Hormone therapy is widely used in clinic for breast cancer treatment, such as tamoxifen, but long-term use can cause drug resistance. In this regard, a strategy based on small molecule-induced protein degradation, i.e. selective estrogen receptor downregulator (SERD), might be an effective alternative to hormone therapy for breast cancer. However, most of the SERD candidates involve very limited scaffolds and are still in clinical trials, and none of them has been approved for marketing. In this study, a series of novel 7-oxabicyclo[2.2.1]heptene sulfonamide (OBHSA) derivatives with long alkyl chains were identified as novel SERDs. We found that the position and the length of alkyl side chain have significant effect on the biological activity of the SERD compounds and with the six-carbon side chain was the best. Among them, compounds 23a and 36 displayed potent inhibitory activity against MCF-7 breast cancer cell line with IC₅₀ values of 0.84 μM and 0.77 μM, respectively, as well as excellent ERα degradation activity. Primary mechanism study indicated that the degradation of ERα is mediated through proteasome-mediated process. Flow cytometry analysis of apoptosis of 36 suggested that the effect of this type compounds on MCF-7 cells is associated with apoptosis. As such, these compounds have shown potential to become promising leads for the development of highly efficient SERDs for drug-resistance breast cancer therapies.

激素疗法在临床上广泛用于乳腺癌的治疗，如他莫昔芬，但长期使用会引起耐药性。在这方面，基于小分子诱导蛋白质降解的策略，即选择性雌激素受体下调剂 (SERD)，可能是乳腺癌激素治疗的有效替代方案。然而，大多数 SERD 候选者涉及的支架非常有限，并且仍在临床试验中，并且没有一个被批准上市。在这项研究中，一系列具有长烷基链的新型 7-氧杂双环 [2.2.1] 庚烯磺酰胺 (OBHSA) 衍生物被鉴定为新型 SERD。我们发现烷基侧链的位置和长度对SERD化合物的生物活性有显着影响，其中六碳侧链的效果最好。其中，化合物23a和36显示出对 MCF-7 乳腺癌细胞系的有效抑制活性，IC ₅₀值分别为 0.84 μM 和 0.77 μM，以及优异的 ERα 降解活性。主要机制研究表明，ERα 的降解是通过蛋白酶体介导的过程介导的。36个细胞凋亡的流式细胞术分析表明该类型化合物对MCF-7细胞的作用与细胞凋亡有关。因此，这些化合物已显示出有潜力成为开发用于耐药性乳腺癌治疗的高效 SERD 的有希望的先导物。