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

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...

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Bibliographic Details
Published in:Tetrahedron 2004-01, Vol.60 (4), p.943-959
Main Authors: Gibson, Colin L, La Rosa, Salvatore, Ohta, Kyuji, Boyle, Peter H, Leurquin, Fabien, Lemaçon, Alexandra, Suckling, Colin J
Format: Article
Language:English
Subjects:
Deazaguanines
GTP cyclohydrolase 1
Inhibition
Mechanism
Purine analogues
Synthesis
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Summary: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. 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. Several compounds show inhibitory activity with respect to GTP cyclohydrolase I, and some show evidence for chemical transformation by that enzyme.
ISSN:0040-4020
1464-5416
DOI:10.1016/j.tet.2003.11.030