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Design, synthesis and systematic evaluation of cytotoxic 3-heteroarylisoquinolinamines as topoisomerases inhibitors.
Eur J Med Chem. 2014 Jul 23; 82:181-94.EJ

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+Show Affiliations

College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju 500-757, Republic of Korea.College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Global Top 5 Program, Ewha Womans University, Seoul 120-750, Republic of Korea.College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju 500-757, Republic of Korea.College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju 500-757, Republic of Korea.College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju 500-757, Republic of Korea.College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju 500-757, Republic of Korea.College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju 500-757, Republic of Korea.College of Pharmacy, Yeungnam University, Kyongsan 712-749, Republic of Korea.College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju 500-757, Republic of Korea.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.College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju 500-757, Republic of Korea. Electronic address: wjcho@chonnam.ac.kr.

Pub Type(s)

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

Language

eng

PubMed ID

24904965

Citation

My Van, Hue Thi, et al. "Design, Synthesis and Systematic Evaluation of Cytotoxic 3-heteroarylisoquinolinamines as Topoisomerases Inhibitors." European Journal of Medicinal Chemistry, vol. 82, 2014, pp. 181-94.
My Van HT, Woo H, Jeong HM, et al. Design, synthesis and systematic evaluation of cytotoxic 3-heteroarylisoquinolinamines as topoisomerases inhibitors. Eur J Med Chem. 2014;82:181-94.
My Van, H. T., Woo, H., Jeong, H. M., Khadka, D. B., Yang, S. H., Zhao, C., Jin, Y., Lee, E. S., Youl Lee, K., Kwon, Y., & Cho, W. J. (2014). Design, synthesis and systematic evaluation of cytotoxic 3-heteroarylisoquinolinamines as topoisomerases inhibitors. European Journal of Medicinal Chemistry, 82, 181-94. https://doi.org/10.1016/j.ejmech.2014.05.047
My Van HT, et al. Design, Synthesis and Systematic Evaluation of Cytotoxic 3-heteroarylisoquinolinamines as Topoisomerases Inhibitors. Eur J Med Chem. 2014 Jul 23;82:181-94. PubMed PMID: 24904965.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Design, synthesis and systematic evaluation of cytotoxic 3-heteroarylisoquinolinamines as topoisomerases inhibitors. AU - My Van,Hue Thi, AU - Woo,Hyunjung, AU - Jeong,Hyung Min, AU - Khadka,Daulat Bikram, AU - Yang,Su Hui, AU - Zhao,Chao, AU - Jin,Yifeng, AU - Lee,Eung-Seok, AU - Youl Lee,Kwang, AU - Kwon,Youngjoo, AU - Cho,Won-Jea, Y1 - 2014/05/21/ PY - 2013/10/24/received PY - 2014/05/13/revised PY - 2014/05/20/accepted PY - 2014/6/7/entrez PY - 2014/6/7/pubmed PY - 2015/3/31/medline KW - 3-Heteroarylisoquinolinamine KW - Cell cycle arrest KW - Molecular docking KW - Selective cytotoxicity KW - Topoisomerase I KW - Topoisomerase II SP - 181 EP - 94 JF - European journal of medicinal chemistry JO - Eur J Med Chem VL - 82 N2 - 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. SN - 1768-3254 UR - https://www.unboundmedicine.com/medline/citation/24904965/Design_synthesis_and_systematic_evaluation_of_cytotoxic_3_heteroarylisoquinolinamines_as_topoisomerases_inhibitors_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0223-5234(14)00471-1 DB - PRIME DP - Unbound Medicine ER -