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  • Title: Synthesis and transdermal permeation of novel N4-methoxypoly(ethylene glycol) carbamates of cytarabine.
    Author: Legoabe LJ, N'Da DD, Breytenbach JC, du Preez JL, du Plessis J.
    Journal: Drug Dev Ind Pharm; 2010 Dec; 36(12):1477-85. PubMed ID: 20560790.
    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. METHOD: 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. CONCLUSION: 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.
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