vincaleukoblastine and Head-and-Neck-Neoplasms

Head and neck squamous cell carcinoma (HNSCC) is a lethal disease with a terrible prognosis, accounting for more than 900,000 new cases and 500,000 deaths each year, nevertheless, its pharmacotherapy is rather limited. Parbendazole was previously identified as a potential HNSCC therapy candidate in our research. Herein, we report the discovery of two series of parbendazole derivatives as tubulin inhibitors. Structure-activity relationship (SAR) analyses led to the discovery of compound 9q with the best pharmacological activities and pharmacokinetic properties. This compound exhibited reasonable inhibition activity on cell proliferation (HN6, CAL-27, Fadu) and tubulin polymerization, induced cell apoptosis, blocked cell cycle and suppressed cell migration and invasion. Compound 9q also displayed low toxicity and a favorable therapeutic effect on a xenograft tumor, indicating that it is a promising starting point for further research.

Topics: Apoptosis; Benzimidazoles; Cell Line, Tumor; Cell Proliferation; Head and Neck Neoplasms; Humans; Squamous Cell Carcinoma of Head and Neck

A number of indole-3-glyoxylamides have previously been reported as tubulin polymerization inhibitors, although none has yet been successfully developed clinically. We report here a new series of related compounds, modified according to a strategy of reducing aromatic ring count and introducing a greater degree of saturation, which retain potent tubulin polymerization activity but with a distinct SAR from previously documented libraries. A subset of active compounds from the reported series is shown to interact with tubulin at the colchicine binding site, disrupt the cellular microtubule network, and exert a cytotoxic effect against multiple cancer cell lines. Two compounds demonstrated significant tumor growth inhibition in a mouse xenograft model of head and neck cancer, a type of the disease which often proves resistant to chemotherapy, supporting further development of the current series as potential new therapeutics.

Topics: Animals; Antineoplastic Agents; Caco-2 Cells; Cell Proliferation; Drug Screening Assays, Antitumor; Head and Neck Neoplasms; Heterografts; Humans; Indoles; Male; Mice; Mice, Nude; Microtubules; Neoplasm Transplantation; Structure-Activity Relationship; Tubulin; Tubulin Modulators