School of Pharmacy and Pharmaceutical Sciences, Redwood Building, King Edward VII Avenue, CF10 3NB, Cardiff, Wales, UK.
School of Pharmacy and Pharmaceutical Sciences, Redwood Building, King Edward VII Avenue, CF10 3NB, Cardiff, Wales, UK.
Eur J Med Chem. 2016 Aug 8;118:230-43. doi: 10.1016/j.ejmech.2016.04.052. Epub 2016 Apr 22.
Prostate cancer (PC) is one of the major causes of male death worldwide and the development of new and more potent anti-PC compounds is a constant requirement. Among the current treatments, (R)-bicalutamide and enzalutamide are non-steroidal androgen receptor antagonist drugs approved also in the case of castration-resistant forms. Both these drugs present a moderate antiproliferative activity and their use is limited due to the development of resistant mutants of their biological target. Insertion of fluorinated and perfluorinated groups in biologically active compounds is a current trend in medicinal chemistry, applied to improve their efficacy and stability profiles. As a means to obtain such effects, different modifications with perfluoro groups were rationally designed on the bicalutamide and enzalutamide structures, leading to the synthesis of a series of new antiproliferative compounds. Several new analogues displayed improved in vitro activity towards four different prostate cancer cell lines, while maintaining full AR antagonism and therefore representing promising leads for further development. Furthermore, a series of molecular modelling studies were performed on the AR antagonist conformation, providing useful insights on potential protein-ligand interactions.
前列腺癌（PC）是全球男性死亡的主要原因之一，因此不断需要开发新的、更有效的抗 PC 化合物。在当前的治疗方法中，（R）-比卡鲁胺和恩杂鲁胺是两种非甾体雄激素受体拮抗剂药物，也可用于治疗去势抵抗性疾病。这两种药物都具有中等的抗增殖活性，但由于其生物靶标耐药突变体的出现，其应用受到限制。在药物化学中，将氟化和全氟化基团插入生物活性化合物是一种当前的趋势，用于提高其疗效和稳定性。作为获得这种效果的一种手段，我们在比卡鲁胺和恩杂鲁胺的结构上进行了合理的全氟基团修饰，从而合成了一系列新的具有抗增殖活性的化合物。一些新的类似物在体外对四种不同的前列腺癌细胞系表现出更好的活性，同时保持对 AR 的完全拮抗作用，因此代表了进一步开发的有希望的先导化合物。此外，我们还对 AR 拮抗剂构象进行了一系列分子建模研究，为潜在的蛋白-配体相互作用提供了有用的见解。
