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.
Kandil, S., Westwell, A. D., & Mcguigan, C. (2016). 7-Substituted umbelliferone derivatives as androgen receptor antagonists for the potential treatment of prostate and breast cancer. Bioorganic and Medicinal Chemistry Letters, 26(8), 2000–2004. https://doi.org/10.1016/j.bmcl.2016.02.088