Alkyl Shikimates Promote Proliferation of Human Dermal Fibroblasts and Exhibit Structure–Activity Relationships

The study investigated the effects of alkyl shikimates (SAEs) on human dermal fibroblast proliferation, revealing that SAEs with shorter alkyl chains (CH3, C2H5, C3H7) increased proliferation by 30-50% at 5.5 mM, while those with longer chains (C4H9, C5H11) showed low proliferation or cytotoxicity. The proliferation rates correlated with the hydrophobicity and membrane permeability of SAEs, suggesting that membrane-permeable SAEs form complexes with carboxylesterase in fibroblasts, leading to intracellular hydrolysis into shikimic acid (SA) and alcohols (ALs), with SA promoting proliferation. The study found no significant differences in binding energy between CES and SAEs, indicating that the differences in proliferation are likely due to the intracellular regeneration of SA and the varying toxicity of ALs based on alkyl chain length.