title: Modification of 3-arylisoquinolines into 3,4-diarylisoquinolines and assessment of their cytotoxicity and topoisomerase inhibition.
abstract: Inspired by the initial success of the monoarylisoquinolines and the quest to identify more potent and selective anticancer agents with topoisomerase (topo) inhibitory activity, series of diarylisoquinolines (3,4-diarylisoquinolones and 3,4-diarylisoquinolinamines) were designed and synthesized. Synthesis of these compounds primarily involved lithiated toluamide-benzonitrile cycloaddition, Suzuki coupling, and nucleophilic aromatic substitution reactions. Eight of the derivatives were selectively toxic against human ductal breast epithelial tumor cells (T47D), human prostate cancer cells (DU145), and human colorectal adenocarcinoma cells (HCT-15), but had no effect on normal human breast epithelial cells (MCF10A). The topo inhibitory activities of the diarylisoquinoline compounds were relatively dependent upon their chemical structure. 3,4-Diarylisoquinolones generally did not inhibit topo I and only showed moderate inhibition of topo II. In contrast, several 3,4-diarylisoquinolinamines showed superior topo I inhibitory activity. Isoquinolinamine derivatives had greater affinity for topo I than for topo II. Topo inhibition by 3,4-diarylisoquinolines was further supported by docking models showing intercalative and/or H-bond interactions between these compounds and the DNA/topo(s). An analysis of the correlation between the cytotoxicity and topo inhibition of these compounds indicated that the primary biological target of derivatives with potent cytotoxicity was topo, which in turn establishes diaryl-substituted isoquinolines as a novel class of potential anticancer drugs.
authors.affiliation: College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju 500-757, Republic of Korea.
authors.forename: Daulat Bikram
authors.initials: DB
authors.lastname: Khadka
authors.affiliation: College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Global Top 5 Program, Ewha Womans University, Seoul 120-750, Republic of Korea.
authors.forename: Hyunjung
authors.initials: H
authors.lastname: Woo
authors.affiliation: College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju 500-757, Republic of Korea.
authors.forename: Su Hui
authors.initials: SH
authors.lastname: Yang
authors.affiliation: College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju 500-757, Republic of Korea.
authors.forename: Chao
authors.initials: C
authors.lastname: Zhao
authors.affiliation: College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju 500-757, Republic of Korea.
authors.forename: Yifeng
authors.initials: Y
authors.lastname: Jin
authors.affiliation: Center for Drug Research and Development, Institute of Marine Biochemistry, Vietnam Academy of Science and Technology, 18-Hoang Quoc Viet, Caugiay, Hanoi, Vietnam.
authors.forename: Thanh Nguyen
authors.initials: TN
authors.lastname: Le
authors.affiliation: College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Global Top 5 Program, Ewha Womans University, Seoul 120-750, Republic of Korea. Electronic address: ykwon@ewha.ac.kr.
authors.forename: Youngjoo
authors.initials: Y
authors.lastname: Kwon
authors.affiliation: College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju 500-757, Republic of Korea. Electronic address: wjcho@chonnam.ac.kr.
authors.forename: Won-Jea
authors.initials: WJ
authors.lastname: Cho
mesh_terms: D045744:Cell Line, Tumor; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007546:Isoquinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D059004:Topoisomerase I Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D007546:Isoquinolines; D059004:Topoisomerase I Inhibitors; D004264:DNA Topoisomerases, Type I
keywords: 3,4-Diarylisoquinoline; Molecular docking; Selective cytotoxicity; Suzuki coupling; Topoisomerase