Three-component Castagnoli-Cushman reaction with ammonium acetate delivers 2-unsubstituted isoquinol-1-ones as potent inhibitors of poly(ADP-ribose) polymerase (PARP)

Alexander Safrygin; Petr Zhmurov; Dmitry Dar'in; Sergey Silonov; Mariia Kasatkina; Yulia Zonis; Maxim Gureev; Mikhail Krasavin

doi:10.1080/14756366.2021.1969386

Three-component Castagnoli-Cushman reaction with ammonium acetate delivers 2-unsubstituted isoquinol-1-ones as potent inhibitors of poly(ADP-ribose) polymerase (PARP)

J Enzyme Inhib Med Chem. 2021 Dec;36(1):1916-1921. doi: 10.1080/14756366.2021.1969386.

Authors

Alexander Safrygin¹, Petr Zhmurov¹, Dmitry Dar'in¹, Sergey Silonov², Mariia Kasatkina², Yulia Zonis², Maxim Gureev³, Mikhail Krasavin¹

Affiliations

¹ Chemistry, Saint Petersburg State University, Saint Petersburg, Russia.
² JSC BIOCAD, Saint Petersburg, Russia.
³ Digital Biodesign and Personalized Healthcare Research Center, Sechenov First Moscow State Medical University, Moscow, Russia.

Abstract

An earlier described three-component variant of the Castagnoli-Cushman reaction employing homophthalic anhydrides, carbonyl compound and ammonium acetate was applied towards the preparation of 1-oxo-3,4-dihydroisoquinoline-4-carboxamides with variable substituent in position 3. These compounds displayed inhibitory activity towards poly(ADP-ribose) polymerase (PARP), a clinically validated cancer target. The most potent compound (PARP1/2 IC₅₀ = 22/4.0 nM) displayed the highest selectivity towards PARP2 in the series (selectivity index = 5.5), more advantageous ADME prameters compared to the clinically used PARP inhibitor Olaparib.

Keywords: 1-oxo-3,4-dihydroisoquinoline-4-carboxamides; Castagnoli-Cushman reaction; NAD+ mimetics; PARP1/2 selectivity; druglikeness; poly(ADP-ribose) polymerase.

MeSH terms

Acetates / chemistry*
Acetates / pharmacology
Amino Acid Sequence
Antineoplastic Agents / chemistry*
Antineoplastic Agents / pharmacology
Binding Sites
DNA Damage / drug effects
Drug Screening Assays, Antitumor
Humans
NAD / metabolism
Phthalazines / pharmacology
Piperazines / pharmacology
Poly(ADP-ribose) Polymerase Inhibitors / chemistry*
Poly(ADP-ribose) Polymerase Inhibitors / pharmacology
Poly(ADP-ribose) Polymerases / metabolism*
Protein Binding
Protein Conformation
Quinolones / chemistry*
Structure-Activity Relationship

Substances

Acetates
Antineoplastic Agents
Phthalazines
Piperazines
Poly(ADP-ribose) Polymerase Inhibitors
Quinolones
NAD
Poly(ADP-ribose) Polymerases
ammonium acetate
olaparib

Grants and funding

This research was supported by the Russian Foundation for Basic Research [grant 21–53-12001]. Maxim Gureev acknowledges the funding from the Ministry of Science and Higher Education of the Russian Federation [grant 075–15-2020–926].