Design of Fluorescent Coumarin-Hydroxamic Acid Derivatives as Inhibitors of HDACs: Synthesis, Anti-Proliferative Evaluation and Docking Studies

• Published in: Molecules (Basel, Switzerland) Switzerland), 2020-11, Vol.25 (21), p.5134
• Main Authors: García, Santiago, Mercado-Sánchez, Itzel, Bahena, Luis, Alcaraz, Yolanda, García-Revilla, Marco A, Robles, Juvencio, Santos-Martínez, Nancy, Ordaz-Rosado, David, García-Becerra, Rocío, Vazquez, Miguel A
• Format: Article
• Language: English
• Subjects: Acids; Antiproliferatives; Apoptosis; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell cycle; Cell growth; Cell proliferation; Cell Proliferation - drug effects; Coumarin; coumarins; Coumarins - chemical synthesis; Coumarins - chemistry; Coumarins - pharmacology; Cyclin D1; Cyclin-dependent kinase; Cyclin-dependent kinase inhibitor p21; Cyclin-dependent kinases; docking analysis; Drug Screening Assays, Antitumor; Enzyme inhibitors; Enzymes; Female; Fluorescent Dyes - chemistry; Fluorescent Dyes - pharmacology; Fluorescent indicators; fluorescent probe; Gene expression; Gene regulation; HDAC; Histone Deacetylase Inhibitors - chemical synthesis; Histone Deacetylase Inhibitors - chemistry; Histone Deacetylase Inhibitors - pharmacology; Histones; Humans; Hydroxamic acid; hydroxamic acids; Hydroxamic Acids - chemistry; Hydroxamic Acids - pharmacology; Kinases; Male; Molecular docking; Molecular Docking Simulation; Neoplasm Proteins - antagonists & inhibitors; Neoplasm Proteins - metabolism; p53 Protein; PC-3 Cells; Prostate cancer; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Structure-Activity Relationship; Tumor cell lines; Tumor suppressor genes
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules25215134

Coumarin-hydroxamic acid derivatives - were herein designed with a dual purpose: as antiproliferative agents and fluorescent probes. The compounds were synthesized in moderate yields (30-87%) through a simple methodology, biological evaluation was carried out on prostate (PC3) and breast cancer (BT-474 and MDA-MB-231) cell lines to determine the effects on cell proliferation and gene expression. For compounds , , , and the inhibition of cancer cell proliferation was similar to that found with the reference compound at a comparable concentration (10 μM), in addition, their molecular docking studies performed on histone deacetylases 1, 6 and 8 showed strong binding to the respective active sites. In most cases, antiproliferative activity was accompanied by greater levels of cyclin-dependent kinase inhibitor p21, downregulation of the p53 tumor suppressor gene, and regulation of cyclin D1 gene expression. We conclude that compounds , , , and may be considered as potential anticancer agents, considering their antiproliferative properties, their effect on the regulation of the genes, as well as their capacity to dock to the active sites. The fluorescent properties of compound and suggest that they can provide further insight into the mechanism of action.