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. 

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

Novel coumarin-indole derivatives were designed, synthesized and evaluated as tubulin polymerization inhibitors targeting the colchicine binding site. Among these compounds, compound MY-413 displayed the most potent inhibitory activities against gastric cancer cell line MGC-803 with an IC50 value of 0.011 μM. Furthermore, the IC50 values of compound MY-413 was less than 0.1 μM for other 17 cancer cell lines and less than 0.05 μM for other 8 cancer cell lines. Compound MY-413 effectively inhibited the tubulin polymerization (IC50 = 2.46 μM) by binding to the colchicine site. Screening for the inhibitory effects of compound MY-413 on 61 kinases, it was found that compound MY-413 could inhibit MAPK pathways-related kinases. Because of the inhibitory effects of compound MY-413 on tubulin polymerization and MAPK signaling pathway, compound MY-413 induced cell apoptosis, arrested the cell cycle in the G2/M phase, induced the inhibition of cell proliferation and migration in gastric cancer cells MGC-803 and HGC-27. In addition, compound MY-413 could significantly inhibit tumor growth in MGC-803 xenograft tumor models with tumor growth inhibition (TGI) rates of 70% (15 mg/kg) and 80% (30 mg/kg) without obvious toxicity. Consistent with the in vitro results, compound MY-413 also inhibited MAPK signaling pathway, and induced apoptosis and proliferation inhibition in vivo. In conclusion, this work indicated that compound MY-413 was a promising lead compound for the further investigation as a potential anti-gastric cancer agent. 

Discovery of novel coumarin-indole derivatives as tubulin polymerization inhibitors with potent anti-gastric cancer activities.

Discovery of 1,2,4-triazine dithiocarbamate derivatives as NEDDylation agonists to inhibit gastric cancers

Discovery of novel indole derivatives that inhibit NEDDylation and MAPK pathways against gastric cancer MGC803 cells.

Solvent-promoted and -controlled regioselective bond alkylation reactions of para-quinone methides (p-QMs) with N-H free-indoline and 1,2,3,4-tetrahydroquinoline (THQ) under metal-free conditions have been developed. In the presence of 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) as the solvent, 1,6-addition alkylation reactions of p-QMs with NH-free indolines and THQs efficiently gave C5-alkylated indolines and C6-alkylated THQs. Using catalytic amounts of HFIP in DCM, the reaction of indolines and p-QMs resulted in the alkylation of indolines at the N1-position. HFIP plays two roles in the reactions: converting the indoline and THQ into bidentate nucleophiles and activating the p-QMs to achieve the 1,6-addition alkylation via hydrogen bond clusters. The indoline and THQ act as a C-nucleophile due to the H-bond clusters between HFIP and the nitrogen atom, whereas upon using catalytic amounts of HFIP, the compounds act as an N-nucleophile. All alkylation products were transformed into the corresponding indoles and quinolines via oxidation in the presence of diethyl azodicarboxylate (DEAD). Furthermore, the synthetic utilities have been showcased with both the removal of the tert-butyl groups from the C5-alkylated indole products and submission to their Suzuki coupling reactions.

Solvent-controlled regioselective C(5)-H/N(1)-H bond alkylations of indolines and C(6)-H bond alkylations of 1,2,3,4-tetrahydroquinolines with para-quinone methides.

Hong-Yu Zhang

Papers

Discovery of indoline derivatives as anticancer agents via inhibition of tubulin polymerization

Review of NEDDylation inhibition activity detection methods