Abstract

In continuation of our efforts to develop new antiproliferative agents that could be effective and selective in treatment of cancer, we designed and synthesized new hybrid structures containing an arylsulfonamide scaffold linked to a steroidal skeleton through a 1,2,3-triazole ring. Both in vitro cytotoxicity on breast MCF-7 cancer cells and human placental aromatase enzyme (pAROM) inhibition assays were performed on new hybrids. All new hybrids showed marked cytotoxic activity against breast MCF-7 cancer cells (IC₅₀ = 3.56–43.76 μM) in comparison to staurosporine (IC₅₀ = 4.06 μM). Tumor selectivity index was higher for some of the new hybrids on normal fibroblast (F-180) cells (TS = 1.5–25) in comparison to staurosporine (TS = 2.5). The p-nitro derivative exhibited the best inhibitory activity on the pAROM with an IC₅₀ of 64.6 ng/cm³, compared to hybrids unsubstituted derivative, p-bromo derivative, and letrozole (IC₅₀ = 375.14, 269.86, and 132.86 ng/cm³, respectively). Furthermore, the p-nitro hybrid arrested the cell cycle selectively at the G2/M phase, in addition to inducing both early and late apoptotic processes of breast MCF-7 cancer cells. Molecular docking studies were performed within pAROM to explore the binding modes of the new hybrids. Collectively, the antiproliferative profile of new hybrids indicates how good they are as promising leads for developing tumor-specific cytotoxins, and deserve further studies to optimize their structure and in vivo activity.

Graphic abstract

中文翻译：

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对MCF-7乳腺癌细胞具有抗增殖活性的新型杂类固醇杂种的开发

摘要

为了继续努力开发可以有效和选择性地治疗癌症的新型抗增殖药，我们设计并合成了新的杂化结构，其中包含通过1,2,3-三唑环与甾体骨架连接的芳基磺酰胺支架。在新的杂种上进行了对乳腺癌MCF-7癌细胞的体外细胞毒性和人胎盘芳香化酶（pAROM）抑制试验。 与星形孢菌素（IC ₅₀  = 4.06μM）相比，所有新杂种均显示出对乳腺癌MCF-7癌细胞具有明显的细胞毒活性（IC ₅₀ = 3.56-43.76μM ）。与星形孢菌素（TS = 2.5）相比，在正常成纤维细胞（F-180）（TS = 1.5–25）上，一些新杂种的肿瘤选择性指数更高。该p与未取代的衍生物，对溴衍生物和来曲唑的杂化物相比，-硝基衍生物对pAROM表现出最佳的抑制活性，IC ₅₀为64.6 ng / cm ³，IC _50分别 为375.14、269.86和132.86 ng / cm ³，分别）。此外，p除诱导乳腺MCF-7癌细胞的早期和晚期凋亡过程外，硝基硝基杂合体选择性地将细胞周期阻滞在G2 / M期。在pAROM内进行了分子对接研究，以探索新杂种的结合模式。总的来说，新杂种的抗增殖特性表明它们作为开发肿瘤特异性细胞毒素的有前途的线索有多好，值得进一步研究以优化其结构和体内活性。

图形摘要