2. Academic Validation
  3. Design, synthesis and systematic evaluation of cytotoxic 3-heteroarylisoquinolinamines as topoisomerases inhibitors

Design, synthesis and systematic evaluation of cytotoxic 3-heteroarylisoquinolinamines as topoisomerases inhibitors

  • Eur J Med Chem. 2014 Jul 23:82:181-94. doi: 10.1016/j.ejmech.2014.05.047.
Hue Thi My Van 1,  Hyunjung Woo 2,  Hyung Min Jeong 1,  Daulat Bikram Khadka 1,  Su Hui Yang 1,  Chao Zhao 1,  Yifeng Jin 1,  Eung-Seok Lee 3,  Kwang Youl Lee 1,  Youngjoo Kwon 4,  Won-Jea Cho 5
Affiliations

Affiliations

  • 1 College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju 500-757, Republic of Korea.
  • 2 College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Global Top 5 Program, Ewha Womans University, Seoul 120-750, Republic of Korea.
  • 3 College of Pharmacy, Yeungnam University, Kyongsan 712-749, Republic of Korea.
  • 4 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.
  • 5 College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju 500-757, Republic of Korea. Electronic address: wjcho@chonnam.ac.kr.
PMID: 24904965 DOI: 10.1016/j.ejmech.2014.05.047
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.

Keywords

3-Heteroarylisoquinolinamine; Cell cycle arrest; Molecular docking; Selective cytotoxicity; Topoisomerase I; Topoisomerase II.

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