title: A series of novel terpyridine-skeleton molecule derivants inhibit tumor growth and metastasis by targeting topoisomerases.
abstract: A series of novel terpyridine-skeleton molecules containing conformational rigidity, 14 containing benzo[4,5]furo[3,2-b]pyridine core and 15 comprising chromeno[4,3-b]pyridine core, were synthesized, and their biological activities were evaluated. 3-(4-Phenylbenzo[4,5]furo[3,2-b]pyridin-2-yl)phenol (8) was determined to be a nonintercalative topo I and II dual catalytic inhibitor and 3-(4-phenylchromeno[4,3-b]pyridine-2-yl)phenol (22) was determined to be a nonintercalative topo IIα specific catalytic inhibitor by various assays. These two catalytic inhibitors induced apoptosis in addition to G1 arrest in T47D human breast cancer cells with much less DNA toxicity than etoposide. Compounds 8 and 22 significantly inhibited tumor growth in HCT15 subcutaneously implanted xenografted mice. The modification of compounds 8 and 22 with the introduction of a methoxy instead of a hydroxy group enhanced endogenous topo inhibitory activity, metabolic stability in diverse types of liver microsomes and improved pharmacokinetic parameters in rat plasma such as augmentation of bioavailability (41.3% and 33.2% for 2-(3-methoxyphenyl)-4-phenylbenzofuro[3,2-b]pyridine (8-M) and 3-(4-phenylchromeno[4,3-b]pyridine-2-yl)methoxybenzene (22-M), respectively).
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: Han-Byeol
authors.initials: HB
authors.lastname: Kwon
authors.forename: Chanmi
authors.initials: C
authors.lastname: Park
authors.forename: Kyung-Hwa
authors.initials: KH
authors.lastname: Jeon
authors.forename: Eunyoung
authors.initials: E
authors.lastname: Lee
authors.forename: So-Eun
authors.initials: SE
authors.lastname: Park
authors.forename: Kyu-Yeon
authors.initials: KY
authors.lastname: Jun
authors.forename: Tara Man
authors.initials: TM
authors.lastname: Kadayat
authors.forename: Pritam
authors.initials: P
authors.lastname: Thapa
authors.forename: Radha
authors.initials: R
authors.lastname: Karki
authors.forename: Younghwa
authors.initials: Y
authors.lastname: Na
authors.forename: Mi Sun
authors.initials: MS
authors.lastname: Park
authors.forename: Seung Bae
authors.initials: SB
authors.lastname: Rho
authors.forename: Eung-Seok
authors.initials: ES
authors.lastname: Lee
authors.forename: Youngjoo
authors.initials: Y
authors.lastname: Kwon
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; 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; D057809:HEK293 Cells; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D059003:Topoisomerase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D011725:Pyridines; D059003:Topoisomerase Inhibitors; D004264:DNA Topoisomerases, Type I; D004250:DNA Topoisomerases, Type II