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

• DOI: 10.3390/ph16020145
• Publication Date: 2023-01-19T10:50:20Z
• Authors: Carolina Pressete; Flávia Pereira Di...; Thâmara Gaspar Ca...; Ester Siqueira Ca...; João Adolfo Costa...; Guilherme Álvaro ...; Bruno Zavan; Alexandre Ferro A...; Marta Miyazawa; Claudio Viegas; Marisa Ionta
• Keywords: Piperine; Aurora kinase; PLK1

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