TY - JOUR

T1 - 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

AU - Sherstyuk, Yuliya V.

AU - Ivanisenko, Nikita V.

AU - Zakharenko, Alexandra L.

AU - Sukhanova, Maria V.

AU - Peshkov, Roman Y.

AU - Eltsov, Ilia V.

AU - Kutuzov, Mikhail M.

AU - Kurgina, Tatjana A.

AU - Belousova, Ekaterina A.

AU - Ivanisenko, Vladimir A.

AU - Lavrik, Olga I.

AU - Silnikov, Vladimir N.

AU - Abramova, Tatyana V.

N1 - Publisher Copyright: © 2019 by the authors. Licensee MDPI, Basel, Switzerland.

PY - 2020/1/1

Y1 - 2020/1/1

N2 - 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.

AB - 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.

KW - DNA repair

KW - molecular modeling

KW - morpholino nucleosides

KW - NAD+ analogs

KW - PARP

KW - Molecular modeling

KW - Morpholino nucleosides

KW - POLY(ADP-RIBOSE) POLYMERASE

KW - ANALOGS

KW - NICOTINAMIDE

KW - POTENT INHIBITORS

KW - CANCER

KW - DISCOVERY

KW - RIBOSYLATION

KW - NAD

KW - TALAZOPARIB

KW - NAD plus analogs

KW - DERIVATIVES

UR - http://www.scopus.com/inward/record.url?scp=85077468511&partnerID=8YFLogxK

U2 - 10.3390/ijms21010214

DO - 10.3390/ijms21010214

M3 - Article

C2 - 31892271

AN - SCOPUS:85077468511

VL - 21

JO - International Journal of Molecular Sciences

JF - International Journal of Molecular Sciences

SN - 1661-6596

IS - 1

M1 - 214

ER -