| 15708793 |
Nguewa PA, Fuertes MA, Iborra S, Najajreh Y, Gibson D, Martinez E, Alonso C, Perez JM: Water soluble cationic trans-platinum complexes which induce programmed cell death in the protozoan parasite Leishmania infantum. J Inorg Biochem. 2005 Mar;99(3):727-36. Epub 2005 Jan 1.
We have evaluated the cytotoxic properties against the protozoan Leishmania infantum of four water soluble cationic trans-Pt (II) Cl (2) compounds containing as inert groups NH3 and piperazine (1), 4-picoline and piperazine (2), n-butylamine and piperazine (3), and NH3 and 4-piperidino-piperidine (4). The leishmanicidal activity of compounds 3 and 4 against promastigotes of the parasite Leishmania infantum was 2.5- and 1.6-times higher than that of the cytotoxic drug cis-diamminedichloroplatinum (II), respectively. Interestingly, compounds 3 and 4 produce in Leishmania infantum promastigotes a higher amount of programmed cell death than cisplatin, which is associated with cell cycle arrest in G2/M. In contrast to cis-diamminedichloroplatinum (II), binding of compounds 3 and 4 to calf thymus DNA induces conformational changes more similar to those of trans-diamminedichloroplatinum (II) that may be attributed to denaturation of the double helix. Similarly to cis-diamminedichloroplatinum (II) and trans-diamminedichloroplatinum (II), the interaction of compounds 3 and 4 with ubiquitin results in an increase of the alpha-helix content of the protein as observed by circular dichroism spectroscopy. However, fluorescence studies indicate that compounds 3 and 4 produce a decrease in the fluorescence of the tyrosine 59 residue of ubiquitin higher than both cis-diamminedichloroplatinum (II) and trans-diamminedichloroplatinum (II). Altogether, our results suggest that the biochemical mechanism of cytotoxic activity of compounds 3 and 4 against Leishmania infantum must be different from that of cis-diamminedichloroplatinum (II). To the best of our knowledge, compounds 3 and 4 are the first reported trans-platinum complexes that show antiparasitic activity. |
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