Anti-tumor and anti-angiogenic activity of novel hydantoin derivatives: Inhibition of VEGF secretion in liver metastatic osteosarcoma cells.
A series of new azaspiro bicyclic hydantoin derivatives has been designed and synthesized. Initially, the anti-proliferative effect of the hydantoin derivatives was evaluated against human ovarian cancer cells (SKOV-3 and OVSAHO) and murine osteosarcoma cells (LM8 and LM8G7). Among the tested compounds, 8-(3-fluorobenzyl)-1'-(4-(methylsulfonyl)benzyl)-8-azaspiro[bicyclo[3.2.1]octane-3,4'-imidazolidine]-2',5'-dione (7h) and 8-(3,4-difluorobenzyl)-1'-(4-(methylsulfonyl)benzyl)-8-azaspiro[bicyclo[3.2.1]octane-3,4'-imidazolidine]-2',5'-dione (7i) showed a significant anti-proliferative activity against the OVSAHO and LM8G7 cells. The real-time monitoring of the effect of the compounds 7h and 7i against the proliferation of LM8G7 was revealed that resulting IC(50) values were 102microM and 13microM, respectively. We reasoned that the presence of fluorine atom at the 3rd position of the phenyl ring of the hydantoin side chain may determine the potency of the molecule. Furthermore, the compound 7i inhibited the tube formation of the mouse endothelial cells. Finally, the treatment of the compound 7i against the proliferation of LM8G7 cells demonstrated the down regulation of the secretion of VEGF, indicate the potential angioinhibitory effects. In conclusion, our findings demonstrate the suppression of the secretion of VEGF by LM8G7 cells by the compound 7i might contribute at least in part to the antitumor action.
Basappa
Graduate School of Life Science, Hokkaido University, Sapporo 001-0021, Japan.
Ananda Kumar
C S
CS
Nanjunda Swamy
S
S
Sugahara
Kazuyuki
K
Rangappa
Kanchugarakoppal S
KS
D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006801:Humans; D006827:Hydantoins / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D008099:Liver / Q000166:cytology / Q000473:pathology; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000556:secondary; D051379:Mice; D015394:Molecular Structure; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D012516:Osteosarcoma / Q000188:drug therapy* / Q000556:secondary; D010051:Ovarian Neoplasms / Q000188:drug therapy; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D006827:Hydantoins; D042461:Vascular Endothelial Growth Factor A