Alkyl shikimates promote proliferation of human dermal fibroblasts and exhibit structure-activity relationships
Abstract
Alkyl shikimates (SAEs) bearing linear and branched alkyl groups (R) ranging from CH3 to C5H11 were synthesized and assayed for proliferative activity toward human dermal fibroblasts; proliferation increase (PRA), measured using a CCK-8 assay kit, was used as the primary endpoint. Several SAEs exhibited significant PRA, depending on the concentration added to the culture medium and alkyl group structure. However, shikimic acid (SA) added to the culture medium did not induce fibroblast proliferation. SAEs with CH3, C2H5, and C3H7 alkyl groups (SAE-1, SAE-2, and SAE-3a,b) induced a 30-50% increase in cell proliferation at a concentration of 5.5 mM, while SAEs with a C4H9 groups (SAE-4a,b,c) showed low PRA and those with a C5H11 groups (SAE-5a,b,c) exhibited strong cytotoxicity (CYT: decrease in cell viability) at this concentration. The proliferation rates of SAEs at 5.5 mM correlated significantly with their calculated log P (ClogP) values, which reflect hydrophobicity and cell membrane permeability (quadratic regression; coefficient of determination, r2 = 0.977-0.953. Based on these results, we proposed a mechanism in which membrane-permeable SAEs could form complexes with carboxylesterase (CES) present in dermal fibroblasts and be subsequently hydrolyzed into SA and alcohols (ALs) intracellularly, with the resulting SA potentially inducing PRA. In contrast, SA added extracellularly cannot enter cells due to its high hydrophilicity and therefore cannot induce PRA. In order…
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