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

Title
Design and synthesis of conformationally constrained hydroxylated 4-phenyl-2-aryl chromenopyridines as novel and selective topoisomerase II-targeted antiproliferative agents
Authors
Thapa, PritamJun, Kyu-YeonKadayat, Tara ManPark, ChanmiZheng, ZhiMagar, Til Bahadur ThapaBist, GaneshShrestha, AarajanaNa, YounghwaKwon, YoungjooLee, Eung-Seok
Ewha Authors
권영주전규연
SCOPUS Author ID
권영주scopus
Issue Date
2015
Journal Title
BIOORGANIC & MEDICINAL CHEMISTRY
ISSN
0968-0896JCR Link1464-3391JCR Link
Citation
vol. 23, no. 19, pp. 6454 - 6466
Keywords
Antiproliferative agentsCytotoxicityHydroxylated 4-phenyl-2-aryl chromenopyridinesStructure-activity relationshipsTopoisomerase II inhibitor
Publisher
PERGAMON-ELSEVIER SCIENCE LTD
Indexed
SCI; SCIE; SCOPUS WOS scopus
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 mu M and 20 mu M. 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. (C) 2015 Elsevier Ltd. All rights reserved.
DOI
10.1016/j.bmc.2015.08.018
Appears in Collections:
약학대학 > 약학과 > Journal papers
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