CAPE synthetic derivatives and their potential role in skin regeneration

Morbidity due to non-healing wounds significantly affects the patient's quality of life which makes long healing process a large and growing interdisciplinary clinical problem [1]. The development of new agents that could accelerate the healing of ulcers, acute and chronic wounds is needed. Apitherapy is an alternative therapy using products coming from honeybees as therapeutic approach in many conditions, including wound care. The caffeic acid phenethyl ester (CAPE), one of the main component of propolis, has antiseptic, anti- inflammatory, astringent, anesthetic and antioxidant activity, and its positive effects on skin regeneration have already been explored [2]. Hence, two different novel series of CAPE derivatives were designed, synthesized and evaluated as potential skin regenerative agents. The first series was designed to have an ester linkage (series A) while the second series would contain an amide linkage (series B) with different heterocyclic rings such as quinoline and isoquinoline. The 12 compounds were administered in different concentrations (0-80 µM) to two different cell types: human gingival fibroblasts (HGFs) and the keratinocyte cell line HACAT, meant to represent epidermidis and derma using both CAPE and caffeic acid as reference compounds. The viability and cell proliferation were evaluated by crystal violet. All the compounds showed no cytotoxicity at the lowest concentrations (0-20 µM), but four of them proved to stimulate cell proliferation, in a manner very similar to the cell exposed to CAPE. The most promising compounds were administered at very low concentrations (0, 0.5, 1 and 5 µM) to both types of cells submitted to a wound healing assay. Interestingly, both HGFs and HACAT treated with two compounds from series A and one compound from series B were more effective than the control cells and the CAPE-treated cells in closing the scratch. Since an interesting structure-activity relationship (SAR) was found, further studies on the most promising compounds will include investigation of the antibacterial activity, their effects on cells challenged with inflammatory and/or oxidative stimuli, absorption on biopolymers used for wound dressing applications and evaluation of biocompatibility, biodegradability, and toxicity.