In Vitro Antioxidant and Pancreatic Anticancer Activity of Novel 5-Fluorouracil-Coumarin Conjugates

Abstract

Molecular hybridization consists of the combination of two or more non-identical pharmacophores in a single molecule. It has emerged as a promising strategy that allows the design of molecular frameworks with enhanced activity and affinity compared to their parent drugs. In this work, two novel hybrids that combine the well-known anticancer chemotherapeutic agent 5-fluorouracil with antioxidant coumarin derivatives have been synthesized and characterized by means of a copper-catalyzed azide-alkyne cycloaddition (CuAAC). The conjugates showed good antioxidant properties and a high tendency to aggregate and form stable nanoparticles in aqueous media, with regular shape and uniform size. These materials have proven to be preferential cytotoxic agents in vitro against human pancreatic cancer cells PANC-1, with an activity superior to free 5-fluorouracil. These results open up the possibility of exploiting the synergistic combination between 5-fluorouracil and coumarin derivatives and warrant further investigation of these hybrids as promising pancreatic anticancer agents.

Recent updates in click and computational chemistry for drug discovery and development

“…Similarly, the synthetic efficiency of biosynthesis of anti-fungal drug candidate Ilicicolin H increased 3 × 10 5 times via IEDDA ( Figure 1D ) ( Zhang et al, 2019 ). Moreover, 5-fluorouracil-coumarin conjugation ( Figure 1E ) as anti-cancer drug candidate ( ópez et al, 2022 ) and pH responsive doxorubicin delivery polymers nano-particles ( Wallat et al, 2018 )for treatment of breast and ovarian cancer were generated by modification of natural products via CuAAC. In addition, quercetin-gold quantum dots for adenocarcinoma treatment ( Pansare et al, 2022 ) and chondroitin sulfate-multiarmed PEG hydrogels for skin tissue engineering ( Sousa et al, 2022 ) had been developed by modification of natural products ( Figure 1F ).…”

Uracil: A Pharmacophore with Diverse Biological Potential

“…Lopez et al [38] synthesised novel 5-fluorouracil coumarin conjugates. The reaction involved treatment of 7-hydroxycoumarin 14 with propargyl bromide 15 in the presence of potassium carbonate to yield 7-propargyloxycoumarin 16 which on further treatment with 1,3-bis(5-azidopentyl)-5-fluorouracil 17 and pentamethyldiethylenetriamine (PMDTA) ligand using copper wire resulted in the formation of click product 18 (Scheme 5).…”