Topoisomerase I and II inhibitory activity, cytotoxicity, and structure–activity relationship study of dihydroxylated 2,6-diphenyl-4-aryl pyridines

• Published in: Bioorganic & medicinal chemistry Vol. 23; no. 13; pp. 3638 - 3654
• Main Authors: Karki, Radha, Song, Chanju, Kadayat, Tara Man, Magar, Til Bahadur Thapa, Bist, Ganesh, Shrestha, Aarajana, Na, Younghwa, Kwon, Youngjoo, Lee, Eung-Seok
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01-07-2015
• Subjects: Anticancer agents; Antigens, Neoplasm - chemistry; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacology; Cell Line, Tumor; Cell Survival - drug effects; Cytotoxicity; Dihydroxylated 2,6-diphenyl-4-aryl pyridines; DNA Topoisomerases, Type I - chemistry; DNA Topoisomerases, Type II - chemistry; DNA-Binding Proteins - antagonists & inhibitors; DNA-Binding Proteins - chemistry; Humans; Pyridines - chemical synthesis; Pyridines - pharmacology; Structure-Activity Relationship; Topoisomerase I; Topoisomerase I Inhibitors - chemical synthesis; Topoisomerase I Inhibitors - pharmacology; Topoisomerase II; Topoisomerase II Inhibitors - chemical synthesis; Topoisomerase II Inhibitors - pharmacology; Topoisomerase I; Cytotoxicity; Anticancer agents; Topoisomerase II; Dihydroxylated 2,6-diphenyl-4-aryl pyridines
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2015.04.002

Total thirty-six dihydroxylated 2,6-diphenyl-4-aryl pyridines were designed, synthesized and tested for topo I and II inhibitory activity and cytotoxicity for the development of novel anticancer agents. [Display omitted]
A new series of thirty-six dihydroxylated 2,6-diphenyl-4-aryl pyridines containing hydroxyl groups at the ortho, meta, or para position of 2- and 6-phenyl rings attached to the central pyridine were designed and synthesized. They were evaluated for topoisomerase I and II inhibitory activity and cytotoxicity against several human cancer cell lines for the development of novel anticancer agents. Most of the compounds with hydroxyl moiety either at the meta or para position of 2- or 6-phenyl ring in combination with thienyl or furyl group at 4-position of central pyridine displayed significant topoisomerase II inhibitory activity and cytotoxicity. Positive correlation between topoisomerase II inhibitory activity and cytotoxicity was observed for the compounds 9–11, 15–17, 19, 21–23, 28, and 41. Among all the synthesized compounds, compound 17 emerged as the most promising topoisomerase II inhibitor with significant cytotoxicity.