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Mono-, di- and trisubstituted derivatives of eflornithine: synthesis for in vivo delivery of DL-alpha-difluoromethylornithine in plasma

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dc.contributor.author Ashton, Michael
dc.contributor.author Breytenbach, Jaco Cornelius
dc.contributor.author Cloete, Theunis Theodorus
dc.contributor.author Johansson, Carl
dc.contributor.author N'da, David Dago
dc.contributor.author Rottenberg, Martin
dc.contributor.author Vodnala, Suman
dc.date.accessioned 2012-09-03T09:26:02Z
dc.date.available 2012-09-03T09:26:02Z
dc.date.issued 2011
dc.identifier.citation Cloete, T.T. et al. 2011. Mono-, di- and trisubstituted derivatives of eflornithine: synthesis for in vivo delivery of DL-alpha-difluoromethylornithine in plasma. Arzneimittelforschung: drug research, 61(5):317-325. [http://www.thieme.com/index.php?page=shop.product_details&flypage=flypage.tpl&product_id=1380&category_id=2&keyword=Arzneimittelforschung&option=com_virtuemart&Itemid=53] en_US
dc.identifier.issn 0004-4172
dc.identifier.uri http://hdl.handle.net/10394/7199
dc.description.abstract The aim of this study was to synthesize a series of mono-, di- and trisubstituted derivatives of the human African trypanosomiasis drug eflornithine (alpha-difluoromethylornithine, DMFO, CAS 70052-12-9) to determine their partition coefficients, and to assess whether they deliver the parent drug in the plasma. If increased plasma concentrations of eflornithine could be achieved in this way, an oral dosage form would be possible. The derivatives, nine in total, were successfully synthesized by multi-step derivatisation of eflornithine on either its alpha-carboxylic or/and alpha-amino or/and delta-amino groups by either esterification or/and amidation or/and carbamylation, and their structures confirmed by NMR and MS spectroscopy. The majority of derivatives were more lipophilic than eflornithine with log D values in phosphate buffer solution (pH 7.4) ranging from -1.34 to 1.59 (vs. -0.98 for eflornithine). The in vivo absorption after oral administration to Sprague-Dawley rats showed that no derivative delivered eflornithine in the plasma, indicating that the derivatives were either not absorbed from the gastrointestinal tract or not metabolized to the parent drug. Two of the monosubstituted activities were toxic for T. brucei blood stream forms. en_US
dc.language.iso en en_US
dc.publisher Thieme publishing en_US
dc.title Mono-, di- and trisubstituted derivatives of eflornithine: synthesis for in vivo delivery of DL-alpha-difluoromethylornithine in plasma en_US
dc.type Article en_US


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