Kandil Sahar, Westwell Andrew D, McGuigan Christopher
School of Pharmacy & Pharmaceutical Sciences, Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, Wales, United Kingdom.
School of Pharmacy & Pharmaceutical Sciences, Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, Wales, United Kingdom.
Bioorg Med Chem Lett. 2016 Apr 15;26(8):2000-4. doi: 10.1016/j.bmcl.2016.02.088. Epub 2016 Mar 2.
The clinically used androgen receptor (AR) antagonists (bicalutamide, flutamide and nilutamide) bind with low affinity to AR and can induce escape mechanisms. Furthermore, under AR gene amplification or mutation conditions they demonstrate agonist activity and fail to inhibit AR, causing relapse into castration resistant prostate cancer (CRPC). Discovery of new scaffolds distinct from the 4-cyano/nitro-3-(trifluoromethyl)phenyl group common to currently used antiandrogens is urgently needed to avoid cross-resistance with these compounds. In this study, a series of twenty-nine 7-substituted umbelliferone derivatives was prepared and their antiproliferative activities were evaluated. The most active compound 7a demonstrated submicromolar inhibitory activity in the human prostate cancer cell line (22Rv1); IC50=0.93 μM which represents a 50 fold improvement over the clinical antiandrogen bicalutamide (IC50=46 μM) and a more than 30 fold improvement over enzalutamide (IC50=32 μM). Interestingly, this compound showed even better activity against the human breast cancer cell line (MCF-7); IC50=0.47 μM. Molecular modelling studies provided a plausible theoretical explanation for our findings.
临床上使用的雄激素受体（AR）拮抗剂（比卡鲁胺、氟他胺和尼鲁米特）与AR的亲和力较低，且可诱导逃逸机制。此外，在AR基因扩增或突变的情况下，它们表现出激动剂活性，无法抑制AR，导致前列腺癌复发为去势抵抗性前列腺癌（CRPC）。迫切需要发现不同于目前使用的抗雄激素药物所共有的4-氰基/硝基-3-（三氟甲基）苯基的新骨架，以避免与这些化合物产生交叉耐药性。在本研究中，制备了一系列29种7-取代伞形酮衍生物，并评估了它们的抗增殖活性。活性最高的化合物7a在人前列腺癌细胞系（22Rv1）中表现出亚微摩尔级的抑制活性；IC50=0.93 μM，相较于临床抗雄激素药物比卡鲁胺（IC50=46 μM）有50倍的改善，相较于恩杂鲁胺（IC50=32 μM）有超过30倍的改善。有趣的是，该化合物对人乳腺癌细胞系（MCF-7）表现出更好的活性；IC50=0.47 μM。分子模拟研究为我们的发现提供了合理的理论解释。
