Elucidation of the mechanism of selective inhibition of mammalian DNA polymerase alpha by 2-butylanilinopurines: development and characterization of 2-(p-n-butylanilino) adenine and its deoxyribonucleotides

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Abstract
2-(p-n-Butylailino)adenine (BuAA), an homolog of the DNA polyrmerase alpha (pol α)-specific inhibitor, N2-(p-n-butylphenyl) guanine (BuPG), was transformed to its 2′-deoxyribonucleoside, BuAdA, and the corresponding 2′-deoxyribonucleoside 5′-phosphates, BuAdAMP, BuAdADP, and BuAdATP. All five forms of BuAA are highly selective inhibitors of mammalian pol α, and the action of each is subject to specific competitive antagonism by dATP. BuAdADP, and BuAdATP, like the corresponding forms of BuPG, are very potent pol α inhibitors, displaying apparent Ki′s of less than 3 nanomolar on natural activated templates. BuAdATP, like BuPdGTP, also inhibits pol α-catalysed reactions directed by non-complementary, thymine-deficient templates, and it does so via a mechanism subject to specific antagonism by its natural homolog, dATP. The results of the BuAdATP-homopolymer experiments complement those of analogous experiments with BuPdGTP and the dCTP-specific pol α inhibitor, aphidicolin, and strengthen the suggestion that mammalian pol α contains dNDP and dNTP binding sites which can recognize specific bases without direction by templates.

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