Copper Conjugates of Nimesulide Schiff Bases Targeting VEGF, COX and Bcl-2 in Pancreatic Cancer Cells

Abstract

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 µM for COX-2 positive and 5-9 µM for COX-2 negative cell line) than the parent nimesulide (35 µM for COX-2 positive and >100 µM 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.

Department(s)

Chemistry

Keywords and Phrases

copper complex; cyclooxygenase 2 inhibitor; nimesulide; prostaglandin synthase; protein bcl 2; protein bcl xl; Schiff base; vasculotropin; article; controlled study; drug cytotoxicity; drug structure; drug synthesis; enzyme inhibition; human; human cell; pancreas cancer; structure analysis; X ray crystallography; Animals; Cell Line, Tumor; Cell Proliferation; Copper; Cyclooxygenase 2; Electron Spin Resonance Spectroscopy; Humans; Models, Molecular; Proto-Oncogene Proteins c-bcl-2; Schiff Bases; Spectrophotometry, Infrared; Sulfonamides; Vascular Endothelial Growth Factor A; BxPC-3; Copper complexes; Cyclooxygenase; MiaPaCa-2; Nimesulide

International Standard Serial Number (ISSN)

0162-0134

Document Type

Article - Journal

Document Version

Citation

File Type

text

Language(s)

English

Rights

© 2007 Elsevier, All rights reserved.

Publication Date

01 Oct 2007

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