title: Synthesis and biological activity of 2,4-di-p-phenolyl-6-2-furanyl-pyridine as a potent topoisomerase II poison.
abstract: Dihydroxylated 2,4-diphenyl-6-aryl pyridine derivatives were simply achieved using Claisen-Schmidt condensation reaction and modified Kröhnke pyridine synthetic method. Total forty-five compounds were designed and synthesized which contain hydroxyl groups at ortho, meta or para position of 2- and 4-phenyl rings attached to the central pyridine. They were evaluated for topoisomerase I and II inhibitory activity, and cytotoxicity against several human cancer cell lines for the development of novel antitumor agents. Most of the prepared compounds exhibited significant antiproliferative activity on human cancer cell lines, HCT15 and K562, as well as potent topo II inhibitory activity comparable to or stronger than etoposide. The structure-activity relationship demonstrated that compounds with hydroxyl group at meta or para position of 2-phenyl ring in combination with hydroxyl at ortho, meta or para position of 4-phenyl ring displayed the most potent topoisomerase II inhibitory activity and cytotoxicity. Positive correlation between topoisomerase II inhibition and cytotoxicity was obtained for several compounds (30, 35, 36, 40-45, 49, 54, 56). Compound 56 showed the most potent topoisomerase II inhibitory activity at low concentration and functioned as a topoisomerase poison like the mode of action of etoposide.
authors.affiliation: College of Pharmacy, Yeungnam University, Gyeongsan 712-749, Republic of Korea.
authors.forename: Radha
authors.initials: R
authors.lastname: Karki
authors.affiliation: College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Global Top 5 Program Ewha Womans University, Seoul 120-750, Republic of Korea.
authors.forename: Chanmi
authors.initials: C
authors.lastname: Park
authors.affiliation: College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Global Top 5 Program Ewha Womans University, Seoul 120-750, Republic of Korea.
authors.forename: Kyu-Yeon
authors.initials: KY
authors.lastname: Jun
authors.affiliation: College of Pharmacy, Yeungnam University, Gyeongsan 712-749, Republic of Korea.
authors.forename: Tara Man
authors.initials: TM
authors.lastname: Kadayat
authors.affiliation: College of Pharmacy, Yeungnam University, Gyeongsan 712-749, Republic of Korea. Electronic address: eslee@ynu.ac.kr.
authors.forename: Eung-Seok
authors.initials: ES
authors.lastname: Lee
authors.affiliation: 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.
authors.forename: Youngjoo
authors.initials: Y
authors.lastname: Kwon
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006367:HeLa Cells; D006801:Humans; D020014:K562 Cells; D061986:MCF-7 Cells; D015394:Molecular Structure; D010636:Phenols / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C000602514:2,4-di-p-phenolyl-6-(2-furanyl)pyridine; D000970:Antineoplastic Agents; D010636:Phenols; D011725:Pyridines; D059005:Topoisomerase II Inhibitors; D004250:DNA Topoisomerases, Type II
keywords: Antitumor agents; Cytotoxicity; Dihydroxylated 2,4-diphenyl-6-aryl pyridine; Terpyridine bioisosteres; Topoisomerase poison