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Title

Synthesis and biological evaluation of fluorescent leishmanicidal analogues of hexadecylphosphocholine (Miltefosine) as probes of antiparasite mechanisms

AuthorsSaugar, José María; Delgado, Javier; Hornillos, Valentín CSIC ORCID; Luque-Ortega, Juan Román CSIC ORCID ; Amat-Guerri, Francisco CSIC; Acuña, A. Ulises CSIC; Rivas, Luis CSIC ORCID
Issue Date2007
PublisherAmerican Chemical Society
CitationJournal of Medicinal Chemistry 50(24):5994-6003(2007)
AbstractThe 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 emitting analogues. In this regard, the synthesis and biological characterization of two fully competent MT fluorescent analogues 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 absorption coefficients and a modest, but usable, fluorescence yield. Their activities were very similar to that of MT and were recognized by the MT uptake system of Leishmania. Their localization in living L. donovani promastigotes 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 to its external concentration. These results are consistent with a multiple target leishmanicidal mechanism for MT and validate the application of these analogues for pharmacokinetic and diagnostic studies concerning the chemotherapy of leishmaniasis. © 2007 American Chemical Society.
Description10 páginas, 9 figuras, 1 tabla, 1 esquema
URIhttp://hdl.handle.net/10261/77595
DOIhttp://dx.doi.org/10.1021/jm070595
Identifiersdoi: 10.1021/jm070595
issn: 0022-2623
e-issn: 1520-4804
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