title: Screening and Biological Effects of Marine Pyrroloiminoquinone Alkaloids: Potential Inhibitors of the HIF-1α/p300 Interaction.
abstract: Inhibition of the hypoxia-inducible factor 1α (HIF-1α) pathway by disrupting its association with the transcriptional coactivator p300 inhibits angiogenesis and tumor development. Development of HIF-1α/p300 inhibitors has been hampered by preclinical toxicity; therefore, we aimed to identify novel HIF-1α/p300 inhibitors. Using a cell-free assay designed to test compounds that block HIF-1α/p300 binding, 170 298 crude natural product extracts and prefractionated samples were screened, identifying 25 active extracts. One of these extracts, originating from the marine sponge Latrunculia sp., afforded six pyrroloiminoquinone alkaloids that were identified as positive hits (IC50 values: 1-35 μM). Luciferase assays confirmed inhibition of HIF-1α transcriptional activity by discorhabdin B (1) and its dimer (2), 3-dihydrodiscorhabdin C (3), makaluvamine F (5), discorhabdin H (8), discorhabdin L (9), and discorhabdin W (11) in HCT 116 colon cancer cells (0.1-10 μM, p < 0.05). Except for 11, all of these compounds also reduced HIF-1α transcriptional activity in LNCaP prostate cancer cells (0.1-10 μM, p < 0.05). These effects occurred at noncytotoxic concentrations (<50% cell death) under hypoxic conditions. At the downstream HIF-1α target level, compound 8 (0.5 μM) significantly decreased VEGF secretion in LNCaP cells (p < 0.05). In COLO 205 colon cancer cells no activity was shown in the luciferase or cytotoxicity assays. Pyrroloiminoquinone alkaloids are a novel class of HIF-1α inhibitors, which interrupt the protein-protein interaction between HIF-1α and p300 and consequently reduce HIF-related transcription.
authors.forename: Andrew K L
authors.initials: AK
authors.lastname: Goey
authors.forename: Cindy H
authors.initials: CH
authors.lastname: Chau
authors.forename: Tristan M
authors.initials: TM
authors.lastname: Sissung
authors.forename: Kristina M
authors.initials: KM
authors.lastname: Cook
authors.forename: David J
authors.initials: DJ
authors.lastname: Venzon
authors.affiliation: Molecular Targets Laboratory, Center for Cancer Research, National Cancer Institute , Frederick, Maryland 21702-1201, United States.
authors.forename: Amaya
authors.initials: A
authors.lastname: Castro
authors.affiliation: Molecular Targets Laboratory, Center for Cancer Research, National Cancer Institute , Frederick, Maryland 21702-1201, United States.
authors.forename: Tanya R
authors.initials: TR
authors.lastname: Ransom
authors.affiliation: Molecular Targets Laboratory, Center for Cancer Research, National Cancer Institute , Frederick, Maryland 21702-1201, United States.|Basic Science Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research , Frederick, Maryland 21702-1201, United States.
authors.forename: Curtis J
authors.initials: CJ
authors.lastname: Henrich
authors.affiliation: Molecular Targets Laboratory, Center for Cancer Research, National Cancer Institute , Frederick, Maryland 21702-1201, United States.
authors.forename: Tawnya C
authors.initials: TC
authors.lastname: McKee
authors.affiliation: Molecular Targets Laboratory, Center for Cancer Research, National Cancer Institute , Frederick, Maryland 21702-1201, United States.
authors.forename: James B
authors.initials: JB
authors.lastname: McMahon
authors.affiliation: School of Chemical Sciences, University of Auckland , Auckland 1142, New Zealand.
authors.forename: Tanja
authors.initials: T
authors.lastname: Grkovic
authors.affiliation: School of Chemical Sciences, University of Auckland , Auckland 1142, New Zealand.
authors.forename: Melissa M
authors.initials: MM
authors.lastname: Cadelis
authors.affiliation: School of Chemical Sciences, University of Auckland , Auckland 1142, New Zealand.
authors.forename: Brent R
authors.initials: BR
authors.lastname: Copp
authors.affiliation: Molecular Targets Laboratory, Center for Cancer Research, National Cancer Institute , Frederick, Maryland 21702-1201, United States.
authors.forename: Kirk R
authors.initials: KR
authors.lastname: Gustafson
authors.forename: William D
authors.initials: WD
authors.lastname: Figg
mesh_terms: D000470:Alkaloids / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D050881:E1A-Associated p300 Protein / Q000037:antagonists & inhibitors*; D045325:HCT116 Cells; D006576:Heterocyclic Compounds, 4 or More Rings; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors*; D008297:Male; D008386:Marine Biology; D015394:Molecular Structure; D009389:Neovascularization, Pathologic; D011161:Porifera / Q000737:chemistry*; D011471:Prostatic Neoplasms / Q000188:drug therapy; D047608:Pyrroloiminoquinones / Q000737:chemistry / Q000494:pharmacology*; D011809:Quinones; D013141:Spiro Compounds; D013841:Thiazepines; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D000470:Alkaloids; D006576:Heterocyclic Compounds, 4 or More Rings; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D047608:Pyrroloiminoquinones; D011809:Quinones; D013141:Spiro Compounds; D013841:Thiazepines; D042461:Vascular Endothelial Growth Factor A; C484924:discorhabdin L; C507038:discorhabdin W; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human