Derivatization of honokiol by integrated acetylation and methylation for improved cutaneous delivery and anti-inflammatory potency.

A set of honokiol derivatives was synthesized to evaluate skin permeation and bioactivity. The reaction for derivatization included acetylation and methylation. The anti-inflammatory activity against neutrophils and macrophages was examined. The experimental setup for the assessment of cutaneous absorption was the in vitro Franz diffusion assembly. Honokiol and its derivatives significantly downregulated superoxide anion and elastase production in neutrophils, with honokiol showing the greatest inhibition. All derivatives could be completely hydrolyzed to the parent compounds after passing into the skin. The skin deposition of honokiol at an infinite dose (3mM) was 0.33nmol/mg 4'-O-acetylhonokiol (AH), and 2,4'-diacetylhonokiol (DAH) exhibited comparable or less absorption than honokiol. The integrated acetylation and methylation (2-O-acetyl-4'-O-methylhonokiol, AMH) led to a 10.5-fold improvement of absorption compared to honokiol. AMH was advantageous for the targeted cutaneous treatment due to the high skin deposition and minimal penetration across the skin (8.40nmol/cm2 compared to 93.49nmol/cm2 for honokiol). The predicted therapeutic index for superoxide and interleukin (IL)-6 inhibition was much higher for topically applied AMH than for the other penetrants tested. The total polarity surface and hydrogen bond acceptor number calculated by molecular modeling were the parameters used to anticipate the cutaneous absorption. Our data suggest that AMH is a potent and safe candidate for cutaneous inflammation therapy.