GMP Synthetase: Synthesis and Biological Evaluation of a Stable Analog of the Proposed AMP-XMP Reaction Intermediate

Edward J. Salaski; Hans Maag

doi:10.1055/s-1999-3104

Synlett 1999; 1999(S1): 897-900
DOI: 10.1055/s-1999-3104

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GMP Synthetase: Synthesis and Biological Evaluation of a Stable Analog of the Proposed AMP-XMP Reaction Intermediate

Edward J. Salaski^* , Hans Maag

^*Division of Bio-Organic Chemistry, Institute of Organic Chemistry, Syntex Discovery Research, 3401 Hillview Avenue, Palo Alto, CA 94304, USA; Fax +1(6 50)3 54 24 42; E-mail: hans.maag@roche.com

Abstract

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The enzyme guanosine monophosphate synthetase is part of the de novo purine synthesis pathway and is responsible for the conversion of xanthosine monophosphate to guanosine monophosphate. The phosphate-linked adenyl-XMP 1 has been proposed as the intermediate in a stepwise mechanism for this conversion. Direct observation of 1; either as produced in the enzymatic reaction, or as a potential synthetic target is not readily feasible due to the high lability of the phosphate linkage. We therefore undertook the synthesis of the phosphonate 2 as a stable analog of this proposed intermediate. The successful synthetic strategy involved the coupling under Mitsunobu conditions of a 2-phosphorylmethyl inosine with an adenosine derivative. This gave 2 after deprotection and 5′ monophosphate formation of the initial coupling product. Compound 2 inhibited GMP synthetase with a K_i of 0.56 μM.

GMP synthetase - AMP-XMP intermediate - phosphorylation

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