Design and synthesis of 4-amino-2-phenylquinazolines as novel topoisomerase i inhibitors with molecular modeling

Thanh Nguyen Le, Su Hui Yang, Daulat Bikram Khadka, Hue Thi My Van, Suk Hee Cho, Youngjoo Kwon, Eung Seok Lee, Kyung Tae Lee, Won Jea Cho

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

4-Amino-2-phenylquinazolines 7 were designed as bioisosteres of 3-arylisoquinolinamines 6 that were energy minimized to provide stable conformers. Interestingly, the 2-phenyl ring of 4-amino-2-phenylquinazolines was parallel to the quinazoline ring and improved their DNA intercalation ability in the DNA-topo I complex. Among the synthesized 4-amino group-substituted analogs, 4-cyclohexylamino-2-phenylquinazoline 7h exhibited potent topo I inhibitory activity and strong cytotoxicity. Interestingly, consistency was observed between the cytotoxicities and topo I activities in these quinazoline analogs, suggesting that the target of 4-amino-2-phenylquinazolines is limited to topo I. Molecular docking studies were performed with the Surflex-Dock program to afford the ideal interaction mode of the compound into the binding site of the DNA-topo I complex in order to clarify the topo I activity of 7h.

Original languageEnglish
Pages (from-to)4399-4404
Number of pages6
JournalBioorganic and Medicinal Chemistry
Volume19
Issue number14
DOIs
StatePublished - 15 Jul 2011

Bibliographical note

Funding Information:
This work was supported by Korea Research Foundation grant ( KRF-2009-0071379 ).

Keywords

  • 4-Amino-2-phenylquinazolines
  • Cytotoxicity
  • DNA intercalation
  • Docking study
  • Topoisomerase I

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