Copper conjugates of nimesulide Schiff bases targeting VEGF, COX and Bcl-2 in pancreatic cancer cells.
Copper conjugates of Schiff base derivatives of nimesulide (1), a well-known cyclooxygenase-2 (COX-2) inhibitor, were synthesized, structurally characterized and evaluated for their COX selectivity indices and cytotoxicities on pancreatic tumor, BxPC-3 (COX-2 positive) and MiaPaCa (COX-2 negative) cell lines. Copper conjugates exhibit distorted square planar geometries as revealed by the single crystal X-ray structure determination of Cu(L1)(2) and show significant growth inhibition in both cell lines (IC50 values 3-26 microM for COX-2 positive and 5-9 microM for COX-2 negative cell line) than the parent nimesulide (35 microM for COX-2 positive and >100 microM for COX-2 negative cell line). The mechanistic pathway for the biological activity involves inhibition of vascular endothelial growth factor (VEGF) and COX inhibition, as well as down regulation of antiapoptotic Bcl-2 and Bcl-(XL) proteins.
Ambike
Vinita
V
Department of Chemistry, University of Pune, Pune 411 007, India.
Adsule
Shreelekha
S
Ahmed
Fakhara
F
Wang
Zhiwei
Z
Afrasiabi
Zahra
Z
Sinn
Ekkehard
E
Sarkar
Fazlul
F
Padhye
Subhash
S
D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003300:Copper / Q000737:chemistry*; D051546:Cyclooxygenase 2 / Q000737:chemistry*; D004578:Electron Spin Resonance Spectroscopy; D006801:Humans; D008958:Models, Molecular; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000737:chemistry*; D012545:Schiff Bases; D013055:Spectrophotometry, Infrared; D013449:Sulfonamides / Q000737:chemistry*; D042461:Vascular Endothelial Growth Factor A / Q000737:chemistry*
D019253:Proto-Oncogene Proteins c-bcl-2; D012545:Schiff Bases; D013449:Sulfonamides; D042461:Vascular Endothelial Growth Factor A; D003300:Copper; D051546:Cyclooxygenase 2; C012655:nimesulide