title: Methylation and Esterification of Magnolol for Ameliorating Cutaneous Targeting and Therapeutic Index by Topical Application.
abstract: As a continuing effort to elucidate the impact of structure modification upon cutaneous absorption behavior, we attempted to assess the skin permeation of magnolol by methylation and acetylation.
  
  
  
  Diacetylmagnolol and 2-O-acetyl-2'-O-methylmagnolol (AMM) were designed and synthesized in this study. The anti-inflammatory activity against stimulated neutrophils and keratinocytes was evaluated to check the bioactivity of the analogues. In vitro skin absorption was investigated using nude mouse and pig skin models at both equimolar and saturated doses.
  
  
  
  Magnolol generally showed the strongest anti-inflammatory potential, followed by diacetylmagnolol and AMM. The antibacterial activity was observed for magnolol and diacetylmagnolol but not AMM. Diacetylmagnolol and AMM could be partly hydrolyzed to magnolol and 2-O-methylmagnolol after entering the skin. The hydrolysis rate of diacetylmagnolol was faster than that of AMM. The lipophilicity played a crucial role in cutaneous absorption, with AMM exhibiting the highest skin deposition. AMM accumulation within nude mouse skin was about 2.5-fold greater than that of magnolol and diacetylmagnolol. On the other hand, the transdermal penetration across the skin was lessened by methylation and esterification. This led to a superior skin targeting of AMM. Although the pharmacological activity of AMM was low, the high skin uptake and bioconversion into 2-O-methylmagnolol in the skin contributed to a greater therapeutic index (TI, skin deposition x inflammatory inhibition percentage) compared to the others. The accumulation of AMM in the hair follicles was 77.12 nmol/cm(2), which was significantly greater than that with magnolol (44.84 nmol/cm(2)) and diacetylmagnolol (26.96 nmol/cm(2)). The synthetic analogues were tolerable to the nude mouse skin.
  
  
  
  Based on the experimental results, we may suggest topically applied AMM as a potent and safe candidate for the treatment of cutaneous inflammation.
authors.affiliation: Department of Cosmetic Science, Chang Gung University of Science and Technology, Kweishan, Taoyuan, Taiwan.
authors.forename: Chwan-Fwu
authors.initials: CF
authors.lastname: Lin
authors.affiliation: School of Medicine, Fu Jen Catholic University, Hsinchuang, New Taipei City, Taiwan.
authors.forename: Chi-Feng
authors.initials: CF
authors.lastname: Hung
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Ibrahim A
authors.initials: IA
authors.lastname: Aljuffali
authors.affiliation: Department of Cosmetic Science, Chang Gung University of Science and Technology, Kweishan, Taoyuan, Taiwan.|National Research Institute of Chinese Medicine, Taipei, Taiwan.
authors.forename: Yu-Ling
authors.initials: YL
authors.lastname: Huang
authors.affiliation: Research Center for Industry of Human Ecology, Chang Gung University of Science and Technology, Kweishan, Taoyuan, Taiwan.
authors.forename: Wei-Chun
authors.initials: WC
authors.lastname: Liao
authors.affiliation: Research Center for Industry of Human Ecology, Chang Gung University of Science and Technology, Kweishan, Taoyuan, Taiwan. fajy@mail.cgu.edu.tw.|Pharmaceutics Laboratory, Graduate Institute of Natural Products, Chang Gung University, 259 Wen-Hwa 1st Road, Kweishan, Taoyuan, 333, Taiwan. fajy@mail.cgu.edu.tw.|Chinese Herbal Medicine Research Team, Healthy Aging Research Center, Chang Gung University, Kweishan, Taoyuan, Taiwan. fajy@mail.cgu.edu.tw.|Department of Anesthesiology, Chang Gung Memorial Hospital, Kweishan, Taoyuan, Taiwan. fajy@mail.cgu.edu.tw.
authors.forename: Jia-You
authors.initials: JY
authors.lastname: Fang
mesh_terms: D000279:Administration, Cutaneous; D000818:Animals; D001713:Biphenyl Compounds / Q000008:administration & dosage* / Q000737:chemistry* / Q000378:metabolism; D003879:Dermatologic Agents / Q000008:administration & dosage* / Q000737:chemistry* / Q000378:metabolism; D004951:Esterification; D005260:Female; D018859:Hair Follicle / Q000187:drug effects; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects; D017705:Lignans / Q000008:administration & dosage* / Q000737:chemistry* / Q000378:metabolism; D008745:Methylation; D051379:Mice; D008819:Mice, Nude; D009504:Neutrophils / Q000187:drug effects; D012867:Skin / Q000187:drug effects / Q000378:metabolism*; D012869:Skin Absorption / Q000502:physiology; D013552:Swine; D000076162:Therapeutic Index
chemical_list: D001713:Biphenyl Compounds; D003879:Dermatologic Agents; D017705:Lignans; C005498:magnolol
keywords: cutaneous absorption; esterification; magnolol; methylation; skin