Novel nucleotide analogues bearing (1H-1,2,3-triazol-4-yl)phosphonic acid moiety as inhibitors of Plasmodium and human 6-oxopurine phosphoribosyltransferases

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• 作者：Milo&scaron ; Luká ; č^a ; ¹ ; Dana Hocková ; ^a ; Dianne T. Keough^b ; Luke W. Guddat^b ; Zlatko Janeba^a ; ^{janeba@uochb.cas.cz}
• 关键词：Acyclic nucleoside phosphonates ; 6-oxopurine ; Hypoxanthine-guanine-(xanthine) phosphoribosyltransferase ; Copper(I)-catalyzed azide-alkyne cycloaddition
• 刊名：Tetrahedron
• 出版年：2017
• 出版时间：9 February 2017
• 年：2017
• 卷：73
• 期：6
• 页码：692-702
• 全文大小：618 K
• 卷排序：73

文摘

A novel family of acyclic nucleoside phosphonates (ANPs) bearing a (1H-1,2,3-triazol-4-yl)phosphonic acid group in the acyclic side chain have been prepared in order to study the influence of the hetaryl rigidizing element on the biological properties of such compounds. The key synthetic step consisted of a copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) between diethyl ethynylphosphonate and the corresponding azidoalkyl precursor. Two ANPs in this family, bearing a guanine base, exhibited the highest potency for the human 6-oxopurine phosphoribosyltransferase irrespective of the stereochemistry on the C-2′ atom. Four compounds inhibited Plasmodium falciparum 6-oxopurine phosphoribosyltransferase with little differences in their Ki values irrespective of whether the base was guanine, hypoxanthine or xanthine but only two, with guanine as base, inhibited PvHGPRT.