title: Novel 2-aryl-4-(4'-hydroxyphenyl)-5H-indeno[1,2-b]pyridines as potent DNA non-intercalative topoisomerase catalytic inhibitors.
abstract: On the basis of previous reports on the importance of thienyl, furyl or phenol group substitution on 5H-indeno[1,2-b]pyridine skeleton, a new series of rigid 2-aryl-4-(4'-hydroxyphenyl)-5H-indeno[1,2-b]pyridine derivatives were systematically designed and synthesized. Topoisomerase inhibitory activity and antiproliferative activity of all the synthesized compounds were determined using human colorectal (HCT15), breast (T47D), prostate (DU145) and cervix (HeLa) cancer cells. Compounds 9, 10, 12, 13, 15, 16, 18 and 19 with thienyl or furyl moiety at the 2-position and hydroxyl group at the meta or para positions of 4-phenyl ring displayed strong to moderate topoisomerase IIα (topo IIα) inhibitory activity and significant antiproliferative activity. The evaluation of compound 16 to determine its mechanism of action was performed with topo IIα-DNA cleavable complex, topo IIα-mediated ATPase assay, DNA unwinding and in vitro and ex vivo topo IIα relaxation assay. Compound 16 functioned as a DNA non-intercalative topo IIα catalytic inhibitor with better potency than etoposide in T47D breast cancer cells. Molecular docking study revealed that compound 16 cannot intercalate into regularly stacked base-pairs of DNA duplex but can interact or intercalate to topo IIα-bound DNA.
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, 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: Kyu-Yeon
authors.initials: KY
authors.lastname: Jun
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, Yeungnam University, Gyeongsan 712-749, Republic of Korea. Electronic address: eslee@yu.ac.kr.
authors.forename: Eung-Seok
authors.initials: ES
authors.lastname: Lee
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
mesh_terms: D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents / Q000138:chemical synthesis*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004247:DNA / Q000378:metabolism; D004250:DNA Topoisomerases, Type II; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D062105:Molecular Docking Simulation; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D011725:Pyridines; D059005:Topoisomerase II Inhibitors; D004247:DNA; D004250:DNA Topoisomerases, Type II
keywords: 2-Aryl-4-(4′-hydroxyphenyl)-5H-indeno[1,2-b]pyridine; Anticancer agents; Antiproliferative activity; Docking study; Dual topoisomerase I and II inhibitors