A versatile strategy for the design and synthesis of novel ADP conjugates and their evaluation as potential poly(ADP-ribose) polymerase 1 inhibitors

Abstract

A versatile strategy for the synthesis of [Formula: see text] mimetics was developed, involving an efficient pyrophosphate linkage formation in key conjugates containing a functional amino group which acts as useful reactive anchor for further derivatization. These [Formula: see text] mimetics consist of ADP conjugated through a diphosphate chain to an extended aliphatic linker bearing an aromatic acid residue. A number of conjugates containing aromatic carboxylic acids were found to inhibit poly(ADP-ribose) synthesis catalyzed by poly(ADP-ribose) polymerase-1 (PARP-1). A new class of potential PARP-1 inhibitors mimicking [Formula: see text], a substrate in the PARP-1 catalyzed reaction, was proposed.

Design, Synthesis and Molecular Modeling Study of Conjugates of ADP and Morpholino Nucleosides as A Novel Class of Inhibitors of PARP-1, PARP-2 and PARP-3

“…To prepare ADP conjugates 4, we activated a phosphate group in derivatives 3 by Ph 3 P/(PyS) 2 in a presence of MeIm in dry 1,3-dimethyl-2-imidazolidinone (DMI) at room temperature for 15-20 min according to [44]. Further coupling of phosphoro(N-methyl)imidazolidate of morpholino nucleoside with AMP was carried out in situ in dry DMI for 1 h. After chromatographic purification and deblocation procedures, we obtained target conjugates 4 in an overall yield of 70%-80% (Scheme 1).…”

“…Recently we have proposed a versatile method for the synthesis of ADP conjugates functionalized at the terminal phosphate [44,45]. In that study, we developed an effective protocol for the coupling of two monoester phosphate derivatives under the action of the redox coupling pair triphenylphosphine/2,2 -dipyridyldisulfide (Ph 3 P/(PyS) 2 ) in the presence of 1-methylimidazole (MeIm).…”

“…These were found to inhibit NAD kinase [41], bacterial DNA ligases [42] and CD38 NAD glycohydrolase [43]. Recently, we have developed a number of NAD+ mimetics presented by conjugates of ADP and nicotinamide riboside analogs [44,45].…”

Novel group of tyrosyl-DNA-phosphodiesterase 1 inhibitors based on disaccharide nucleosides as drug prototypes for anti-cancer therapy

“…Recently it was shown, that some pyrimidine disaccharide derivatives inhibit poly(ADP-ribose)polymerase-1 (PARP-1), a key enzyme of DNA repair 28 , 29 . Moreover, in the studies 30 , 31 series of nicotinamide adenine dinucleotide (NAD + ) mimetics, which comprise morpholino analogues of nucleosides were synthetised to inhibit PARP-1 enzyme. Here we describe a series of disaccharide nucleosides as a novel class of tyrosyl-DNA phosphodiesterase 1 (TDP1) inhibitors.…”

Structural modeling of NAD+ binding modes to PARP-1

“…Такие ингибиторы связываются с сайтом посадки никотинамида и внешней стороной донорного сайта, осуществляя конкурентное ингибирование взаимодействия НАД+ с этим сайтом (Basu et al, 2012). Другим подходом к созданию искусственных низкомолекулярных ингибиторов ПАРП-1 является дизайн малых молекул на основе производных природных соединений, таких как НАД+ (Sherstyuk et al, 2016). В частности, перспективным подходом может являться дизайн нового класса ингибиторов ПАРП-1, способных дополнительно с никотинамид-связывающим сайтом занимать фосфат-и аденин-рибоза-связывающие сайты.…”