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

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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.

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Abbreviations

AMP:

adenosine monophosphate

APRT:

adenine phosphoribosyltransferase

BNPP:

bis(4-nitrophenyl)-phosphate

5-FU:

5-fluorouracil

HLM:

human liver microsome

HPLC:

high performance liquid chromatography

IC 50 :

concentration required to produce 50% inhibition

LC-MS:

liquid chromatography-mass spectrometry

MLM:

mouse liver microsome

MTA:

5′-methylthioadenosine

MTAP:

MTA phosphorylase

NADPH:

nicotinamide adenine dinucleotide phosphate

PRPP:

phosphoribosyl-1-pyrophosphate

6-TG:

6-thioguanine

TLC:

thin layer chromatography

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Correspondence to Longqin Hu.

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Dedicated to Professor Gary Grunewald for his more than 50 years of dedicated service on the faculty of the Department of Medicinal Chemistry, University of Kansas School of Pharmacy.

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Ranade, A.S., Bertino, J.R. & Hu, L. Design, synthesis, and evaluation of potential carbamate prodrugs of 5′-methylthioadenosine (MTA). Med Chem Res 30, 1358–1365 (2021). https://doi.org/10.1007/s00044-021-02730-9

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  • DOI: https://doi.org/10.1007/s00044-021-02730-9

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