title: Design, synthesis, and biological evaluation of dibromotyrosine analogues inspired by marine natural products as inhibitors of human prostate cancer proliferation, invasion, and migration.
abstract: Bioactive secondary metabolites originating from dibromotyrosine are common in marine sponges, such as sponges of the Aplysina species. Verongiaquinol (1), 3,5-dibromo-1-hydroxy-4-oxocyclohexa-2,5-diene-1-acetamide, and aeroplysinin-1 are examples of such bioactive metabolites. Previous studies have shown the potent antimicrobial as well as cytotoxic properties of verongiaquinol and the anti-angiogenic activity of aeroplysinin-1. The work presented herein shows the design and synthesis of dibromotyrosine-inspired phenolic ester and ether analogues with anti-angiogenic, anti-proliferative and anti-migratory properties and negligible cytotoxicity. Several analogues were synthesized based on docking experiments in the ATP binding site of VEGFR2 and their anti-angiogenic potential and ability to inhibit angiogenesis and prostate cancer proliferation, migration and invasion were evaluated using the chick chorioallantoic membrane (CAM) assay, MTT, wound-healing, and Cultrex® BME cell invasion assay models, respectively. Analogues with high docking scores showed promising anti-angiogenic activity in the CAM assay. In general, ester analogues (5, 6, and 8-10) proved to be of higher anti-migratory activity whereas ether analogues (11-14) showed better anti-proliferative activity. These results demonstrate the potential of dibromotyrosines as promising inhibitory scaffolds for the control of metastatic prostate cancer proliferation and migration.
authors.affiliation: Department of Basic Pharmaceutical Sciences, College of Pharmacy, University of Louisiana at Monroe, 1800 Bienville Drive, Monroe, LA 71201, USA.
authors.forename: Asmaa A
authors.initials: AA
authors.lastname: Sallam
authors.forename: Sindhura
authors.initials: S
authors.lastname: Ramasahayam
authors.forename: Sharon A
authors.initials: SA
authors.lastname: Meyer
authors.forename: Khalid A
authors.initials: KA
authors.lastname: El Sayed
mesh_terms: D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D000818:Animals; D001665:Binding Sites; D001688:Biological Products / Q000737:chemistry*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003198:Computer Simulation; D015195:Drug Design; D006801:Humans; D008297:Male; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D011161:Porifera / Q000737:chemistry; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D001688:Biological Products; C475724:bromotyrosine; D014443:Tyrosine; D040301:Vascular Endothelial Growth Factor Receptor-2