期刊
JOURNAL OF INORGANIC BIOCHEMISTRY
卷 103, 期 10, 页码 1300-1306出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.jinorgbio.2009.02.011
关键词
Pyridine-2-thiol N-oxide; Gold; Leishmania; Trypanosoma cruzi; NADH fumarate reductase
In the search for new therapeutic tools against parasitic diseases caused by the Kinetoplastids Leishmania spp. and Trypanosoma cruzi, a novel gold(I) triphenylphosphine complex with the bioactive coligand pyridine-2-thiol N-oxide (mpo) was synthesized and characterized by using analytical and conductometric measurements, electrospray ionization-mass spectrometry (ESI) and electronic, FTIR and H-1 and P-31 NMR spectroscopies. A dinuclear structure is suggested for the complex. At a 1 microM concentration the complex induced in vitro after 30 min a potent leishmanicidal effect (LD50) against promastigotes of Leishmania (L.) mexicana while on Leishmania (V.) braziliensis with the same concentration only a leishmanistatic effect (IC75) Was observed 48 h after treatment. Similar differential susceptibilities were also found when testing the ligand mpo, but at a higher dose (5 mu M). In addition, the compound showed growth inhibitory effect on Dm28cT cruzi epimastigotes in culture (IC50 0-09 mu M), being even more active than the anti-trypanosomal reference drug Nifurtimox (IC50 6 mu M). DNA interaction studies showed that this biomolecule does not constitute a main target for the mpo complex currently tested. Instead, the significant potentiation of the anti proliferative effect against both Leishmania species and T cruzi could be associated to the inhibition of NADH fumarate reductase, a kinetoplastid parasite-specific enzyme absent in the host. Furthermore, due to its low unspecific cytotoxicity on mammalian cells (J774 macrophages), the new gold complex showed a selective anti-parasite activity. It constitutes a promising new potent chemotherapeutic alternative to be evaluated in vivo in experimental models of leishmaniasis and Chagas disease. (C) 2009 Elsevier Inc. All rights reserved.
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