Design, synthesis, and biological evaluation of dibromotyrosine analogues inspired by marine natural products as inhibitors of human prostate cancer proliferation, invasion, and migration.
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.
Sallam
Asmaa A
AA
Department of Basic Pharmaceutical Sciences, College of Pharmacy, University of Louisiana at Monroe, 1800 Bienville Drive, Monroe, LA 71201, USA.
Ramasahayam
Sindhura
S
Meyer
Sharon A
SA
El Sayed
Khalid A
KA
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
D020533:Angiogenesis Inhibitors; D001688:Biological Products; C475724:bromotyrosine; D014443:Tyrosine; D040301:Vascular Endothelial Growth Factor Receptor-2