Design and Synthesis of Novel Celecoxib Analogues with Potential Cytotoxic and Pro-apoptotic Activity against Breast Cancer Cell Line MCF-7

Abstract

Background: Breast cancer is currently the leading cause of worldwide cancer incidence exceeding lung cancer. In addition, breast cancer accounts for 1 in 4 cancer cases and 1 in 6 cancer deaths among women. Cytotoxic chemotherapy is still the main therapeutic approach for patients with metastatic breast cancer. Objective: The aim of the study was to synthesize a series of novel celecoxib analogues to evaluate their anticancer activity against the MCF-7 cell line. Method: Our design of target compounds was based on preserving the pyrazole moiety of celecoxib attached to two phenyl rings, one of them having a polar hydrogen bonding group (sulfonamide or methoxy group). The methyl group of the second phenyl ring was replaced with chlorine or bromine atom. Finally, the trifluoromethyl group was replaced with arylidene hydrazine-1-carbonyl moiety, which is substituted either with fluoro or methoxy group, offering various electronic and lipophilic environments. These modifications were carried out to investigate their effects on the antiproliferative activity of the newly synthesized celecoxib analogues and to provide a valuable structure- activity relationship. Results: Four compounds, namely 4e-h, exhibited significant antitumor activity. Compounds 4e, 4f and 4h showed 1.2-2 folds more potent anticancer activity than celecoxib. Celecoxib analogue 4f showed the most potent anti-proliferative activity. Its anti-proliferative activity seems to associate well with its ability to inhibit BCL-2. Moreover, activation of the damage response pathway of the DNA leads to cell cycle arrest at the G2/M phase and accumulation of cells in the pre-G1 phase, indicating that cell death proceeds through an apoptotic mechanism. Compound 4f exhibited a potent pro-apoptotic effect via induction of the intrinsic mitochondrial pathway of apoptosis. This mechanistic pathway was proved by a significant increase in the expression of the tumor suppressor gene p53, elevation in Bax/BCL-2 ratio, and a significant increase in the level of active caspase-7. Furthermore, compound 4f showed moderate COX-2 inhibitory activity. Conclusion: Celecoxib analogue 4f is a promising multi-targeted lead for the design and synthesis of potent anticancer agents.