title: Synthesis and biological evaluation of 2-phenol-4-chlorophenyl-6-aryl pyridines as topoisomerase II inhibitors and cytotoxic agents.
abstract: A new series of 2-phenol-4-chlorophenyl-6-aryl pyridines were designed, synthesized, and evaluated for topoisomerase (topo) I and II inhibitory activities as well as cytotoxic activity against four different human cancer cell lines such as HCT15, T47D, DU145, and Hela. Most of the tested compounds exhibited stronger topo II inhibitory activity at 100μM as compared to etoposide. All the compounds, except 39, did not show topo I inhibitory activity. Interestingly, compounds that showed better topo II inhibition than etoposide have ortho- or para-chlorophenyl at 4-position of central pyridine, and none of the compounds possess meta-chlorophenyl. SAR study revealed the importance of ortho- or para-chlorophenyl at 4-position of the central pyridine for selective topo II inhibitory activity. Similarly, all compounds possessing meta- or para-hydroxyphenyl moieties showed moderate to significant cytotoxic effects. Particularly, compounds 27-37, and 39 which showed excellent cytotoxicity (IC50=0.68-1.25μM) against T47D breast cancer cells suggest the importance of meta- or para-hydroxyphenyl moiety at 2-position of the central pyridine for the design of anticancer agents with related scaffolds.
authors.affiliation: College of Pharmacy, Yeungnam University, Gyeongsan 712-749, Republic of Korea.
authors.forename: Pritam
authors.initials: P
authors.lastname: Thapa
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, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 120-750, Republic of Korea.
authors.forename: Seojeong
authors.initials: S
authors.lastname: Park
authors.affiliation: College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 120-750, Republic of Korea.
authors.forename: Somin
authors.initials: S
authors.lastname: Shin
authors.affiliation: College of Pharmacy, Yeungnam University, Gyeongsan 712-749, Republic of Korea.
authors.forename: Til Bahadur
authors.initials: TB
authors.lastname: Thapa Magar
authors.affiliation: College of Pharmacy, Yeungnam University, Gyeongsan 712-749, Republic of Korea.
authors.forename: Ganesh
authors.initials: G
authors.lastname: Bist
authors.affiliation: College of Pharmacy, Yeungnam University, Gyeongsan 712-749, Republic of Korea.
authors.forename: Aarajana
authors.initials: A
authors.lastname: Shrestha
authors.affiliation: College of Pharmacy, Cha University, Pochon 487-010, Republic of Korea.
authors.forename: Younghwa
authors.initials: Y
authors.lastname: Na
authors.affiliation: College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 120-750, Republic of Korea. Electronic address: ykwon@ewha.ac.kr.
authors.forename: Youngjoo
authors.initials: Y
authors.lastname: Kwon
authors.affiliation: College of Pharmacy, Yeungnam University, Gyeongsan 712-749, Republic of Korea. Electronic address: eslee@yu.ac.kr.
authors.forename: Eung-Seok
authors.initials: ES
authors.lastname: Lee
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; 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; D059004:Topoisomerase I Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D059005:Topoisomerase II Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D010636:Phenols; D011725:Pyridines; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D004264:DNA Topoisomerases, Type I; D004250:DNA Topoisomerases, Type II
keywords: 2-Phenol-4-chlorophenyl-6-aryl pyridines; Cytotoxicity; Synthesis; Topoisomerase I and II inhibition