Potent combretastatin A-4 analogs containing 1,2,4-triazole: Synthesis, antiproliferative, anti-tubulin activity, and docking study

• Published in: European journal of medicinal chemistry Vol. 183; p. 111697
• Main Authors: Mustafa, Muhamad, Anwar, Sirajudheen, Elgamal, Firgani, Ahmed, Esam R., Aly, Omar M.
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 01-12-2019
• Subjects: 1,2,4-Triazole; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antiproliferation; Apoptosis - drug effects; Cell Proliferation - drug effects; Combretastatin A-4; Dose-Response Relationship, Drug; Hep G2 Cells; Humans; Molecular docking; Molecular Docking Simulation; Molecular Structure; Stilbenes - chemical synthesis; Stilbenes - chemistry; Stilbenes - pharmacology; Structure-Activity Relationship; Triazoles - chemistry; Triazoles - pharmacology; Tubulin; Tubulin - metabolism; Tubulin Modulators - chemical synthesis; Tubulin Modulators - chemistry; Tubulin Modulators - pharmacology; Antiproliferation; 1,2,4-Triazole; Combretastatin A-4; Tubulin; Molecular docking
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2019.111697

A series of cis restricted 1,2,4-triazole analogs of combretastatin A-4 (CA-4) were designed and synthesized. The antiproliferative activity of these compounds was measured on hepatocellular carcinoma HepG2, leukemia HL-60, and breast cancer MCF-7 cell lines. The obtained results showed a substantial ability of the synthesized anilides to inhibit tumor growth. On HepG2 cells, 5o and 5r showed potent IC50 values of 0.10 and 0.04 μM, respectively. While on HL-60 cells, the IC50 values were 0.004 and 0.01 μM for 5b and 5i, respectively. The inhibitory activity of tubulin polymerization was evaluated on HepG2 cells. The anilide 5r showed a remarkable tubulin inhibition compared to CA-4. Moreover, flow cytometry studies showed that HepG2 cells treated with the most potent compounds 5b and 5r were arrested in the G2/M phase of the cell cycle. This effect was accompanied by cellular apoptosis and activation of caspase-3. Molecular modeling showed several hydrogen bonding and van der Waals interactions with several important amino acids inside the colchicine binding site of tubulin.
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•New 1,2,4-triazole-3-carboxamide derivatives were designed and synthesized as potent combretastatin analogs.•In vitro antiproliferative activity was evaluated against HepG2, HL-60, and MCF-7 cell lines.•Compounds 5b, 5k, 5o, 5q, and 5r showed the highest promising anticancer activities.•Compounds 5b and 5r induced apoptosis, arrested cell cycle at G2/M phase and activated caspase-3.•Molecular modelling was carried out on the colchicine binding site of β-tubulin subunit.