The synthesis of 7-deazaguanines as potential inhibitors of guanosine triphosphate cyclohydrolase 1

C.L. Gibson, S. La Rosa, K. Ohta, P.H. Boyle, F. Leurquin, A. Lemaçon, C.J. Suckling

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Abstract

Variously substituted 7-deazaguanines are of interest as inhibitors of GTP cyclohydrolase I, the first enzyme in the biosynthetic pathway leading to dihydrofolate and tetrahydrobiopterin. Methods are described for the synthesis of 7-deazaguanines substituted at positions 2, 6 and 9 (purine numbering) such that a wide diversity of compounds can be prepared. These methods supplement our previous work that established routes for the synthesis of 7- and 8-substituted 7-deazaguanines. Emphasis is placed on the properties of 2-thioalkyl pyrimidines as intermediates because they provide the basis for a traceless solid-state synthesis of purines, pteridines, and their analogues. Compounds prepared have been assessed in a primary screen for their ability to inhibit GTPCH I and 8-methyldeazaguanine has been shown to be significantly more potent than any inhibitor yet described. Several compounds appeared to undergo transformation by GTPCH I; with the aid of a model reaction, their behaviour can be interpreted in the context of the mechanism of the hydrolytic phase of GTPCH I.
Original languageEnglish
Pages (from-to)943-959
Number of pages16
JournalTetrahedron
Volume60
Issue number4
DOIs
Publication statusPublished - 19 Jan 2004

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Keywords

  • Purine analogues
  • Synthesis
  • Deazaguanines
  • GTP cyclohydrolase 1
  • Inhibition
  • Mechanism

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