title: Design, synthesis, and biological evaluation of novel deguelin-based heat shock protein 90 (HSP90) inhibitors targeting proliferation and angiogenesis.
abstract: Deguelin exhibits potent apoptotic and antiangiogenic activities in a variety of transformed cells and cancer cells. Deguelin also exhibits potent tumor suppressive effects in xenograft tumor models for many human cancers. Our initial studies confirmed that deguelin disrupts ATP binding to HSP90 and consequently induces destabilization of its client proteins such as HIF-1α. Interestingly, a fluorescence probe assay revealed that deguelin and its analogues do not compete with ATP binding to the N-terminus of HSP90, unlike most HSP90 inhibitors. To determine the key parts of deguelin that contribute to its potent HSP90 inhibition, as well as its antiproliferative and antiangiogenic activities, we have established a structure-activity relationship (SAR) of deguelin. In the course of these studies, we identified a series of novel and potent HSP90 inhibitors. In particular, analogues 54 and 69, the B- and C-ring-truncated compounds, exhibited excellent antiproliferative activities with IC(50) of 140 and 490 nM in the H1299 cell line, respectively, and antiangiogenic activities in zebrafish embryos in a dose dependent manner (0.25-1.25 μM).
authors.affiliation: College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 151-742, Korea.
authors.forename: Dong-Jo
authors.initials: DJ
authors.lastname: Chang
authors.forename: Hongchan
authors.initials: H
authors.lastname: An
authors.forename: Kyoung-suk
authors.initials: KS
authors.lastname: Kim
authors.forename: Hyun Ho
authors.initials: HH
authors.lastname: Kim
authors.forename: Jinkyung
authors.initials: J
authors.lastname: Jung
authors.forename: Jung Min
authors.initials: JM
authors.lastname: Lee
authors.forename: Nam-Jung
authors.initials: NJ
authors.lastname: Kim
authors.forename: Young Taek
authors.initials: YT
authors.lastname: Han
authors.forename: Hwayoung
authors.initials: H
authors.lastname: Yun
authors.forename: Sujin
authors.initials: S
authors.lastname: Lee
authors.forename: Geumwoo
authors.initials: G
authors.lastname: Lee
authors.forename: Seungbeom
authors.initials: S
authors.lastname: Lee
authors.forename: Ju Sung
authors.initials: JS
authors.lastname: Lee
authors.forename: Jong-Ho
authors.initials: JH
authors.lastname: Cha
authors.forename: Ji-Hyeon
authors.initials: JH
authors.lastname: Park
authors.forename: Ji Won
authors.initials: JW
authors.lastname: Park
authors.forename: Su-Chan
authors.initials: SC
authors.lastname: Lee
authors.forename: Sang Geon
authors.initials: SG
authors.lastname: Kim
authors.forename: Jeong Hun
authors.initials: JH
authors.lastname: Kim
authors.forename: Ho-Young
authors.initials: HY
authors.lastname: Lee
authors.forename: Kyu-Won
authors.initials: KW
authors.lastname: Kim
authors.forename: Young-Ger
authors.initials: YG
authors.lastname: Suh
mesh_terms: D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001578:Benzopyrans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D004625:Embryo, Nonmammalian / Q000098:blood supply / Q000187:drug effects; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects; D011485:Protein Binding; D012402:Rotenone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D015027:Zebrafish
chemical_list: C578797:(S)-2-(3,4-dimethoxyphenyl)-1-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)propan-1-one; C578796:2-(3,4-dimethoxyphenyl)-1-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)ethanone; D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D001578:Benzopyrans; C497442:HIF1A protein, human; D018841:HSP90 Heat-Shock Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012402:Rotenone; C107676:deguelin