Design and synthesis of conformationally constrained hydroxylated 4-phenyl-2-aryl chromenopyridines as novel and selective topoisomerase II-targeted antiproliferative agents

Pritam Thapa, Kyu Yeon Jun, Tara Man Kadayat, Chanmi Park, Zhi Zheng, Til Bahadur Thapa Magar, Ganesh Bist, Aarajana Shrestha, Younghwa Na, Youngjoo Kwon, Eung Seok Lee

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

Abstract

To develop novel selective topoisomerase II inhibitors, we designed and synthesized a series of conformationally constrained hydroxylated 4-phenyl-2-aryl chromenopyridines and evaluated their topoisomerase inhibitory activity and cytotoxicity against three human cancer cell lines (DU145, HCT15, and T47D) and a normal cell line (MCF10A). All of the prepared compounds displayed stronger or similar topoisomerase II inhibitory activity as well as cytotoxicity against three human cancer cell lines compared to etoposide. Compounds 10a, 10g, 11a, 11f, 11g, 12a, 12f, and 12g especially showed stronger topoisomerase II inhibitory activity as compared to etoposide at both 100 μM and 20 μM. A structure-activity relationship study revealed that hydroxyphenyl moiety at 4-position of pyridine and ortho-hydroxyphenyl or thienyl moiety at 2-position of pyridine has an important role in displaying selective topoisomerase II inhibition. The compound 12b with para-hydroxyphenyl and meta-hydroxyphenyl at 4- and 2-position of pyridine, respectively, showed the most significant cytotoxicity against all three cancer cell lines, whereas less cytotoxicity to a normal cell line as compared to adriamycin.

Original languageEnglish
Article number12522
Pages (from-to)6454-6466
Number of pages13
JournalBioorganic and Medicinal Chemistry
Volume23
Issue number19
DOIs
StatePublished - 1 Oct 2015

Bibliographical note

Funding Information:
This research was supported by the Basic Science Research Program through the (NRF) funded by Korea government (MEST) ( National Research Foundation of Korea NRF-2013R1A1A2060408 ).

Publisher Copyright:
© 2015 Elsevier Ltd.

Keywords

  • Antiproliferative agents
  • Cytotoxicity
  • Hydroxylated 4-phenyl-2-aryl chromenopyridines
  • Structure-activity relationships
  • Topoisomerase II inhibitor

Fingerprint

Dive into the research topics of 'Design and synthesis of conformationally constrained hydroxylated 4-phenyl-2-aryl chromenopyridines as novel and selective topoisomerase II-targeted antiproliferative agents'. Together they form a unique fingerprint.

Cite this