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Diversity oriented syntheses of fused pyrimidines designed as potential antifolates

Gibson, Colin L. and Huggan, J.K. and Kennedy, Alan and Kiefer, L. and Lee, Jeong Hwan and Suckling, C.J. and Clements, Caorl J. and Harvey, Alan L. and Hunter, William N. and Tulloch, Lindsay B. (2009) Diversity oriented syntheses of fused pyrimidines designed as potential antifolates. Organic and Biomolecular Chemistry, 7 (9). pp. 1829-1842. ISSN 1477-0520

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Abstract

Diversity oriented syntheses of some furo[2,3-d]pyrimidines and pyrrolo[2,3-d]pyrimidines related to folate, guanine, and diaminopyrimidine-containing drugs have been developed for the preparation of potential anti-infective and anticancer compounds. Amide couplings and Suzuki couplings on the basic heterocyclic templates were used, in the latter case yields being especially high using aromatic trifluoroborates as the coupling partner. A new ring synthesis of 6-aryl-substituted deazaguanines bearing 2-alkylthio groups has been developed using Michael addition of substituted nitrostyrenes. Diversity at C-2 has been introduced by oxidation and substitution with a range of amino nucleophiles. The chemical reactivity of these pyrrolopyrimidines with respect to both electrophilic substitution in ring synthesis and nucleophilic substitution for diversity is discussed. Several compounds were found to inhibit pteridine reductases from the protozoan parasites Trypanosoma brucei and Leishmania major at the micromolar level and to inhibit the growth of Trypanosma brucei brucei in cell culture at higher concentrations. From these results, significant structural features required for inhibition of this important drug target enzyme have been identified.