A Novel MDM2-Binding Chalcone Induces Apoptosis of Oral Squamous Cell Carcinoma

Oral squamous cell carcinoma (OSCC) represents similar to 90% of all oral cancers, being the eighth most common cancer in men. The overall 5-year survival rate is only 39% for metastatic cancers, and currently used chemotherapeutics can cause important side effects. Thus, there is an urgency in developing new and effective anti-cancer agents. As both chalcones and 1,2,3-triazoles are valuable pharmacophores/privileged structures in the search for anticancer compounds, in this work, new 1,2,3-triazole-chalcone hybrids were synthesized and evaluated against oral squamous cell carcinoma. By using different in silico, in vitro, and in vivo approaches, we demonstrated that compound 1f has great cytotoxicity and selectivity against OSCC (higher than carboplatin and doxorubicin) and other cancer cells in addition to showing minimal toxicity in mice. Furthermore, we demonstrate that induced cell death occurs by apoptosis and cell cycle arrest at the G2/M phase. Moreover, we found that 1f has a potential affinity for MDM2 protein, similar to the known ligand nutlin-3, and presents a better selectivity, pharmacological profile, and potential to be orally absorbed and is not a substrate of Pg-P when compared to nutlin-3. Therefore, we conclude that 1f is a good lead for a new chemotherapeutic drug against OSCC and possibly other types of cancers.

Automated summary

Oral squamous cell carcinoma (OSCC) is the majority of oral cancers and the eighth most common cancer in men. Current chemotherapeutics have significant side effects, necessitating the development of new anti-cancer agents. In this study, new 1,2,3-triazole-chalcone hybrids were synthesized and evaluated against OSCC, showing great cytotoxicity and selectivity. The compound 1f was found to induce apoptosis and cell cycle arrest, and it also showed potential affinity for the MDM2 protein. Overall, 1f is a promising lead for a new chemotherapeutic drug against OSCC and possibly other types of cancers.