title: Synthesis and biological evaluation of C-ring truncated deguelin derivatives as heat shock protein 90 (HSP90) inhibitors.
abstract: Based on the lead compound L-80 (compound 2), a potent heat shock protein 90 (HSP90) inhibitor, a series of C-ring truncated deguelin analogs were designed, synthesized and evaluated for Hypoxia Inducible Factor-1α (HIF-1α) inhibition as a primary screening method. Their structure-activity relationship was investigated in a systematic manner by varying the A/B ring, linker and D/E ring, respectively. Among the synthesized inhibitors, compound 5 exhibited potent HIF-1α inhibition in a dose-dependent manner and significant antitumor activity in human non-small cell lung carcinoma (H1299), with better activities than L-80. It also inhibited in vitro hypoxia-mediated angiogenic processes in human retinal microvascular endothelial cells (HRMEC). The docking study of 5 showed a similar binding mode as L-80: it occupied the C-terminal ATP-binding pocket of HSP90, indicating that the anticancer and antiangiogenic activities of 5 were derived from HIF-1α destabilization by inhibiting the C-terminal ATP-binding site of hHSP90.
authors.affiliation: Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of 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 08826, Republic of Korea.
authors.forename: Mannkyu
authors.initials: M
authors.lastname: Hong
authors.affiliation: Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.
authors.forename: Jihyae
authors.initials: J
authors.lastname: Ann
authors.affiliation: Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.
authors.forename: Suyoung
authors.initials: S
authors.lastname: Yoon
authors.affiliation: Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.
authors.forename: Cong-Truong
authors.initials: CT
authors.lastname: Nguyen
authors.affiliation: Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of 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 08826, Republic of 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 08826, Republic of Korea.
authors.forename: Young-Ger
authors.initials: YG
authors.lastname: Suh
authors.affiliation: SNU-Harvard NeuroVascular Protection Research Center, College of Pharmacy, Seoul National University, Seoul 08826, Republic of 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 08826, Republic of 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 08826, Republic of 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 08826, Republic of Korea; Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul 08826, Republic of Korea.
authors.forename: Kyu-Won
authors.initials: KW
authors.lastname: Kim
authors.affiliation: School of Medicine, Kangwon National University, Kangwon-do 24341, Republic of Korea.
authors.forename: Joohwan
authors.initials: J
authors.lastname: Kim
authors.affiliation: School of Medicine, Kangwon National University, Kangwon-do 24341, Republic of Korea.
authors.forename: Young-Myeong
authors.initials: YM
authors.lastname: Kim
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea.
authors.forename: So-Jung
authors.initials: SJ
authors.lastname: Park
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of 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 08826, Republic of Korea. Electronic address: jeewoo@snu.ac.kr.
authors.forename: Jeewoo
authors.initials: J
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; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors; D008958:Models, Molecular; D015394:Molecular Structure; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000473:pathology; D012402:Rotenone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; C497442:HIF1A protein, human; D018841:HSP90 Heat-Shock Proteins; 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