2. Academic Validation
  3. Substituted 2-arylquinazolinones: Design, synthesis, and evaluation of cytotoxicity and inhibition of topoisomerases

Substituted 2-arylquinazolinones: Design, synthesis, and evaluation of cytotoxicity and inhibition of topoisomerases

  • Eur J Med Chem. 2015 Oct 20:103:69-79. doi: 10.1016/j.ejmech.2015.08.040.
Daulat Bikram Khadka 1,  Giap Huu Tran 2,  Somin Shin 3,  Hang Thi Minh Nguyen 2,  Hue Thi Cao 2,  Chao Zhao 1,  Yifeng Jin 1,  Hue Thi My Van 4,  Minh Van Chau 2,  Youngjoo Kwon 5,  Thanh Nguyen Le 6,  Won-Jea Cho 7
Affiliations

Affiliations

  • 1 College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju 500-757, Republic of Korea.
  • 2 Institute of Marine Biochemistry, Vietnam Academy of Science and Technology, 18-Hoang Quoc Viet, Caugiay, Hanoi, Viet Nam.
  • 3 College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Global Top 5 Program, Ewha Womans University, Seoul 120-750, Republic of Korea.
  • 4 Organic Chemistry Department, Hanoi University of Pharmacy, 15-17 Le Thanh Tong, Hanoi, Viet Nam.
  • 5 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.
  • 6 Institute of Marine Biochemistry, Vietnam Academy of Science and Technology, 18-Hoang Quoc Viet, Caugiay, Hanoi, Viet Nam. Electronic address: lethanh@imbc.vast.vn.
  • 7 College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju 500-757, Republic of Korea. Electronic address: wjcho@jnu.ac.kr.
PMID: 26334499 DOI: 10.1016/j.ejmech.2015.08.040
Abstract

A series of 2-arylquinazolinones with structural homology to known 3-arylisoquinolines were designed and synthesized in order to develop safe, effective, and selective cytotoxic agents targeting topoisomerases (topos). 2-Arylquinzolinones with various substitutions on the aromatic rings were obtained by thermal cyclodehydration/dehydrogenation on reacting anthranilamides and benzaldehydes. The compounds had superior topo I-inhibitory activities but were generally inactive against topo IIα. Among the 6-methyl-, 6-amino-, and 7-methylquinazolinones, 6-amino-substituted derivatives displayed potent cytotoxicity at submicromolar to nanomolar concentrations against human colorectal adenocarcinoma cells (HCT-15), human ductal breast epithelial tumor cells (T47D), and cervical Cancer cells (HeLa). There was a good correlation between Topo I inhibition and the cytotoxic effects of 6-aminoquinazolinones. Docking models demonstrated that Topo I inhibition by these compounds is owing to intercalation and H-bond interactions with the DNA Bases and amino acid residues at the enzymatic site.

Keywords

2-Arylquinazolinone; 3-Arylisoquinoline; Cytotoxicity; Molecular docking; Topoisomerase.

Figures