Evaluation of 5-hydroxy-2,3-diaryl (substituted)-cyclopent-2-en-1-ones as cis-restricted analogues of combretastatin A-4 as novel anti angiogenic and anticancer agents.
Two potent cis-restricted CA-4 analogues 11 and 42 belonging to 2,3-diaryl-5-hydroxycyclopent-2-en-1-one class were evaluated for anticancer and anti angiogenic activity. The compound 42 displayed potent cytotoxic activity (IC(50) < 1 muM) against a panel of human cancer cell lines viz PTC, MDA.MB.453, PA1, SKOV3, DU145 and Miapaca2, whereas compound 11 displayed cytotoxicity activity (IC(50) < 1 microM) only in Miapaca2. Both the compounds inhibit growth factor stimulated endothelial cell proliferation, migration and capillary tube formation. In all the above parameter compound 42 was superior to 11. Based on the above results compound 42 was assessed for inhibition of vasculature in vivo and showed significant inhibition at 25 mg/kg dose. Further it was evaluated for in vivo anti tumor activity in athymic mice bearing DU145 and SKVO3 tumor xenograft and showed regression in tumor volume (T/C) of 23.8% (CA-4), 50.1% (compound 42) and 23.5% (CA-4), 56% (compound 42) respectively at a dose of 20 mg/kg (i.v.) daily for 14 days.
Preclinical Research Lab, Dabur Research Foundation, 22, Site-IV, Sahibabad, Ghaziabad, Uttar Pradesh, 201010, India. vinod.sanna@daburresearch.in
Vinod Kumar
VK
Sanna
Manu
M
Jaggi
Vadlapudi
V
Kumar
Anand C
AC
Burman
D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D013267:Stilbenes / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014945:Wound Healing / Q000187:drug effects
D020533:Angiogenesis Inhibitors; D000972:Antineoplastic Agents, Phytogenic; D013267:Stilbenes; D053148:Caspase 3; C058728:fosbretabulin