title: Discovery of dihydroxylated 2,4-diphenyl-6-thiophen-2-yl-pyridine as a non-intercalative DNA-binding topoisomerase II-specific catalytic inhibitor.
abstract: We describe our rationale for designing specific catalytic inhibitors of topoisomerase II (topo II) over topoisomerase I (topo I). Based on 3D-QSAR studies of previously published dihydroxylated 2,4-diphenyl-6-aryl pyridine derivatives, 9 novel dihydroxylated 2,4-diphenyl-6-thiophen-2-yl pyridine compounds were designed, synthesized, and their biological activities were evaluated. These compounds have 2-thienyl ring substituted on the R(3) group on the pyridine ring and they all showed excellent specificity toward topo II compared to topo I. In vitro experiments were performed for compound 13 to determine the mechanism of action for this series of compounds. Compound 13 inhibited topoisomerase II specifically by non-intercalative binding to DNA and did not stabilize enzyme-cleavable DNA complex. Compound 13 efficiently inhibited cell viability, cell migration, and induced G1 arrest. Also from 3D-QSAR studies, the results were compared with other previously published dihydroxylated 2,4-diphenyl-6-aryl pyridine derivatives to explain the structure-activity relationships.
authors.affiliation: College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Global Top5, Ewha Womans University, Seoul 120-750, Republic of Korea.
authors.forename: Kyu-Yeon
authors.initials: KY
authors.lastname: Jun
authors.affiliation: College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Global Top5, Ewha Womans University, Seoul 120-750, Republic of Korea.
authors.forename: Hanbyeol
authors.initials: H
authors.lastname: Kwon
authors.affiliation: College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Global Top5, Ewha Womans University, Seoul 120-750, Republic of Korea.
authors.forename: So-Eun
authors.initials: SE
authors.lastname: Park
authors.affiliation: College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Global Top5, Ewha Womans University, Seoul 120-750, Republic of Korea.
authors.forename: Eunyoung
authors.initials: E
authors.lastname: Lee
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, Yeungnam University, Gyeongsan 712-749, Republic of Korea.
authors.forename: Pritam
authors.initials: P
authors.lastname: Thapa
authors.affiliation: Department of Emergency Medical Technology, Daejeon University, Daejeon 300-716, Republic of Korea.
authors.forename: Jun-Ho
authors.initials: JH
authors.lastname: Lee
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 Top5, 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: D017209:Apoptosis / Q000187:drug effects; D055162:Biocatalysis; D045744:Cell Line, Tumor; D004247:DNA / Q000378:metabolism*; D004250:DNA Topoisomerases, Type II / Q000737:chemistry / Q000378:metabolism*; D015195:Drug Design; D006801:Humans; D006878:Hydroxides / Q000737:chemistry; D008958:Models, Molecular; D011487:Protein Conformation; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D006878:Hydroxides; D011725:Pyridines; D059005:Topoisomerase II Inhibitors; D004247:DNA; C031356:hydroxide ion; D004250:DNA Topoisomerases, Type II; C023666:pyridine
keywords: 3D-QSAR; Anticancer agents; Cytotoxicity; Dihydroxylated 2,4-diphenyl-6-thiophen-2-yl-pyridines; Topoisomerase I; Topoisomerase II