Gibson, C.L. and La Rosa, S. and Ohta, K. and Boyle, P.H. and Leurquin, F. and Lemaçon, A. and Suckling, C.J. (2004) The synthesis of 7-deazaguanines as potential inhibitors of guanosine triphosphate cyclohydrolase 1. Tetrahedron, 60 (4). pp. 943-959. ISSN 0040-4020Full text not available in this repository. (Request a copy from the Strathclyde author)
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.
|Keywords:||Purine analogues, Synthesis, Deazaguanines, GTP cyclohydrolase 1, Inhibition, Mechanism, Chemistry, Biochemistry, Organic Chemistry, Drug Discovery|
|Subjects:||Science > Chemistry|
|Department:||Faculty of Science > Pure and Applied Chemistry
|Depositing user:||Allison Crawford|
|Date Deposited:||11 Apr 2006|
|Last modified:||29 Apr 2016 07:39|