title: Ring-truncated deguelin derivatives as potent Hypoxia Inducible Factor-1α (HIF-1α) inhibitors.
abstract: A series of fluorophenyl and pyridine analogues of 1 and 2 were synthesized as ring-truncated deguelin surrogates and evaluated for their HIF-1α inhibition. Their structure-activity relationship was systematically investigated based on the variation of the linker B-region moiety. Among the inhibitors, compound 25 exhibited potent HIF-1α inhibition in a dose-dependent manner and significant antitumor activity in H1299 with less toxicity than deguelin. It also inhibited in vitro hypoxia-mediated angiogenic processes in HRMECs. The docking study indicates that 25 occupied the C-terminal ATP-binding pocket of HSP90 in a similar mode as 1, which implies that the anticancer and antiangiogenic activities of 25 are derived from HIF-1α destabilization by binding to the C-terminal ATP-binding site of hHSP90.
authors.affiliation: Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, 151-742, South Korea.
authors.forename: Ho Shin
authors.initials: HS
authors.lastname: Kim
authors.affiliation: Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, 151-742, South Korea.
authors.forename: Mannkyu
authors.initials: M
authors.lastname: Hong
authors.affiliation: Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, 151-742, South Korea.
authors.forename: Su-Chan
authors.initials: SC
authors.lastname: Lee
authors.affiliation: Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, 151-742, South Korea.
authors.forename: Ho-Young
authors.initials: HY
authors.lastname: Lee
authors.affiliation: Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, 151-742, South Korea.
authors.forename: Young-Ger
authors.initials: YG
authors.lastname: Suh
authors.affiliation: Natural Products Research Institute, College of Pharmacy, Seoul National University, Seoul, 151-742, South Korea.
authors.forename: Dong-Chan
authors.initials: DC
authors.lastname: Oh
authors.affiliation: SNU-Harvard NeuroVascular Protection Research Center, College of Pharmacy, Seoul National University, Seoul, 151-742, South Korea.
authors.forename: Ji Hae
authors.initials: JH
authors.lastname: Seo
authors.affiliation: SNU-Harvard NeuroVascular Protection Research Center, College of Pharmacy, Seoul National University, Seoul, 151-742, South Korea.
authors.forename: Hoon
authors.initials: H
authors.lastname: Choi
authors.affiliation: SNU-Harvard NeuroVascular Protection Research Center, College of Pharmacy, Seoul National University, Seoul, 151-742, South Korea.
authors.forename: Jun Yong
authors.initials: JY
authors.lastname: Kim
authors.affiliation: SNU-Harvard NeuroVascular Protection Research Center, College of Pharmacy, Seoul National University, Seoul, 151-742, South Korea; Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, 151-742, South Korea.
authors.forename: Kyu-Won
authors.initials: KW
authors.lastname: Kim
authors.affiliation: College of Medicine, Seoul National University, Seoul, 151-742, South Korea.
authors.forename: Jeong Hun
authors.initials: JH
authors.lastname: Kim
authors.affiliation: School of Medicine, Kangwon National University, Kangwon-do, 200-701, South Korea.
authors.forename: Joohwan
authors.initials: J
authors.lastname: Kim
authors.affiliation: School of Medicine, Kangwon National University, Kangwon-do, 200-701, South Korea.
authors.forename: Young-Myeong
authors.initials: YM
authors.lastname: Kim
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon, 440-746, South Korea.
authors.forename: So-Jung
authors.initials: SJ
authors.lastname: Park
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon, 440-746, South Korea.
authors.forename: Hyun-Ju
authors.initials: HJ
authors.lastname: Park
authors.affiliation: Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, 151-742, South Korea. Electronic address: jeewoo@snu.ac.kr.
authors.forename: Jeewoo
authors.initials: J
authors.lastname: Lee
mesh_terms: D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D042783:Endothelial Cells / Q000187:drug effects; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors*; D015394:Molecular Structure; D012171:Retinal Vessels / Q000166:cytology / Q000187:drug effects; D012402:Rotenone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012402:Rotenone; C107676:deguelin
keywords: Antitumor; Deguelin; HIF-1; HSP90; Heat shock protein 90; Hypoxia Inducible Factor-1