title: Synthesis and biological evaluation of isoindoloisoquinolinone, pyroloisoquinolinone and benzoquinazolinone derivatives as poly(ADP-ribose) polymerase-1 inhibitors.
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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Pondicherry University, Puducherry 605 014, India.
authors.forename: Arumugam
authors.initials: A
authors.lastname: Suyavaran
authors.affiliation: Department of Biochemistry and Molecular Biology, Pondicherry University, Puducherry 605 014, India.
authors.forename: Chitteti
authors.initials: C
authors.lastname: Ramamurthy
authors.affiliation: Department of Biochemistry and Molecular Biology, Pondicherry University, Puducherry 605 014, India.
authors.forename: Ramachandran
authors.initials: R
authors.lastname: Mareeswaran
authors.affiliation: Department of Biochemistry and Molecular Biology, Pondicherry University, Puducherry 605 014, India.
authors.forename: Yagna Viswa
authors.initials: YV
authors.lastname: Shanthi
authors.affiliation: Department of Chemistry, Pondicherry University, Puducherry 605 014, India.
authors.forename: Jayaraman
authors.initials: J
authors.lastname: Selvakumar
authors.affiliation: Department of Chemistry, Pondicherry University, Puducherry 605 014, India.
authors.forename: Selvaraj
authors.initials: S
authors.lastname: Mangalaraj
authors.affiliation: Centre for Advance Studies in Bioinformatics, School of Life Sciences, Pondicherry University, Puducherry 605 014, India.
authors.forename: Muthuvel Suresh
authors.initials: MS
authors.lastname: Kumar
authors.affiliation: Department of Chemistry, Pondicherry University, Puducherry 605 014, India. Electronic address: crrnath.che@pondiuni.edu.in.
authors.forename: Chinnasamy Ramaraj
authors.initials: CR
authors.lastname: Ramanathan
authors.affiliation: Department of Biochemistry and Molecular Biology, Pondicherry University, Puducherry 605 014, India. Electronic address: tchinnasamy@hotmail.com.
authors.forename: Chinnasamy
authors.initials: C
authors.lastname: Thirunavukkarasu
mesh_terms: D000818:Animals; D002645:Chickens; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D007546:Isoquinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000737:chemistry; D011485:Protein Binding; D011487:Protein Conformation; D052999:Quinazolinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D007211:Indoles; D007546:Isoquinolines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D052999:Quinazolinones; D011065:Poly(ADP-ribose) Polymerases
keywords: DNA damage; Inflammation; Isoquinolinones; Oxidative stress; PARP-1