A novel series of (Z)-3,5-disubstituted thiazolidine-2,4-diones 4-16 has been designed and synthesized. Preliminary screening of these compounds for their anti-breast cancer activity revealed that compounds 5, 7, and 9 possess the highest anti-cancer activities. The anti-tumor effects of compounds 5, 7, and 9 were evaluated against human breast cancer cell lines (MCF-7 and MDA-MB-231) and human breast cancer cells. They were also evaluated against normal non-cancerous breast cells, isolated from the same patients, to conclude about their use in a potential targeted therapy. Using MTT uptake method, these three compounds 5, 7, and 9 blunt the proliferation of these cancer cells in a dose-dependent manner with an IC50 of 1.27, 1.50 and 1.31 µM respectively. Interestingly, using flow cytometry analysis these three compounds significantly mediated apoptosis of human breast cancer cells without affecting the survival of normal non-cancerous breast cells that were isolated from the same patients. Mechanistically, these compounds blunt the proliferation of MCF-7 breast cancer cells by robustly decreasing the phosphorylation of AKT, mTOR and the expression of VEGF and HIF-1α. Most importantly, compounds 5, 7, and 9 without affecting the phosphorylation and expression of these crucial cellular factors in normal non-cancerous breast cells that were isolated from the same patients. Additionally, using Western blot analysis the three compounds significantly (P < 0.05) decreased the expression of the anti-apoptotic Bcl-2 members (Bcl-2, Bcl-XL and Mcl-1) and increased the expression of the pro-apoptotic Bcl-2 members (Bak, Bax and Bim) in MCF-7, MDA-MB-231 and human breast cancer cells making these breast cancer cells susceptible for apoptosis induction. Taken together, these data provide great evidences for the inhibitory activity of these compounds against breast cancer cells without affecting the normal breast cells.

中文翻译：

---

合成一系列新颖的（Z）-3,5-二取代噻唑烷-2,4-二酮作为有希望的抗乳腺癌药物。

设计并合成了一系列新的（Z）-3,5-二取代的噻唑烷-2,4-二酮4-16。对这些化合物的抗乳腺癌活性进行初步筛选显示，化合物5、7和9具有最高的抗癌活性。评价了化合物5、7和9对人乳腺癌细胞系（MCF-7和MDA-MB-231）和人乳腺癌细胞的抗肿瘤作用。还对它们从同一个患者中分离出来的正常非癌性乳腺癌细胞进行了评估，以得出它们在潜在靶向治疗中的用途的结论。使用MTT摄取方法，这三种化合物5、7和9以剂量依赖性方式抑制了这些癌细胞的增殖，IC50分别为1.27、1.50和1.31 µM。有趣的是 使用流式细胞仪分析这三种化合物可显着介导人乳腺癌细胞的凋亡，而不会影响从同一患者中分离的正常非癌性乳腺癌细胞的存活。从机理上讲，这些化合物通过强有力地降低AKT，mTOR的磷酸化以及VEGF和HIF-1α的表达来抑制MCF-7乳腺癌细胞的增殖。最重要的是，化合物5、7和9不会影响从同一患者中分离出来的正常非癌性乳腺癌细胞中这些关键细胞因子的磷酸化和表达。此外，使用蛋白质印迹分析，这三种化合物显着（P <0.05）降低了抗凋亡Bcl-2成员（Bcl-2，Bcl-XL和Mcl-1）的表达，并增加了促凋亡Bcl的表达。 -2个成员（Bak，Bax和Bim）在MCF-7，MDA-MB-231和人乳腺癌细胞中，使得这些乳腺癌细胞容易诱导凋亡。总之，这些数据提供了这些化合物对乳腺癌细胞的抑制活性而又不影响正常乳腺癌细胞的有力证据。