Zahran Sally S, El-Gazzar Mostafa G M, El-Gazzar Marwa G, Ghorab Mostafa M
Department of Drug Radiation Research, National Center for Radiation Research and Technology (NCRRT), Egyptian Atomic Energy Authority (EAEA), Cairo 11787, Egypt.
Department of Drug Radiation Research, National Center for Radiation Research and Technology (NCRRT), Egyptian Atomic Energy Authority (EAEA), Cairo 11787, Egypt.
Bioorg Chem. 2025 Jun 15;160:108470. doi: 10.1016/j.bioorg.2025.108470. Epub 2025 Apr 15.
Aromatase catalyzes the rate-limiting and final step in the biosynthesis of estrogen. Inhibitors of this enzyme are effective targeted therapy for breast cancer. Molecular hybridization is a promising strategy in drug discovery that combines two or more biologically active moieties in a single structure. In this work, we aim at combining sulfonamide, chloropyridazine and pyrrole in a single design as potential aromatase inhibitors for breast cancer. The synthesized compounds were subjected to in vitro cytotoxic screening against MCF-7 breast cancer cell line, then were assessed for their ability to inhibit aromatase enzyme. Compound 10 exhibited a promising cytotoxic activity (IC 1.83 μM) that nearly equal to the reference drug (doxorubicin, IC 1.94 μM) on MCF-7 cells. Also, compound 10 was the most potent aromatase inhibitor with the lowest IC (0.06 μM) compared to letrozole (IC 0.05 μM). Based on the promising results of compound 10, it was selected to investigate its apoptotic effect that disclosed a marked increase in Bax level to 5.42 folds and down-regulation in Bcl-2 expression to 0.34 folds in MCF-7 cells compared to letrozole. Moreover, compound 10 increased caspase 9 level by 4.84 folds. Also, compound 10 arrested the cell cycle at G1 phase and caused induction of early and late apoptosis in an AnnexinV-FITC assay. Compound 10 had been evaluated to study its synergistic effect with γ-radiation by evaluating the cytotoxicity against MCF-7 after exposure to gamma rays (8 Gy). In addition, compound 10 showed low toxicity against human normal breast (MCF-10 A) cell line. Docking study of compound 10 was performed and showed binding with the key amino acids in aromatase active site.
芳香化酶催化雌激素生物合成中的限速及最终步骤。该酶的抑制剂是治疗乳腺癌的有效靶向疗法。分子杂交是药物研发中一种很有前景的策略，它将两个或更多生物活性部分结合在一个单一结构中。在本研究中，我们旨在将磺酰胺、氯哒嗪和吡咯结合在一个单一设计中，作为潜在的乳腺癌芳香化酶抑制剂。对合成的化合物进行针对MCF-7乳腺癌细胞系的体外细胞毒性筛选，然后评估它们抑制芳香化酶的能力。化合物10表现出有前景的细胞毒性活性（IC为1.83 μM），在MCF-7细胞上几乎与参考药物（阿霉素，IC为1.94 μM）相当。此外，与来曲唑（IC为0.05 μM）相比，化合物10是最有效的芳香化酶抑制剂，IC最低（0.06 μM）。基于化合物10的有前景结果，选择它来研究其凋亡效应，结果显示与来曲唑相比，在MCF-7细胞中，Bax水平显著增加至5.42倍，Bcl-2表达下调至0.34倍。此外，化合物10使半胱天冬酶9水平增加4.84倍。而且，在膜联蛋白V-异硫氰酸荧光素检测中，化合物10使细胞周期停滞在G1期并诱导早期和晚期凋亡。通过评估暴露于γ射线（8 Gy）后对MCF-7的细胞毒性，对化合物10进行了研究以考察其与γ辐射的协同效应。此外，化合物10对人正常乳腺（MCF-10 A）细胞系显示出低毒性。对化合物10进行了对接研究，结果显示它与芳香化酶活性位点的关键氨基酸结合。
