Design, synthesis, and evaluation of potential carbamate prodrugs of 5′-methylthioadenosine (MTA)

5′-Methylthioadenosine (MTA) is a natural substrate of MTA phosphorylase (MTAP) and converted to adenine via salvage pathway for AMP production in normal healthy cells. The lack MTAP expression many solid tumors hematologic malignancies compared cells has been explored potential therapeutic strategy selectively target tumor using antimetabolites such as 5-fluorouracil (5-FU) 6-thioguanine (6-TG) while protecting with MTA. Herein, series carbamate prodrugs, namely the N-(alkyloxy)carbonyl-MTA derivatives 2a-f, was designed, synthesized, evaluated prodrugs All were stable phosphate buffer, pH 7.4 at 37 °C. In presence mouse liver microsomes, varying rates hexyl butyl carbamates 2a 2b most readily activated (t1/2 1.2 9.4 h, respectively). activation shown be mediated by carboxyesterases present microsomes.