Piperine-Chlorogenic Acid Hybrid Inhibits the Proliferation of the SK-MEL-147 Melanoma Cells by Modulating Mitotic Kinases

Melanoma is considered the most aggressive form of skin cancer, showing high metastatic potential and persistent high mortality rates despite the introduction of immunotherapy and targeted therapies. Thus, it is important to identify new drug candidates for melanoma. The design of hybrid molecules, with different pharmacophore fragments combined in the same scaffold, is an interesting strategy for obtaining new multi-target and more effective anticancer drugs. We designed nine hybrid compounds bearing piperine and chlorogenic acid pharmacophoric groups and evaluated their antitumoral potential on melanoma cells with distinct mutational profiles SK-MEL-147, CHL-1 and WM1366. We identified the compound named PQM-277 (3a) to be the most cytotoxic one, inhibiting mitosis progression and promoting an accumulation of cells in pro-metaphase and metaphase by altering the expression of genes that govern G2/M transition and mitosis onset. Compound 3a downregulated FOXM1, CCNB1, CDK1, AURKA, AURKB, and PLK1, and upregulated CDKN1A. Molecular docking showed that 3a could interact with the CUL1-RBX1 complex, which activity is necessary to trigger molecular events essential for FOXM1 transactivation and, in turn, G2/M gene expression. In addition, compound 3a effectively induced apoptosis by increasing BAX/BCL2 ratio. Our findings demonstrate that 3a is an important antitumor candidate prototype and support further investigations to evaluate its potential for melanoma treatment, especially for refractory cases to BRAF/MEK inhibitors.

Automated summary

Melanoma, the most aggressive form of skin cancer, remains highly metastatic and deadly despite advances in immunotherapy and targeted therapies. In this study, we designed hybrid compounds combining pharmacophores from piperine and chlorogenic acid to explore potential antitumoral properties. Among the compounds tested, PQM-277 (3a) showed the highest cytotoxicity on melanoma cells, inhibiting mitosis progression and altering gene expression related to G2/M transition and mitosis onset. Furthermore, compound 3a interacted with the CUL1-RBX1 complex and induced apoptosis by increasing the BAX/BCL2 ratio. These findings suggest that compound 3a has promising potential as an antitumor candidate for melanoma treatment, especially in refractory cases.