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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Abstract

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.

About the authors

Yu. V. Sherstyuk

Institute of Chemical Biology and Fundamental Medicine

Email: abramova@niboch.nsc.ru
Russian Federation, Novosibirsk, 630090

A. L. Zakharenko

Institute of Chemical Biology and Fundamental Medicine

Email: abramova@niboch.nsc.ru
Russian Federation, Novosibirsk, 630090

M. M. Kutuzov

Institute of Chemical Biology and Fundamental Medicine

Email: abramova@niboch.nsc.ru
Russian Federation, Novosibirsk, 630090

M. V. Sukhanova

Institute of Chemical Biology and Fundamental Medicine; Novosibirsk State University

Email: abramova@niboch.nsc.ru
Russian Federation, Novosibirsk, 630090; Novosibirsk, 630090

O. I. Lavrik

Institute of Chemical Biology and Fundamental Medicine; Novosibirsk State University

Email: abramova@niboch.nsc.ru
Russian Federation, Novosibirsk, 630090; Novosibirsk, 630090

V. N. Silnikov

Institute of Chemical Biology and Fundamental Medicine

Email: abramova@niboch.nsc.ru
Russian Federation, Novosibirsk, 630090

T. V. Abramova

Institute of Chemical Biology and Fundamental Medicine

Author for correspondence.
Email: abramova@niboch.nsc.ru
Russian Federation, Novosibirsk, 630090

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