Synthesis and activity of the salicylic acid ester of bakuchiol in psoriasiform keratinocytes and skin substitutes. Homo sapiens

Background: Topical retinoids are effective in retarding skin aging and restoring homeostasis in skin conditions, such as psoriasis. However their adverse effects, which include irritation (retinoid dermatitis), photosensitivity and teratogenicity, limit their use level and patient compliance. Development of a retinoid analogue with minimal adverse effects would allow a broader and more compliant use. Objective: Here we report the synthesis of a novel molecule - bakuchiol salicylate (bakusylan) with the gene expression modulatory profile similar to retinoids, using as reference 3 prescription retinoids - tretinoin, tazarotene and adapalene. Methods: Having a structure entirely different from existing retinoids, we hypothesized that at least a partial uncoupling of retinoid adverse effects from retinoid skin normalizing activity may be obtained with bakuchiol salicylate. This hypothesis was tested in psoriasiform cultures of keratinocytes and organotypic skin substitutes by DNA microarrays and custom PCR arrays. Results: The evaluation of the bioactivity of bakuchiol salicylate revealed the elimination of several components of the retinoid-like proinflammatory response and teratogenic signature without a substantial loss of normalizing potential. A possible mechanism of action consisting in keratinocyte desensitization to cytokine signaling through the inhibition of the STAT1/3/interferon inflammatory signal transduction axis has also been identified. Conclusion: Bipartite materials obtained by merging two skin-active entities with specific, complementary bioactivities, such as bakuchiol and salicylic acid, may deliver a new class of functional retinoids. Overall design: Psoriasiform epidermal keratinocyte cultures were generated by incubating keratinocytes with cytokines (IL-17A/IL-22/TNFα) for 24 hours (CnT-PCT media). Keratinocytes were then treated with control solvent (CS; 3% dimethyl isosorbide; 40% glycerin; 57% butylene glycol), control solvent supplemented with bakusylan (SE; 10ug/ml), or control solvent supplemented with all-trans-retinoic acid (ATRA; 0.1ug/ml). Two replicates were generated for each treatment group.