Synthesis of a series of NAD⁺ analogues, potential inhibitors of PARP 1, using ADP conjugates functionalized at the terminal phosphate group

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• 作者：Yu. V. Sherstyuk ; A. L. Zakharenko…
• 关键词：morpholino nucleosides ; NAD+analogues ; methoxyoxalate precursors ; PARP 1 ; PARP inhibitors
• 刊名：Russian Journal of Bioorganic Chemistry
• 出版年：2017
• 出版时间：January 2017
• 年：2017
• 卷：43
• 期：1
• 页码：76-83
• 全文大小：
• 刊物类别：Biomedical and Life Sciences
• 刊物主题：Biochemistry, general; Bioorganic Chemistry; Organic Chemistry; Biomedicine general;
• 出版者：Pleiades Publishing
• ISSN：1608-330X
• 卷排序：43

文摘

A convenient approach has been proposed to the synthesis of nicotinamide adenine dinucleotide (NAD+) mimetics, which comprise morpholino analogues of nucleosides. The approach is based on the use of ADP conjugates containing an amino group, which is tethered to the terminal phosphate through the aliphatic linker by the phosphodiester bond. We have synthesized four series of the NAD+ mimetics, which differ in the type of the modified nucleoside (2-aminomethylmorpholine (Mor) or 2-aminomethyl-4-carboxymethylmorpholine (MorGly) derivatives), in the linker length, and in the manner of the nucleoside attachment to the ADP derivative. We have studied the efficiency of NAD+ mimetics in the inhibition of the auto-poly(ADP-ribosyl)ation by the PARP 1 enzyme. The linker length, the mode of the attachment of the morpholino nucleoside analogue, and the nature of the heterocyclic base of the modified nucleoside were shown to inf luence the inhibition efficiency.