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

Abstract

Coumarin-hydroxamic acid derivatives 7a–k 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 7c, 7e, 7f, 7i and 7j 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 7c, 7e, 7f, 7i and 7j 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 7j and 7k suggest that they can provide further insight into the mechanism of action.

Novel Coumarin Derivatives Inhibit the Quorum Sensing System and Iron Homeostasis as Antibacterial Synergists against Pseudomonas aeruginosa

“…In this study, we used a hybridization strategy to design and synthesize a lot of coumarin-hydroxamic acid derivatives − and successfully conducted a hit-to-lead campaign, resulting in a dual-acting biofilm inhibitor as an antibacterial synergist. The hit compound 4t has the lowest IC 50 value at 3.66 μM and exhibited promising antibiofilm activity for P. aeruginosa.…”

Anthracenyl Functionalization of Half-Sandwich Carbene Complexes: In Vitro Anticancer Activity and Reactions with Biomolecules

“…To trace anticancer compounds in cells and learn more about their modes of action, fluorescent moieties have often been conjugated to the drug scaffold. − Such approaches have also been employed in organometallic anticancer drug design using fluorescent probes such as 2,6-bis­(imidazole-2-yl)­pyridine, naphthal­imide, and anthracene derivatives . In the case of Ru­(arene) compounds, functionalization can occur at the arene ring or through the introduction of a fluorophore on one of the other ligands coordinated to the Ru center, and several successful approaches have been reported. − The combination of a bioactive metal complex and fluorescent moieties may also provide a pathway to the development of theranostics, − although such a modification of the bioactive scaffold may alter the cellular uptake and intracellular distribution due to significant changes in the lipophilicity as compared to the pharmacophore.…”

Potential of histone deacetylase inhibitors in the control and regulation of prostate, breast and ovarian cancer

“…In another investigation (García et al, 2020), fluorescent coumarin-hydroxamic acid derivatives were designed as HDACi. The designed compounds, which were actually hybrids of vorinostat and coumarin, were initially tested against two breast carcinoma (i.e., BT-474 and MDA-MB-231) and one prostate cancer (i.e., PC-3) cell lines to choose the most potential hits and some of these were found to downregulate the expressions of cell-cycle regulatory genes such as p21, p53 and cyclin D1 (CD1) in both breast and prostate cancer cells.…”