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

Ashwini Sadanand Ranade, Joseph R. Bertino, Longqin Hu

Research output: Contribution to journalArticlepeer-review

Abstract

5′-Methylthioadenosine (MTA) is a natural substrate of MTA phosphorylase (MTAP) and is converted to adenine via a salvage pathway for AMP production in normal healthy cells. The lack of MTAP expression in many solid tumors and hematologic malignancies compared to normal healthy cells has been explored in a potential therapeutic strategy to selectively target tumor cells using antimetabolites such as 5-fluorouracil (5-FU) and 6-thioguanine (6-TG) while protecting normal healthy cells with MTA. Herein, a series of carbamate prodrugs, namely the N-(alkyloxy)carbonyl-MTA derivatives 2a-f, was designed, synthesized, and evaluated as potential prodrugs of MTA. All carbamate prodrugs were stable in phosphate buffer, pH 7.4 at 37 °C. In the presence of mouse liver microsomes, the prodrugs were converted to MTA at varying rates with the hexyl and butyl carbamates 2a and 2b most readily activated (t1/2 of 1.2 and 9.4 h, respectively). The activation was shown to be mediated by carboxyesterases present in mouse liver microsomes. [Figure not available: see fulltext.].

Original languageEnglish (US)
Pages (from-to)1358-1365
Number of pages8
JournalMedicinal Chemistry Research
Volume30
Issue number7
DOIs
StatePublished - Jul 2021

All Science Journal Classification (ASJC) codes

  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Organic Chemistry

Keywords

  • 5′-Methylthioadenosine (MTA)
  • Antimetabolite
  • Carbamate prodrugs
  • Carboxyesterase
  • N-(alkyloxy)carbonyl-MTA

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