Water soluble cationic trans-platinum complexes which induce programmed cell death in the protozoan parasite Leishmania infantum.
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.
Nguewa
Paul A
PA
Departamento de Parasitología, Facultad de Farmacia, Universidad de la Laguna, Tenerife, Spain.
Fuertes
Miguel A
MA
Iborra
Salvador
S
Najajreh
Yousef
Y
Gibson
Dani
D
Martínez
Enrique
E
Alonso
Carlos
C
Pérez
José M
JM
D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001665:Binding Sites; D002082:Butylamines / Q000737:chemistry / Q000494:pharmacology; D002412:Cations; D002945:Cisplatin / Q000737:chemistry / Q000494:pharmacology; D004247:DNA / Q000737:chemistry; D018314:Leishmania infantum / Q000187:drug effects* / Q000378:metabolism; D008969:Molecular Sequence Data; D010847:Picolines / Q000737:chemistry / Q000494:pharmacology; D000077489:Piperazine; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology; D017671:Platinum Compounds / Q000737:chemistry* / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D025801:Ubiquitin / Q000737:chemistry; D014867:Water / Q000737:chemistry*
D000970:Antineoplastic Agents; D002082:Butylamines; D002412:Cations; D010847:Picolines; D010879:Piperazines; D010880:Piperidines; D017671:Platinum Compounds; D025801:Ubiquitin; D014867:Water; D000077489:Piperazine; C032727:piperidine; D004247:DNA; C427203:calf thymus DNA; C032462:n-butylamine; D002945:Cisplatin