated prodrug kills tumor cells in a dose-dependent manner. Therefore, cephalosporin melphalan has a similar cytotoxicity with melphalan, and has the advantage of targeting, is a promising candidate for cancer treatment.