title: Design, synthesis and systematic evaluation of cytotoxic 3-heteroarylisoquinolinamines as topoisomerases inhibitors.
abstract: A series of 3-heteroarylisoquinolinamines were designed, synthesized and evaluated for cytotoxicity, topoisomerases (topos) inhibitory activities and cell cycle inhibition. Several of the 3-heteroarylisoquinolines exhibited selective cytotoxicity against human ductal breast epithelial tumor (T47D) cells over non-cancerous human breast epithelial (MCF-10A) and human prostate cancer (DU145) cells. Most of the derivatives showed greater cytotoxicity in human colorectal adenocarcinoma (HCT-15) cells than camptothecin (CPT), etoposide and doxorubicin (DOX). Generally, 3-heteroarylisoquinolinamines displayed greater affinity for topo I than topo II. 3-Heteroarylisoquinolinamines with greater topo I inhibitory effect exhibited potent cytotoxicity. Piperazine-substituted derivative, 5b, with potent topo I and moderate topo II activities intercalated between DNA bases and interacted with topos through H-bonds at the DNA cleavage site of a docking model. Moreover, flow cytometry indicated that cytotoxic 3-heteroarylisoquinolinamines led to accumulation of human cervical (HeLa) cancer cells in the different phases of the cell cycle before apoptosis. Taken together, 3-heteroarylisoquinolinamines possessed potent cytotoxicity with topos and cell cycle inhibitory activities.
authors.affiliation: College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju 500-757, Republic of Korea.
authors.forename: Hue Thi
authors.initials: HT
authors.lastname: My Van
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: Hyung Min
authors.initials: HM
authors.lastname: Jeong
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 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: College of Pharmacy, Yeungnam University, Kyongsan 712-749, Republic of Korea.
authors.forename: Eung-Seok
authors.initials: ES
authors.lastname: Lee
authors.affiliation: College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju 500-757, Republic of Korea.
authors.forename: Kwang
authors.initials: K
authors.lastname: Youl Lee
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: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D018360:Crystallography, X-Ray; D004264:DNA Topoisomerases, Type I / Q000378:metabolism*; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007546:Isoquinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D059004:Topoisomerase I Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D059005:Topoisomerase II Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D006571:Heterocyclic Compounds; D007546:Isoquinolines; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D004264:DNA Topoisomerases, Type I; D004250:DNA Topoisomerases, Type II
keywords: 3-Heteroarylisoquinolinamine; Cell cycle arrest; Molecular docking; Selective cytotoxicity; Topoisomerase I; Topoisomerase II