Design, Synthesis, and Evaluation of Niclosamide Analogs as Therapeutic Agents for Enzalutamide-Resistant Prostate Cancer

• Published in: Pharmaceuticals (Basel, Switzerland) Vol. 16; no. 5; p. 735
• Main Authors: Kang, Borui, Mottamal, Madhusoodanan, Zhong, Qiu, Bratton, Melyssa, Zhang, Changde, Guo, Shanchun, Hossain, Ahamed, Ma, Peng, Zhang, Qiang, Wang, Guangdi, Payton-Stewart, Florastina
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 12.05.2023; MDPI
• Subjects: androgen receptor variant 7 (AR-V7) down-regulators; Androgen suppression therapy; Androgens; Cancer therapies; Cytotoxicity; Drug therapy; enzalutamide-resistant prostate cancer; Hormone therapy; Ligands; niclosamide analogs; Patient outcomes; Pharmaceuticals; Prostate cancer; Proteins; structure–activity relationship (SAR); United States; androgen receptor variant 7 (AR-V7) down-regulators; niclosamide analogs; enzalutamide-resistant prostate cancer; structure–activity relationship (SAR)
• ISSN: 1424-8247; 1424-8247
• 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.