title: Synthesis and transdermal permeation of novel N4-methoxypoly(ethylene glycol) carbamates of cytarabine.
abstract: BACKGROUND
  Cytarabine is a deoxycytidine analogue commonly used in the treatment of hematological malignant diseases. Its clinical utility, however, is severely limited by its short plasma half-life because of the catabolic action of nucleoside deaminases.
  
  
  METHODS
  In this study, N(4)-carbamate derivatives of cytarabine (1) were synthesized and evaluated for transdermal penetration because this mode of administration may circumvent its limitations. The synthesis of these compounds was achieved in a two-step process. First, the methoxypoly(ethylene glycol) was activated by p-nitrophenyl chloroformate. Second, the activated intermediates were reacted with cytarabine in the presence of N-hydroxysuccinamide to give the N(4)-methoxypoly(ethylene glycol) carbamate derivatives. The transdermal flux values of the N(4)-carbamates of cytarabine were determined in vitro by Franz diffusion cell methodology. Aqueous solubility and log D (pH 7.4) values were determined and assessed for correlation with transdermal flux values.
  
  
  RESULTS
  The synthesized carbamates, particularly, (9)-(13), showed increased solubility in both aqueous and lipid media. Log D values decreased as the oxyethylene chain lengthened.
  
  
  CONCLUSIONS
  Although none of the derivatives showed significantly higher transdermal penetration than cytarabine (1), it should be mentioned that the mean for cytarabine N(4)-methoxyethyleneoxycarbamate (8) was 10 times higher and the median was 2 times higher.
authors.affiliation: Unit for Drug Research and Development, North-West University, Potchefstroom, South Africa. lesetja.legoabe@nwu.ac.za
authors.forename: Lesetja J
authors.initials: LJ
authors.lastname: Legoabe
authors.forename: David D
authors.initials: DD
authors.lastname: N'Da
authors.forename: Jaco C
authors.initials: JC
authors.lastname: Breytenbach
authors.forename: Jan L
authors.initials: JL
authors.lastname: du Preez
authors.forename: Jeanetta
authors.initials: J
authors.lastname: du Plessis
mesh_terms: D000279:Administration, Cutaneous; D000964:Antimetabolites, Antineoplastic / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D002219:Carbamates / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D002626:Chemistry, Pharmaceutical; D002851:Chromatography, High Pressure Liquid; D003561:Cytarabine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D013058:Mass Spectrometry; D010539:Permeability; D011092:Polyethylene Glycols / Q000737:chemistry*; D012867:Skin / Q000378:metabolism*; D012869:Skin Absorption / Q000187:drug effects; D012995:Solubility
chemical_list: D000964:Antimetabolites, Antineoplastic; D002219:Carbamates; D003561:Cytarabine; D011092:Polyethylene Glycols