S‐(4‐Methoxyphenyl)‐4‐methoxybenzenesulfonothioate as a Promising Lead Compound for the Development of a Renal Carcinoma Agent

• Published in: ChemMedChem 2020-03, Vol.15 (5), p.449-458
• Main Authors: Nantes, Camilla I., Pereira, Ingrid D., Bai, Ruoli, Hamel, Ernest, Burnett, James C., Oliveira, Rodrigo J., F. C. Matos, Maria, Beatriz, Adilson, Yonekawa, Murilo K. A., Perdomo, Renata T., Lima, Dênis P., Bogo, Danielle, A. dos Santos, Edson
• Format: Article
• Language: English
• Subjects: 786-0 cells; Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis; Biotechnology; Cancer; Carcinoma, Renal Cell - drug therapy; Carcinoma, Renal Cell - metabolism; Carcinoma, Renal Cell - pathology; Caspase; caspase-3; Cell death; Cell Line; Cell proliferation; Cell Proliferation - drug effects; Cytotoxicity; Disulfides; Drug Screening Assays, Antitumor; Endoplasmic reticulum; Humans; Kidney cancer; Kidney Neoplasms - drug therapy; Kidney Neoplasms - metabolism; Kidney Neoplasms - pathology; Lead compounds; Mice; Molecular Docking Simulation; Molecular Structure; Organosulfur compounds; Polymerization; Polymerization - drug effects; Protein folding; Proteins; Renal cell carcinoma; thiosulfonates; Tubulin; Tubulin - metabolism; Tumor cell lines; Tumors
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.201900566

Organosulfur compounds show cytotoxic potential towards many tumor cell lines. Disulfides and thiosulfonates act through apoptotic processes, inducing proteins associated with apoptosis, endoplasmic reticulum stress, and the unfolded protein response. Three p‐substituted symmetric diaryl disulfides and three diaryl thiosulfonates were synthesized and analyzed for inhibition of tubulin polymerization and for human cancer cell cytotoxic activity against seven tumor cell lines and a non‐tumor cell line. S‐(4‐methoxyphenyl)‐4‐methoxybenzenesulfonothioate (6) exhibited inhibition of tubulin polymerization and showed the best antiproliferative potential, especially against the 786‐0 cell line, being six times more selective as compared with the non‐tumor cell line. In addition, compound 6 was able to activate caspase‐3 after 24 and 48 h treatments of the 786‐0 cell line and induced cell‐cycle arrest in the G2/M stage at the highest concentration evaluated at 24 and 48 h. Compound 6 was able to cause complete inhibition of proliferation, inducing the death of 786‐0 cells, by increasing the number of cells at G2/M and greater activation of caspase‐3. Repurposing a diaryl thiosulfonate: S‐(4‐methoxyphenyl)‐4‐methoxybenzenesulfonothioate (6) exhibited antitubulin activity. Compound 6 showed antiproliferative activity against the 786‐0 cell line, induces morphological alterations and death in 786‐0 cells, activates caspase‐3, and induces G2/M phase cell‐cycle arrest in 786‐0 cells.