Progesterone receptor (PR) antagonists have been found to be effective for treating certain human cancers. However, the steroidal structure of PR antagonists could bind to other hormone receptors, thus leading to serious side effects. On the other hand, non-steroidal PR antagonists have rarely been evaluated for their anti-cancer efficacy. Therefore, identifying novel non-steroidal PR antagonists possessing potent anti-cancer efficacy would be an attractive project to pursue. In this study, we presented a new metal-free oxidative CH arylation method to rapidly synthesize a series of 6-aryl-6H-benzo[c]chromene derivatives. Multiple cancer cell lines were used for their anti-cancer activity screening. An extensive analysis of structure–activity relationships (SAR) of the derivatives revealed that compounds 32 and 34 markedly inhibited the proliferation of MCF-7 cells with IC₅₀ values of 6.32 ± 0.52 μM and 5.71 ± 0.49 μM, respectively. Further investigation indicated that derivatives 32 and 34 could elevate the expression of p21 and decrease the expressions of CDK4 and cyclin D1, leading to cell cycle arrest at G0/G1 phase. In addition, derivatives 32 and 34 could induce apoptosis of MCF-7 cells in both dose- and time-dependent manners by activation of p53 pathway, i.e., activation of Cleaved Caspase-3, p53 and P-p53 as well as elevation of the Bax/Bcl-2 ratio. Docking of derivatives 32 and 34 into a PR homology model exhibited potent PR antagonistic activity indicating the 6-aryl-6H-benzo[c]chromene derivatives are promising PR antagonists. We envisioned that derivatives 32 and 34 might be potential anti-cancer drug candidates as novel therapeutic treatment for breast cancer.

已发现孕酮受体 (PR) 拮抗剂可有效治疗某些人类癌症。然而，PR拮抗剂的甾体结构可以与其他激素受体结合，从而导致严重的副作用。另一方面，很少评估非甾体 PR 拮抗剂的抗癌功效。因此，鉴定具有有效抗癌功效的新型非甾体 PR 拮抗剂将是一个有吸引力的项目。在这项研究中，我们提出了一种新的无金属氧化 C H 芳基化方法来快速合成一系列 6-芳基-6 H-苯并[ c]色烯衍生物。使用多种癌细胞系进行抗癌活性筛选。衍生物的构效关系 (SAR) 的广泛分析显示，化合物32和34显着抑制 MCF-7 细胞的增殖，IC ₅₀值分别为 6.32 ± 0.52 μM 和 5.71 ± 0.49 μM。进一步研究表明，衍生物32和34可以提高p21的表达，降低CDK4和细胞周期蛋白D1的表达，导致细胞周期停滞在G0/G1期。此外，衍生物32和34可以通过激活 p53 途径，即激活 Cleaved Caspase-3、p53 和 P-p53 以及 Bax/Bcl-2 比率的升高，以剂量和时间依赖性方式诱导 MCF-7 细胞凋亡。将衍生物32和34 对接到 PR 同源模型中表现出有效的 PR 拮抗活性，表明 6-芳基-6 H-苯并 [ c ] 色烯衍生物是有前途的 PR 拮抗剂。我们设想衍生物32和34可能是潜在的抗癌药物候选物，作为乳腺癌的新型治疗方法。