article · Journal of Enzyme Inhibition and Medicinal Chemistry
Triple-negative breast cancer presents a severe clinical challenge because it is aggressive, varied, and lacks standard molecular targets for treatment. To address this therapeutic gap, a single-step, three-component chemical reaction was used to synthesise a series of novel spirooxindole compounds, labelled 6a to 6p. These molecules were evaluated for their capacity to prevent the proliferation of MDA-MB-231 breast cancer cells in laboratory tests. Among the series, compounds 6a, 6e, and 6i demonstrated the highest potency against the malignant cells. Further testing showed that compounds 6a and 6e induced programmed cell death through changes in key apoptotic markers, including the up-regulation of Bax and caspase-3 and down-regulation of Bcl-2. Furthermore, compounds 6e and 6i inhibited the enzyme EGFR at nanomolar concentrations, highlighting compound 6e as a viable lead for anti-cancer drug development.
Triple-negative breast cancer is difficult to manage because it lacks standard therapeutic receptors, leaving patients with few targeted medicinal options. Identifying new chemical structures that can halt tumour cell growth and simultaneously inhibit driving enzymes such as EGFR offers a vital path forward. This research provides concrete molecular templates that could aid the development of more effective therapies for aggressive cancer types.
This research represents early-stage drug discovery aimed at oncology therapeutics. It provides chemical lead compounds, notably 6e, for pharmaceutical companies and medicinal chemistry teams seeking new treatments for triple-negative breast cancer. Significant development lies ahead, as the molecules require extensive chemical optimisation, selectivity profiling, and preclinical animal testing before any clinical or commercial pipeline can be established.
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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 IC<sub>50</sub> = 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 (IC<sub>50</sub> = 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.
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DOI: 10.1080/14756366.2017.1417276
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