Effective Synthesis of 5-Iodo Derivatives of Pyrimidine Morpholino Nucleosides

Vohtancev, Ivan P.; Sherstyuk, Yuliya V.; Silnikov, Vladimir N.; Abramova, Tatyana V.

doi:10.1080/00304948.2018.1462063

Cited by 5 publications

(2 citation statements)

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“…In this way, 2 -aminomethylmorpholino nucleosides 7 were obtained in a nearly quantitative yield by "step-by-step" approach. It should be noted that under reducing the 2 -azidmethylmorpholino nucleosides containing 5-halo-substituited uracil 6IU, BrU, ClU by both Pd/C-catalyzed hydrogenation and Ph 3 P/pyridine, we did not observe any dehalogenation of the heterocyclic base [52].…”

Section: Synthesis Of Adp Conjugates Containing Phosphoramide (P-n) Bondmentioning

confidence: 62%

“…The standard protocol for nucleosides with natural heterocyclic bases was Summerton's procedure [51]. Recently we have published a detailed protocol for the synthesis of 5-iodopyrimidine morpholino nucleosides based on this method [52]. Continuing our research, we have succeeded in obtaining N-Tr-protected morpholino nucleosides 2 from acyl-N-base-protected (when necessary) ribonucleosides 1 without chromatographic purification in an overall yield of 60%-70%.…”

Section: Methodsmentioning

confidence: 92%

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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

Sherstyuk

Ivanisenko

Zakharenko

et al. 2019

IJMS

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We report on the design, synthesis and molecular modeling study of conjugates of adenosine diphosphate (ADP) and morpholino nucleosides as potential selective inhibitors of poly(ADP-ribose)polymerases-1, 2 and 3. Sixteen dinucleoside pyrophosphates containing natural heterocyclic bases as well as 5-haloganeted pyrimidines, and mimicking a main substrate of these enzymes, nicotinamide adenine dinucleotide (NAD+)-molecule, have been synthesized in a high yield. Morpholino nucleosides have been tethered to the β-phosphate of ADP via a phosphoester or phosphoramide bond. Screening of the inhibiting properties of these derivatives on the autopoly(ADP-ribosyl)ation of PARP-1 and PARP-2 has shown that the effect depends upon the type of nucleobase as well as on the linkage between ADP and morpholino nucleoside. The 5-iodination of uracil and the introduction of the P–N bond in NAD+-mimetics have shown to increase inhibition properties. Structural modeling suggested that the P–N bond can stabilize the pyrophosphate group in active conformation due to the formation of an intramolecular hydrogen bond. The most active NAD+ analog against PARP-1 contained 5-iodouracil 2ʹ-aminomethylmorpholino nucleoside with IC50 126 ± 6 μM, while in the case of PARP-2 it was adenine 2ʹ-aminomethylmorpholino nucleoside (IC50 63 ± 10 μM). In silico analysis revealed that thymine and uracil-based NAD+ analogs were recognized as the NAD+-analog that targets the nicotinamide binding site. On the contrary, the adenine 2ʹ-aminomethylmorpholino nucleoside-based NAD+ analogs were predicted to identify as PAR-analogs that target the acceptor binding site of PARP-2, representing a novel molecular mechanism for selective PARP inhibition. This discovery opens a new avenue for the rational design of PARP-1/2 specific inhibitors.

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Section: Synthesis Of Adp Conjugates Containing Phosphoramide (P-n) Bondmentioning

confidence: 62%

Section: Methodsmentioning

confidence: 92%