Department of Pharmaceutical Sciences and Natural Products. Central University of Punjab, Ghudda, Bathinda (Pb) 151401, India.
Department of Zoology, Central University of Punjab, Ghudda, Bathinda (Pb) 151401, India.
Bioorg Chem. 2024 Jun;147:107341. doi: 10.1016/j.bioorg.2024.107341. Epub 2024 Apr 5.
A series of new indole-oxadiazole derivatives was designed and synthesized to develop potential anti-breast cancer agents. The compounds exhibited significant inhibitory activity with IC values ranging from 1.78 to 19.74 μM against ER-positive human breast cancer (BC) cell lines T-47D and MCF-7. Among them, compounds (5a, 5c, 5e-5h, 5j-5o) displayed superior activity against ER-α dominant (ratio of ER-α/ER-β is 9/1) T-47D cells compared to the standard drug bazedoxifene (IC = 12.78 ± 0.92 μM). Compounds 5c and 5o exhibited remarkable anti-proliferative activity with IC values of 3.24 ± 0.46 and 1.72 ± 1.67 μM against T-47D cells, respectively. Further, compound 5o manifested 1589-fold higher ER-α binding affinity (213.4 pM) relative to bazedoxifene (339.2 nM) in a competitive ER-α binding assay, while compound 5c showed a binding affinity of 446.6 nM. The Western blot analysis proved that both compounds influenced the ER-α protein's expression, impeding its subsequent transactivation and signalling pathway within T-47D cells. Additionally, a molecular docking study suggests that compounds 5c and 5o bind in such a fashion that induces conformational changes in the protein, culminating in their antagonistic effect. Also, pharmacokinetic profiles showed that all compounds have drug-like properties. Further, molecular dynamic (MD) simulations and density functional theory (DFT) analysis confirmed the stability, conformational behaviour, reactivity, and biological feasibility of compounds 5c and 5o. In conclusion, based on our findings, compounds 5c and 5o, which exhibit significant ER-α antagonistic activity, can act as potential lead compounds for developing anti-breast cancer agents.
一系列新的吲哚-噁二唑衍生物被设计和合成，以开发潜在的抗乳腺癌药物。这些化合物对 ER 阳性人乳腺癌（BC）细胞系 T-47D 和 MCF-7 的 IC 值范围为 1.78-19.74 μM，表现出显著的抑制活性。其中，化合物（5a、5c、5e-5h、5j-5o）对 ER-α 优势（ER-α/ER-β 比值为 9/1）的 T-47D 细胞的活性优于标准药物巴多昔芬（IC = 12.78 ± 0.92 μM）。化合物 5c 和 5o 对 T-47D 细胞表现出显著的抗增殖活性，IC 值分别为 3.24 ± 0.46 和 1.72 ± 1.67 μM。此外，在竞争性 ER-α 结合测定中，化合物 5o 对 ER-α 的结合亲和力（213.4 pM）相对于巴多昔芬（339.2 nM）高 1589 倍，而化合物 5c 的结合亲和力为 446.6 nM。Western blot 分析证明，这两种化合物均影响 ER-α 蛋白的表达，阻止其在 T-47D 细胞中的后续转激活和信号通路。此外，分子对接研究表明，化合物 5c 和 5o 以诱导蛋白质构象变化的方式结合，从而产生拮抗作用。此外，药代动力学谱表明，所有化合物均具有类药性。进一步的分子动力学（MD）模拟和密度泛函理论（DFT）分析证实了化合物 5c 和 5o 的稳定性、构象行为、反应性和生物可行性。总之，根据我们的研究结果，化合物 5c 和 5o 具有显著的 ER-α 拮抗活性，可作为开发抗乳腺癌药物的潜在先导化合物。
