Design, synthesis and evaluation of novel bis-substituted aromatic amide dithiocarbamate derivatives as colchicine site tubulin polymerization inhibitors with potent anticancer activities

• Published in: European journal of medicinal chemistry Vol. 229; p. 114069
• Main Authors: Sun, Ya-Xin, Song, Jian, Kong, Li-Jun, Sha, Bei-Bei, Tian, Xin-Yi, Liu, Xiu-Juan, Hu, Tao, Chen, Ping, Zhang, Sai-Yang
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 05.02.2022; Elsevier
• Subjects: Amides - chemistry; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacology; Antiproliferative activity; Apoptosis - drug effects; Binding Sites; Bis-substituted aryl; Cell Line, Tumor; Cell Proliferation - drug effects; Chemistry, Medicinal; Colchicine - chemistry; Colchicine binding site; Cytoskeleton - metabolism; Cytoskeleton - ultrastructure; Dithiocarbamate; Drug Screening Assays, Antitumor; Humans; Life Sciences & Biomedicine; Molecular Docking Simulation; N-containing heterocycles; Pharmacology & Pharmacy; Polymerization; Protein Binding; Science & Technology; Signal Transduction; Structure-Activity Relationship; Thiocarbamates - chemical synthesis; Thiocarbamates - pharmacology; Tubulin; Tubulin - metabolism; Tubulin Modulators - chemical synthesis; Tubulin Modulators - pharmacology; Dithiocarbamate; Tubulin; N-containing heterocycles; Antiproliferative activity; Colchicine binding site; Bis-substituted aryl; MICROTUBULES; N -containing heterocycles; COMBRETASTATIN A4; HETEROCYCLES; GROWTH; LSD1; AGENTS; BINDING
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2021.114069

As the continuation of our work on the development of tubulin inhibitors with potential anticancer activities, novel bis-substituted aromatic amide dithiocarbamate derivatives were designed by contacting bis-substituted aryl scaffolds (potential anti-tubulin fragments) with N-containing heterocycles (potential anti-tubulin fragments) in one hybrid using the anticancer dithioformate unit as the linker. The antiproliferative activity against three digestive tract tumor cells was evaluated and preliminary structure activity relationships were summarized. Among these compounds, compound 20q exhibited most potent antiproliferative activity against MGC-803, HCT-116, Kyse30 and Kyse450 cells with IC50 values of 0.084, 0.227, 0.069 and 0.078 μM, respectively. In further studies, compound 20q was identified as a novel tubulin inhibitor targeting the colchicine binding site. Compound 20q could inhibit the microtubule assembly and disrupt cytoskeleton in Kyse30 and Kyse450 cells. The results of molecular docking suggested that compound 20q could tightly bind into the colchicine binding site of tubulin by hydrogen bonds and hydrophobic interactions. Compound 20q dose-dependently inhibited the cell growth and colony formation, effectively arrested cells at the G2/M phase and induce mitochondrial apoptosis in Kyse30 and Kyse450 cells. In addition, Compound 20q could regulate the expression of G2/M phase and mitochondrial apoptosis related proteins. Collectively, compound 20q was here reported as a novel tubulin inhibitor with potential anticancer activities. [Display omitted] •Bis-substituted aromatic amide dithiocarbamate derivatives were prepared.•Compound 20q exhibited low nanomolar antiproliferative efficacies.•Compound 20q acted as a novel colchicine site tubulin polymerization inhibitor.•Compound 20q arrested ESCC cells at G2/M phase and caused cells apoptosis.