Characterization of Mechanism of cell death potentially induced by a binuclear antileishmanial cyclopalladated CP2: a contribution to the rational drug development

Abstract

Leishmaniasis, caused by more than 20 different species of protozoan Leishmania, areconsidered a serious public health problem in Brazil as well as worldwide. The limitedavailability of drugs for the treatment of this parasitic disease together with all side effectsand the emergence of resistant strains strength the importance of focus the research on thediscovery and development of new antileishmanial molecules. Several metal complexesanalogues of cisplatin, which are used as chemotherapeutic agents in the treatment of cancer,have been developed to be used on the battle against trypanosomiasis, mainly because of themany similarities presented in different metabolic pathways. Despite the fact that metalcompounds are usually associated with several side effects, the cyclopalladated derivativeherein studied present high thermodynamic and kinetic stability for the formation of a stablechelate causing reduction in the molecule toxicity. In our previous study, we reported thatthe binuclear cyclopalladated, [Pd(dmba)(µ-N3)]2 (CP2) (Velásquez et al., submitted forpublication), was active against intracellular amastigotes of L. amanzonensis and T. cruzi,the causing agents of cutaneous/mucocutaneous leishmaniasis and Chagas' disease,respectively. Additionally, CP2 did not show cytotoxicity when assayed in murine peritonealmacrophages and high selectivity to the intracellular amastigotes of L. amazonensis (SI =49,90) and T. cruzi (SI = 224,88). According to the analysis of biochemical markers for renaland liver function, CP2 in in vivo assay, using L. amazonensis BALB/c-infected mice, didnot present toxicity and was able to cause a reduction of 80% in the parasite load, promisingand comparable to amphotericin B, the drug currently used in the treatment of leishmaniasis.Regarding its mechanism of action, our data showed that CP2 is able to inhibit the parasiteDNA topoisomerase 1B. Thus, in order to further contribute to the characterization of the molecular events generated in cascade in the parasite after inhibition of its DNATopoisomerase.