Synthesis and Biological Evaluation of Fluorescent Leishmanicidal Analogues of Hexadecylphosphocholine (Miltefosine) as Probes of Antiparasite Mechanisms

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• 作者：José ; M. Saugar ; Javier Delgado ; Valentí ; n Hornillos ; Juan R. Luque-Ortega ; Francisco Amat-Guerri ; A. Ulises Acuñ ; a ; Luis Rivas
• 刊名：Journal of Medicinal Chemistry
• 出版年：2007
• 出版时间：November 29, 2007
• 年：2007
• 卷：50
• 期：24
• 页码：5994 - 6003
• 全文大小：262K
• 年卷期：v.50,no.24(November 29, 2007)
• ISSN：1520-4804

文摘

The leishmanicidal mechanism of miltefosine (hexadecylphosphocholine, MT) is not clearly understood.Valuable insights into its mode of action could be obtained by fluorescence techniques, given suitably emittinganalogues. In this regard, the synthesis and biological characterization of two fully competent MT fluorescentanalogues is reported here: all-(E)-13-phenyltrideca-6,8,10,12-tetraenylphosphocholine (PTE-MT) and all-(E)-13-phenyltrideca-8,10,12-trien-6-ynylphosphocholine (PTRI-MT). Both compounds show large absorptioncoefficients and a modest, but usable, fluorescence yield. Their activities were very similar to that of MTand were recognized by the MT uptake system of Leishmania. Their localization in living L. donovanipromastigotes by confocal microscopy show a homogeneous intracellular distribution of the fluorescence.The concentration of PTRI-MT within the parasites (ca. 1.7 mM) showed a 100-fold enrichment relative toits external concentration. These results are consistent with a multiple target leishmanicidal mechanism forMT and validate the application of these analogues for pharmacokinetic and diagnostic studies concerningthe chemotherapy of leishmaniasis.