Kang Borui, Mottamal Madhusoodanan, Zhong Qiu, Bratton Melyssa, Zhang Changde, Guo Shanchun, Hossain Ahamed, Ma Peng, Zhang Qiang, Wang Guangdi, Payton-Stewart Florastina
Department of Chemistry, Xavier University of Louisiana, 1 Drexel Drive, New Orleans, LA 70125, USA.
RCMI Cancer Research Center, Xavier University of Louisiana, 1 Drexel Drive, New Orleans, LA 70125, USA.
Pharmaceuticals (Basel). 2023 May 12;16(5):735. doi: 10.3390/ph16050735.
Niclosamide effectively downregulates androgen receptor variants (AR-Vs) for treating enzalutamide and abiraterone-resistant prostate cancer. However, the poor pharmaceutical properties of niclosamide due to its solubility and metabolic instability have limited its clinical utility as a systemic treatment for cancer. A novel series of niclosamide analogs was prepared to systematically explore the structure-activity relationship and identify active AR-Vs inhibitors with improved pharmaceutical properties based on the backbone chemical structure of niclosamide. Compounds were characterized using H NMR, C NMR, MS, and elemental analysis. The synthesized compounds were evaluated for antiproliferative activity and downregulation of AR and AR-V7 in two enzalutamide-resistant cell lines, LNCaP95 and 22RV1. Several of the niclosamide analogs exhibited equivalent or improved anti-proliferation effects in LNCaP95 and 22RV1 cell lines (, IC LNCaP95 and 22RV1 = 0.130 and 0.0997 μM, respectively), potent AR-V7 down-regulating activity, and improved metabolic stability. In addition, both a traditional structure-activity relationship (SAR) and 3D-QSAR analysis were performed to guide further structural optimization. The presence of two -CF groups of the most active in the sterically favorable field and the presence of the -CN group of the least active in the sterically unfavorable field seem to make more potent than in the antiproliferative activity.
氯硝柳胺可有效下调雄激素受体变体（AR-Vs），用于治疗恩杂鲁胺和阿比特龙耐药的前列腺癌。然而，氯硝柳胺因其溶解性和代谢不稳定性导致的不良药物性质，限制了其作为癌症全身治疗药物的临床应用。基于氯硝柳胺的骨架化学结构，制备了一系列新型氯硝柳胺类似物，以系统地探索构效关系并鉴定具有改善药物性质的活性AR-Vs抑制剂。通过氢核磁共振（H NMR）、碳核磁共振（C NMR）、质谱（MS）和元素分析对化合物进行表征，并在两种恩杂鲁胺耐药细胞系LNCaP95和22RV1中评估合成化合物的抗增殖活性以及对AR和AR-V7的下调作用。几种氯硝柳胺类似物在LNCaP95和22RV1细胞系中表现出相当或更好的抗增殖效果（LNCaP95和22RV1的半数抑制浓度IC分别为0.130和0.0997 μM）、有效的AR-V7下调活性以及改善的代谢稳定性。此外，还进行了传统的构效关系（SAR）和三维定量构效关系（3D-QSAR）分析以指导进一步的结构优化。活性最高的化合物中两个-CF基团处于空间有利区域，活性最低的化合物中的-CN基团处于空间不利区域，这似乎使得前者在抗增殖活性方面比后者更强。
