Synlett 1999; 1999(S1): 897-900
DOI: 10.1055/s-1999-3104
letter
© Georg Thieme Verlag, Rüdigerstr. 14, 70469 Stuttgart, Germany. All rights reserved. This journal, including all individual contributions and illustrations published therein, is legally protected by copyright for the duration of the copyright period. Any use, exploitation or commercialization outside the narrow limits set by copyright legislation, without the publisher's consent, is illegal and liable to criminal prosecution. This applies in particular to photostat reproduction, copying, cyclostyling, mimeographing or duplication of any kind, translating, preparation of microfilms, and electronic data processing and storage.

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
Further Information

Publication History

Publication Date:
31 December 1999 (online)

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 Ki of 0.56 μM.