Novel Oxadiazole-Based Bioisostere of Caffeic Acid Phenethyl Ester: Synthesis, Anticancer Activity, and Inhibition of Lipoxygenase Product Biosynthesis

Caffeic acid phenethyl ester (1), a honeybee propolis component, possesses many bioactive properties, making it a useful scaffold for drug research. Further, CAPE (1) is a more effective inhibitor of the biosynthesis of 5-lipoxygenase (5-LO) products compared to Zileuton, the only clinically-approved direct 5-LO inhibitor. However, CAPE (1) suffers from a poor metabolic profile, being rapidly metabolized to caffeic acid (CA). In this study, we synthesized and performed several biological assays on a new bioisostere of CAPE (1) possessing a 1,2,4-oxadiazole ring. The new bioisostere (OB-CAPE (5)) has a similar antiproliferative effect to CAPE (1) on NCI-60 cancer cell lines and maintains the activity of CAPE (1) as an inhibitor of the biosynthesis of 5-, 12- and 15-LO products and as an iron chelator. In human polymorphonuclear leukocytes, OB-CAPE (5) inhibits the biosynthesis of 5-LO products with an IC₅₀ of 0.93 µM compared to 1.0 µM for CAPE (1). Both compounds have similar antioxidant activity, with IC₅₀ values of 1.2 µM for OB-CAPE (5) and 1.1 µM for CAPE (1). The new hydrogen bond predicted for the oxadiazole ring and the GLN363 amino acid in the 5-LO active site may explain the small improvement in the affinity of OB-CAPE (5) for the protein compared to CAPE (1). Finally, stability studies in human plasma reveal that OB-CAPE (5) is 25% more stable than CAPE (1). Therefore, the increase in stability associated with the replacement of the ester function with its bioisostere, while maintaining the anti-inflammatory and anticancer properties of CAPE (1), suggests that OB-CAPE (5) may be a comparable yet more stable candidate for in vivo studies in disease models.