This review deals with the most important results published on the structures, reactivity and biomedical applications of palladium(II) complexes in the cancer therapy in the last five years. Biological mechanisms of palladium(II) complexes, especially of palladacycle compounds were boarded. Among the most recent advances in the studies involving correlations between chemical structures of palladacycle compounds and biological activities we mention i) the synthesis of metallic isomer complexes containing ligands derivatives of pyridine and imines in trans position having high antitumoral activities, ii) the development of cationic complexes with biological activity, iii) the discovery of preferential nucleotides for the intercalation of metallic complexes in the double helix of DNA of cancerous cells, configuring irreparable lesions in the macromolecule and iv) the interaction of metallic complexes with other biological molecules, like proteins and peptides, through terminal amine groups, carboxylate groups, imidazolic group of histidine and mostly with the thiol group of methionine. Some of these interactions are related to drug nefrotoxicity effect, which understanding is of fundamental importance. v) Novel ortho-cyclopalladated compounds synthesized from p-isopropylbenzaldehyde thiosemicarbazone have been described with specific cytotoxic properties in tumor cells sensitive to cis-diamminedichloroplatinum(II). The lysosomal cysteine proteinases cathepsins B and L have been implicated in a variety of pathological conditions, especially in diseases involving tissue-remodeling states, such as tumor metastasis. Our research group is studying inhibition of Cathepsin B by new palladacycle compounds derived from N, N-dimethyl-1-phenethylamine and having biphosphine ligands. New palladacycle compounds derived from N,N-dimethyl-1-phenethylamine and the ligand bis(diphenylphosphine)ferrocene were presented as effective antitumoral agents.

Chagas' disease, a neglected tropical infection, affects about 18 million people, and 100 million are at risk. The only drug available, benznidazole, is effective in the acute form and in the early chronic form, but its efficacy and tolerance are inversely related to the age of the patients. Side effects are frequent in elderly patients. The search for new drugs is thus warranted. In the present study we evaluated the in vitro and in vivo effect of a cyclopalladated compound (7a) against Trypanosoma cruzi, the agent of Chagas' disease. The 7a compound inhibits trypomastigote cell invasion, decreases intracellular amastigote proliferation, and is very effective as a trypanocidal drug in vivo, even at very low dosages. It was 340-fold more cytotoxic to parasites than to mammalian cells and was more effective than benznidazole in all in vitro and in vivo experiments. The 7a cyclopalladate complex exerts an apoptosis-like death in T. cruzi trypomastigote forms and causes mitochondrion disruption seen by electron microscopy.

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BackgroundSystemic therapy for cancer metastatic lesions is difficult and generally renders a poor clinical response. Structural analogs of cisplatin, the most widely used synthetic metal complexes, show toxic side-effects and tumor cell resistance. Recently, palladium complexes with increased stability are being investigated to circumvent these limitations, and a biphosphinic cyclopalladated complex {Pd2 [S(-)C2, N-dmpa]2 (μ-dppe)Cl2} named C7a efficiently controls the subcutaneous development of B16F10-Nex2 murine melanoma in syngeneic mice. Presently, we investigated the melanoma cell killing mechanism induced by C7a, and extended preclinical studies.MethodsB16F10-Nex2 cells were treated in vitro with C7a in the presence/absence of DTT, and several parameters related to apoptosis induction were evaluated. Preclinical studies were performed, and mice were endovenously inoculated with B16F10-Nex2 cells, intraperitoneally treated with C7a, and lung metastatic nodules were counted. The cytotoxic effects and the respiratory metabolism were also determined in human tumor cell lines treated in vitro with C7a.ResultsCyclopalladated complex interacts with thiol groups on the mitochondrial membrane proteins, causes dissipation of the mitochondrial membrane potential, and induces Bax translocation from the cytosol to mitochondria, colocalizing with a mitochondrial tracker. C7a also induced an increase in cytosolic calcium concentration, mainly from intracellular compartments, and a significant decrease in the ATP levels. Activation of effector caspases, chromatin condensation and DNA degradation, suggested that C7a activates the apoptotic intrinsic pathway in murine melanoma cells. In the preclinical studies, the C7a complex protected against murine metastatic melanoma and induced death in several human tumor cell lineages in vitro, including cisplatin-resistant ones. The mitochondria-dependent cell death was also induced by C7a in human tumor cells.ConclusionsThe cyclopalladated C7a complex is an effective chemotherapeutic anticancer compound against primary and metastatic murine and human tumors, including cisplatin-resistant cells, inducing apoptotic cell death via the intrinsic pathway.

Recebido em 31/3/98; aceito em 10/9/98 SYNTHESIS AND CYTOTOXICITY OF SOME CYCLOMETALLATED PALLADIUM(II) COM-PLEXES CONTAINING COORDINATED AZIDE AND DIPHOSPHINES. Some cyclopalladated compounds containing the azido group ligand and the (C-N) ring of N,N-dimethylbenzylamine have been prepared by bridge opening reactions of dimmer azide complex precursor with some diphosphines in different stoichiometric quantities. The neutral or ionic, mono or binuclear complexes synthesized were characterized by elemental analyses, I. R. spectroscopy and NMR techniques. The series of complexes was screened for cytotoxicity against a panel three human tumour cells lines(C6,Hep-2,HeLa). All complexes were found to be cytotoxic (IC 50 ) at µM concentrations while one complex having the coordination bond N-Pd ruptured also displayed some differential cytotoxicity.Keywords: azido-cyclopalladated compounds; antitumour agents; palladium (II) complexes. ARTIGO INTRODUÇÃOA eficácia da cisplatina cis-[Pt(NH 3 ) 2 Cl 2 ] e da carboplatina [Pt(NH 3 ) 2 (cbdca)], (cbdca =1,1'-ciclobutanodicarboxilato) no tratamento clínico de tumores do ovário, dos testículos, da cabeça e do pescoço já é bem conhecida 1 . Entretanto existe um grande interesse no desenvolvimento de novos agentes quimioterápicos a base de metais de transição, especialmente de metais pertencentes ao grupo da platina, que sejam menos tóxicos e, ou possuam um espectro de atividade antitumoral mais amplo 2 .Embora o mecanismo de ação dessas drogas seja muito discutido é amplamente aceito no meio científico que tanto a cisplatina quanto a carboplatina possuem o mesmo tipo de atuação na inibição do DNA da célula tumoral, provocando o mesmo tipo de lesão nesta molécula, formando um aduto G-G entre as cadeias de nucleotídeos laterais, que configuram a sua estrutura de dupla hélice 3-4 . Assim sendo, segue que estes compostos apresentam um espectro de atividade similar.Uma das estratégias básicas no desenvolvimento de novas drogas antitumorais a base de metais de transição consiste na síntese de complexos que, mesmo possuindo características estruturais similares a carboplatina ou a cisplatina, sejam capazes de provocar lesões diferentes e irreversíveis na molécula de DNA. No que concerne aos complexos de paládio, observase que os mesmos, em geral, possuem uma atividade antitumoral muito pequena quando comparado aos complexos de platina, devendo-se isto a alta labilidade exibida pelos compostos de paládio (II) em meio biológico 5 . Neste sentido, a classe dos compostos ciclopaladados tem despertado um recente e grande interesse na aplicação dos mesmos como agentes antineoplási-cos, não só por produzirem complexos estáveis o suficiente para permitirem uma eficaz ação da droga no organismo em concentrações muito baixas, mas também por possuirem uma citotoxicidade consideravelmente menor que os compostos aná-logos de platina [5][6][7][8] .O presente trabalho apresenta a síntese e a caracterização estrutural de alguns azido -ciclopaladados estabilizados com bases moles de Lewis 9 , contend...