Estudos de citotoxidez e ação antimicrobiana de tiossemicarbazonas derivadas de piridina: efeitos da coordenação a metais

AUTOR(ES)
DATA DE PUBLICAÇÃO

2008

RESUMO

The present work reports an investigation on the effect of metal coordination on the pharmacological profile of two thiosemicarbazone families: 2-pyridinoformamide thiosemicarbazones and N(4)-tolyl thiosemicarbazonas derived from 2-acetylpyridine and 2-benzoylpyridine. Complexes [Cu(H2Am4DH)Cl2] (1) Cu(H2Am4Me)Cl2] (2), [Cu(H2Am4Et)Cl]Cl (3) e [Cu(2Am4Ph)Cl] (4) with 2-pyridinoformamide thiosemicarbazone (H2Am4DH) and its N(4)-methyl (H2Am4Me), N(4)-ethyl (H2Am4Et) and N(4)-phenyl (H2Am4Ph) derivatives were obtained. The Cu(II) complexes as well as the original thiosemicarbazones were tested against the growth of two gram-negative bacteria strains. Coordination to Cu(II) lead to a 50% decrease of minimum inhibitory concentration (MIC) against Salmonella typhimurium in the case of complexes 1 and 2 relative to the values obtained for the free thiosemicarbazones. However, an increase in MIC was observed against the growth of Pseudomonas aeruginosa. The results suggest that complexation to Cu(II) would not be a good strategy for enhancement of the antibacterial activity for this class of thiosemicarbazones The toxicity of 2-pyridinoformamide thiosemicarbazones and their Cu(II) complexes against Artemia salina was evaluated as a pre-screening of cytotoxicity against solid tumors. Among the thiosemicarbazones H2Am4Ph showed the lowest value of DL50 = 2.2 ìM (DL50, dose which kills 50% of the animals). This value is lower than that determined for lapachol (DL50 = 281ìM) which has been used as reference. Upon coordination to Cu(II) toxicity increases mainly for complexes 2 and 3 (DL50 = 1.2 ìM and DL50 = 1.6 ìM respectively), indicating that these compounds could present activity against solid tumors. Complexes [Pd(2Ac4oT)Cl] (1), [Pd(2Ac4mT)Cl] (2), [Pd(2Ac4pT)Cl] (3), [Pd(2Bz4oT)Cl] (4), [Pd(2Bz4mT)Cl] (5), [Pd(2Bz4pT)Cl] (6), [Pt(2Bz4oT)Cl] (7), [Pt(2Bz4mT)Cl] (8) and [Pt(2Bz4pT)Cl] (9) were obtained with N(4)-ortho, N(4)-meta and N(4)-para-tolyl thiosemicarbazones derived from 2-acetylpyridine (H2Ac4oT, H2Ac4mT, H2Ac4pT) and 2-benzoylpyiridine (H2Bz4oT, H2Bz4mT, H2Bz4pT). The complexes as well as the original thiosemicarbazones were tested for their antiproliferative activity against solid tumors and leukemia. HepG2, (hepatoma), UACC-62 (melanoma) and A 431 (head and neck epidermoid carcinoma) solid tumor cell lines and HL60 (resistant) and Jurkat leukemia cell lines were used in the screening. VIIIAt 50 ìM, H2Ac4pT and H2Bz4mT proved to be the most active among the thiosemicarbazones against solid tumors, being able to inhibit 50% of proliferation of HepG2 cells and 70-80% of A431 cells. The two compounds proved to be more active than cisplatin. All thiosemicarbazones showed similar activity against UACC-62 cells, inhibiting 50% of proliferation at 50 ìM. However, (4)-tolyl-2-benzoylpyridine thiosemicarbazones, which have also been tested against leukemia, only inhibited 6-48% of cell proliferation at 50 ìM, indicating preference of these compounds for solid tumors. Upon coordination to Pd(II) the antiproliferative activity of 2-acetylpyridinederived thiosemicarbazone decreased in all solid tumor cell lines. The Pd(II) complexes with 2-benzoylpyridine hiosemicarbazones presented lower activity than the free thiosemicarbazones against UACC-62 cells; complexes 4 and 6 were more active than the free thiosemicarbazones against HepG2 cells and complex 6 was more active that the free ligand against A431 cells. The order of antiproliferative activity against UACC-62 and A431 cells was 6>5>4. Coordination to Pt(II) lead to a decrease in activity against HepG2 and UACC62 cells and to a small increase in activity against A431 cells in the case of complex 9. In general coordination to Pd(II) and Pt(II) resulted in a decrease of the antiproliferative activity of the thiosemicarbazones against solid tumor cell lines. However, coordination of 2-benzoylpyridine thiosemicarbazones lead to a significant increase of the antiproliferative activity against leukemia. In both leukemia cell lines the order of activity of the complexes was 4>5>6. Since the inverse order of activity has been found against the A431 solid tumor cells and considering that complex 6 was found to be the most active against solid tumors and the least active against leukemia we may suggest that the mechanisms of proliferation inhibition are different for solid tumors and leukemia. Since the studied compounds showed preference either for solid tumors or leukemia they could be good alternatives for the development of new drug candidates.

ASSUNTO(S)

complexos metalicos. teses. química inorgânica. teses.

ACESSO AO ARTIGO

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