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Alterations to the structure of Leishmania major induced by N-arylisoquinolines correlate with compound accumulation and disposition

Alicia Ponte-Sucre^1,, Tanja Gulder^2,,, Tobias A. M. Gulder^2,,||, Gerina Vollmers¹, Gerhard Bringmann² and Heidrun Moll¹

¹ Institute for Molecular Infection Biology, University of Würzburg, Josef-Schneider-Strasse 2/015, 97080 Würzburg, Germany

² Institute of Organic Chemistry, Am Hubland, 97074 Würzburg, Germany

Correspondence
Alicia Ponte-Sucre
aiponte{at}gmail.com
Gerhard Bringmann
bringman{at}chemie.uni-wuerzburg.de

Received July 10, 2009
Accepted September 4, 2009

Naphthylisoquinoline alkaloids equipped with a N,C-hetero-‘biaryl’ axis, and, in particular, simplified synthetic analogues thereof, kill intracellular Leishmania major at concentrations in the low submicromolar range, while being significantly less toxic to their major host cell, the macrophage, at the same concentrations. To further investigate their mechanism of action we evaluated the morphological and ultrastructural changes induced by specific N-arylisoquinolines in L. major, and the correlation of these changes with compound accumulation and disposition by the parasite. After 24 h of treatment with the synthetic arylisoquinolinium salts 3 or 4, dramatic structural changes and cell death were observed. Furthermore, the auto-fluorescent derivative salt 3 accumulates continually in intracellular compartments. Our results thus suggest that the leishmanicidal effect of arylisoquinolinium salts may involve their ability to accumulate and precipitate in intracellular organelles, form a huge vacuole and eventually promote cell lysis.

Present address: Laboratorio de Fisiología Molecular, Universidad Central de Venezuela, Caracas, Venezuela, c/o Alicia Ponte CCS 81720, PO Box 025323 Miami, Fl 33102-5323, USA.

These authors contributed equally to this work.

Present address: Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA 92037, USA.

||Present address: Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California at San Diego, La Jolla, CA 92093, USA.