Cisplatin (cis-diamminedichloroplatinum(II)) and its analogs are known to form 1,2-intrastrand cross-links with guanine bases that lead to DNA distortion and are responsible for cytotoxicity. Reaction with proteins, especially at methionine residues, could also be responsible for cytotoxicity (Sandlin, R. D. et al. 2010). A new tridentate platinum(II) complex with a piperazine ring was successfully designed and synthesized. In this complex, the platinum is coordinating to all three nitrogens of (1,2- dimethylaminoethylpiperazine), which makes it a Platinum triamine compound. A series of chemical reactions of this compound with guanosine 5’-monophosphate (5’-GMP) and N-acetylmethionine (N-AcMet) were conducted under different conditions. Reactions with 5’-GMP show spectra suggesting that the triamine ligand is partially displaced as a second 5’-GMP residue coordinates. We are hoping that this newly synthesized compound may have anticancer properties, due the bulky structure of its nitrogen ligand.

nÃo hà / Oxaliplatina (OXL) à a 3 geraÃÃo de agentes platinos com amplo espectro de atividade antitumoral. Exibe potente atividade citotÃxica, incluindo cÃncer colorretal, ovariano e pulmonar. Dentre os efeitos tÃxicos estÃo: laringoespasmo, nÃuseas, vÃmitos, fadiga e neuropatia perifÃrica, foco desse trabalho. Essa pesquisa objetivou desenvolver um modelo experimental para estudo da neuropatia sensitiva perifÃrica induzida por OXL em camundongos que sÃo animais geneticamente mais semelhantes ao ser humano, econÃmicos e dado a existÃncia de espÃcies diferentes para vÃrios fatores. O estudo foi aprovado pelo Comità de Ãtica em Pesquisa Animal da UFC (protocolo n 70/07). Camundongos Swiss machos (20-40g) foram tratados com OXL (1-4 mg/kg, EV) por 4 semanas paralelamente aos testes neuropÃticos utilizados para avaliar o desenvolvimento da neuropatia sensitiva e Rota Rod para verificar comprometimento motor. A hiperalgesia e alodÃnia tÃrmica foram avaliadas pelo teste de imersÃo da cauda (TIC) em Ãgua fria (4 ou 10ÂC) e em Ãgua aquecida (46 ou 42ÂC). O teste de hiperalgesia e alodÃnia mecÃnico (HPM; Von Frey) consistiu na estimulaÃÃo das patas traseiras com um sensor de forÃa (g) atà a sua retirada por um movimento de âflinchâ. Foi ainda verificado a aÃÃo analgÃsica da carbamezepina (CZP), oxcarbazepina (OZP), gabapentina (GABAP) e indometacina (INDO) no TIC Ãgua fria. Foi realizado a imunohistoquÃmica das patas traseiras dos animais em 24h e de 7 a 28 dias. Como resultados observou-se que no HPM houve uma diminuiÃÃo significativa (p<0,001) no limiar nociceptivo a partir do 14 dia atingindo o mÃximo na dose de 2mg/kg comparado ao grupo controle. No TIC 4ÂC houve uma diminuiÃÃo significativa (p<0,05) no limiar nociceptivo no 56 dia, no TIC alodÃnia pelo frio (10ÂC) foi observado uma diminuiÃÃo significativa (p<0,01) no limiar nociceptivo tambÃm no 56 dia, no TIC alodÃnia pelo quente (42ÂC) foi observado uma diminuiÃÃo significativa (p<0,05) no limiar nociceptivo a partir do 35 dia. Esses testes atingiram o mÃximo na dose de 1mg/kg comparados com o grupo controle e no TIC 46ÂC foi observado uma diminuiÃÃo significativa (p<0,01) no limiar nociceptivo a partir do 49 dia atingindo o mÃximo na dose de 1 e de 4mg/kg comparado ao grupo controle. No teste Rota Rod nenhuma variaÃÃo significativa foi observada em nenhum dos grupos, indicando a ausÃncia de comprometimento motor. O tratamento com CZP (0,3-30mg/kg), OZP (0,3-100mg/kg) e GABAP (6-54mg/kg) aumentou o limiar nociceptivo, indicando efeito analgÃsico e INDO (1-4mg/kg) nÃo demonstrou atividade analgÃsica nesse modelo. Na anÃlise da imunohistoquÃmica ficou comprovado que existe a participaÃÃo provÃvel de SP, CGRP e NMDA perifÃricos e nitrotirosina. Portanto, o uso de camundongos e do diferente mÃtodo de administraÃÃo da OXL (EV) pode ser utilizado em modelos futuros viabilizando o uso do fÃrmaco para tratamento do cÃncer, principalmente o colorretal, com todo o esquema terapÃutico, sem que a NSP interfira nas atividades de vida do paciente tratado. / Oxaliplatin (OXL) is a third-generation platinum-based chemotherapy with broad spectrum of anti-tumoral activity. Exhibt potent cytotoxic activity including against cancer colorectal, ovarian and lung cancer. Among the toxic effects are: laryngospasm, nauseas, vomiting, fatigue and peripheral neuropathy, focus of that work. That research planned to develop an experimental model for study of the peripheral neuropathy induced by OXL in mice that are animal genetically more similar to the human, economic and given the knockout species existence for several factors. The study was approved by the Committee of Ethics in Animal Research of the UFC (protocol n 70/07). Mice Swiss male (20-40g) were treated with OXL (1-4 mg/kg, EV) for 4 weeks in parallel to the neurophatic tests utilized for evaluate the development of the peripheral neuropathy and Route Rod for verify some motor compromise. To mechanical hyperalgesia and allodynia thermal were evaluated by the test of immersion of the tail (TIC) in cold water (4 or 10ÂC) and in water heated (46 or 42ÂC). The test of hyperalgesia and allodynia (HPM; Von Frey) consisted of the stimulation of the rear paws with a sensor of force (g) up to his retreat by a movement of "flinch". It was still verified the analgesic action of the carbamezepine (CZP), oxcarbazepine (OZP), gabapentin (GABAP) and indomethacin (INDO) in the TIC cold water. It was carried out to immunohistochemical of the hands paws of the animals in 24h and of 7 to 28 days. The results shows that in the HPM had a significant reduction (p<0,001) in the nociceptive threshold from the 14 day reaching the maximum one in the dose of 2mg/kg compared to the control group. In the TIC 4ÂC had a significant reduction (p<0,05) in the nociceptive threshold in the 56 day, in the TIC allodynia by the cold one (10ÂC) was observed a significant reduction (p<0,01) in the nociceptive threshold also in the 56 day, in the TIC allodynia by the hot one (42ÂC) was observed a significant reduction (p<0,05) in the nociceptive threshold from the 35 day. Those tests reached the maximum one in the dose of 1mg/kg compared with the control group and in the TIC 46ÂC was observed a significant reduction (p<0,01) in the nociceptive threshold from the 49 day reaching the maximum one in the doses of 1 and 4mg/kg compared to the control group. In the test Route Rod no significant variation was observed in no of the groups, indicating the absence of motor compromise. The handling with CZP (0,3-30mg/kg), OZP (0,3-100mg/kg) and GABAP (6-54mg/kg) increased the nociceptive threshold, indicating analgesic effect and INDO (1-4mg/kg) did not show analgesic activity in that model. In the analysis of the immunohistochemical was verified that exists the probable participation of SP, CGRP and NMDA peripheral and nitrotyrosine. Therefore, the use of mice and of the different approach of administration of the OXL (EV) can be utilized in future models making feasible the use of the drug for handling of the cancer, mainly the colorectal, with all the therapeutic plan without that to NSP interfere in the activities of the treated patient.