One-pot three-component synthesis of novel spirooxindoles with potential cytotoxic activity against triple-negative breast cancer MDA-MB-231 cells

Journal of Enzyme Inhibition and Medicinal Chemistry

Dina H. EL-Naggar¹  Hatem A. Abdel-Aziz¹  Hazem A. Ghabbour²  Hany S. Ibrahim³  Wagdy M. Eldehna⁴  Ahmed R. Hamed⁵ 

[1] Department of Applied Organic Chemistry, National Research Center, Giza, Egypt;Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt;Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabi;Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Egyptian Russian University, Badr City, Cairo, Egypt;Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafr El-Sheikh, Egypt;Department of Phytochemistry, National Research Center, Giza, Egypt;Biology Unit, Central Laboratory of the Pharmaceutical & Drug Industries Research Division, National Research Center, Giza, Egypt;

关键词: Triple-negative breast cancer;    spirooxindoles;    anti-proliferative activity;    apoptosis;    EGFR;   

DOI  :  10.1080/14756366.2017.1417276

来源: publisher

【 摘 要 】

Triple-negative breast cancer (TNBC) is a highly aggressive malignancy with limited treatment options due to its heterogeneity and the lack of well-defined molecular targets. In our endeavour towards the development of novel anti-TNBC agents, herein we report a one-pot three-component synthesis of novel spirooxindoles 6a–p, and evaluation of their potential anti-proliferative activity towards TNBC MDA-MB-231 cells. Spirooxindoles 6a, 6e and 6i emerged as the most potent analogues with IC50 = 6.70, 6.40 and 6.70 µM, respectively. Compounds 6a and 6e induced apoptosis in MDA-MB-231 cells, as evidenced by the up-regulation of the Bax and down-regulation of the Bcl-2, besides boosting caspase-3 levels. Additionally, 6e displayed significant increase in the percent of annexin V-FITC positive apoptotic cells from 1.34 to 44%. Furthermore, spirooxindoles 6e and 6i displayed good inhibitory activity against EGFR (IC50 = 120 and 150 nM, respectively). Collectively, these data demonstrated that 6e might be a potential lead compound for the development of effective anti-TNBC agents.

【 授权许可】

CC BY