Bender Onur, Celik Ismail, Dogan Rumeysa, Atalay Arzu, Shoman Mai E, Ali Taha F S, Beshr Eman A M, Mohamed Mahmoud, Alaaeldin Eman, Shawky Ahmed M, Awad Eman M, Ahmed Al-Shaimaa F, Younes Kareem M, Ansari Mukhtar, Anwar Sirajudheen
Biotechnology Institute, Ankara University, 06135 Ankara, Turkey.
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Erciyes University, 38280 Kayseri, Turkey.
ACS Omega. 2023 Feb 8;8(7):6968-6981. doi: 10.1021/acsomega.2c07793. eCollection 2023 Feb 21.
The structure-based design introduced indoles as an essential motif in designing new selective estrogen receptor modulators employed for treating breast cancer. Therefore, here, a series of synthesized vanillin-substituted indolin-2-ones were screened against the NCI-60 cancer cell panel followed by in vivo, in vitro, and in silico studies. Physicochemical parameters were evaluated with HPLC and SwissADME tools. The compounds demonstrated promising anti-cancer activity for the MCF-7 breast cancer cell line (GI = 6-63%). The compound with the highest activity () was selective for the MCF-7 breast cancer cell line (IC = 17.01 μM) with no effect on the MCF-12A normal breast cell line supported by real-time cell analysis. A morphological examination of the used cell lines confirmed a cytostatic effect of compound . It inhibited both in vivo and in vitro estrogenic activity, triggering a 38% reduction in uterine weight induced by estrogen in an immature rat model and hindering 62% of ER-α receptors in in vitro settings. In silico molecular docking and molecular dynamics simulation studies supported the stability of the ER-α and compound protein-ligand complex. Herein, we report that indolin-2-one derivative is a promising lead compound for further pharmaceutical formulations as a potential anti-breast cancer drug.
基于结构的设计将吲哚作为设计用于治疗乳腺癌的新型选择性雌激素受体调节剂的关键基序引入。因此，在此对一系列合成的香草醛取代的吲哚啉-2-酮针对NCI-60癌细胞系进行筛选，随后进行体内、体外和计算机模拟研究。使用HPLC和SwissADME工具评估理化参数。这些化合物对MCF-7乳腺癌细胞系显示出有前景的抗癌活性（生长抑制率 = 6 - 63%）。活性最高的化合物（）对MCF-7乳腺癌细胞系具有选择性（半数抑制浓度 = 17.01 μM），实时细胞分析表明其对MCF-12A正常乳腺细胞系无影响。对所用细胞系的形态学检查证实了化合物的细胞生长抑制作用。它在体内和体外均抑制雌激素活性，在未成熟大鼠模型中使雌激素诱导的子宫重量降低38%，在体外环境中阻碍62%的雌激素受体α。计算机模拟分子对接和分子动力学模拟研究支持了雌激素受体α与化合物的蛋白质-配体复合物的稳定性。在此，我们报道吲哚啉-2-酮衍生物作为一种潜在的抗乳腺癌药物是进一步药物制剂开发的有前景的先导化合物。
