Synthesis and biological evaluation of isoindoloisoquinolinone, pyroloisoquinolinone and benzoquinazolinone derivatives as poly(ADP-ribose) polymerase-1 inhibitors

Arumugam Suyavaran; Chitteti Ramamurthy; Ramachandran Mareeswaran; Yagna Viswa Shanthi; Jayaraman Selvakumar; Selvaraj Mangalaraj; Muthuvel Suresh Kumar; Chinnasamy Ramaraj Ramanathan; Chinnasamy Thirunavukkarasu

doi:10.1016/j.bmc.2014.12.017

Synthesis and biological evaluation of isoindoloisoquinolinone, pyroloisoquinolinone and benzoquinazolinone derivatives as poly(ADP-ribose) polymerase-1 inhibitors

Bioorg Med Chem. 2015 Feb 1;23(3):488-98. doi: 10.1016/j.bmc.2014.12.017. Epub 2014 Dec 19.

Authors

Arumugam Suyavaran¹, Chitteti Ramamurthy¹, Ramachandran Mareeswaran¹, Yagna Viswa Shanthi¹, Jayaraman Selvakumar², Selvaraj Mangalaraj², Muthuvel Suresh Kumar³, Chinnasamy Ramaraj Ramanathan⁴, Chinnasamy Thirunavukkarasu⁵

Affiliations

¹ Department of Biochemistry and Molecular Biology, Pondicherry University, Puducherry 605 014, India.
² Department of Chemistry, Pondicherry University, Puducherry 605 014, India.
³ Centre for Advance Studies in Bioinformatics, School of Life Sciences, Pondicherry University, Puducherry 605 014, India.
⁴ Department of Chemistry, Pondicherry University, Puducherry 605 014, India. Electronic address: crrnath.che@pondiuni.edu.in.
⁵ Department of Biochemistry and Molecular Biology, Pondicherry University, Puducherry 605 014, India. Electronic address: tchinnasamy@hotmail.com.

PMID: 25555733
DOI: 10.1016/j.bmc.2014.12.017

Abstract

A series of novel fused isoquinolinones with isoindoloisoquinolinone, pyroloisoquinolinone, and benzoquinalizinone skeletons were synthesized from corresponding phenethylimides. The isoquinolinone derivatives were evaluated for their protective effect on chicken erythrocytes subjected to oxidative damage. The effect of isoquinolinone derivatives were analysed by estimation of cell viability, antioxidant enzyme activities, DNA damage (comet assay), PARP-1 inhibition assay and molecular docking of the compounds with PARP-1 active site. The compounds CRR-271, CRR-288 and CRR-224+225 showed significant protective effect at 100 μM concentration. The PARP-1 inhibition assay revealed the IC50 values of CRR-271, CRR-288 and CRR-224+225 as <200 nM, further molecular docking studies shows higher binding energies with PARP-1 active site. Interesting findings in this study suggest that the novel isoquinolinone derivatives inhibit PARP-1 activity and protect cells against oxidative DNA damage, which could be implemented in the treatment of inflammatory diseases.

Keywords: DNA damage; Inflammation; Isoquinolinones; Oxidative stress; PARP-1.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Chickens
Drug Design
Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Indoles / chemical synthesis
Indoles / chemistry
Indoles / pharmacology
Isoquinolines / chemical synthesis
Isoquinolines / chemistry
Isoquinolines / pharmacology
Oxidative Stress / drug effects*
Poly(ADP-ribose) Polymerase Inhibitors*
Poly(ADP-ribose) Polymerases / chemistry
Protein Binding
Protein Conformation
Quinazolinones / chemical synthesis*
Quinazolinones / chemistry
Quinazolinones / pharmacology*
Structure-Activity Relationship

Substances

Enzyme Inhibitors
Indoles
Isoquinolines
Poly(ADP-ribose) Polymerase Inhibitors
Quinazolinones
Poly(ADP-ribose) Polymerases