Novos complexos metálicos bioativos com tiossemicarbazonas: investigação do perfil farmacológico e de mecanismos de ação

Abstract

In the present work novel thiosemicarbazones-derived drug and metal-based-drug candidates were obtained which present antitumor and antimicrobial activities. To investigate the effect of substitution on the antimicrobial and cytotoxic activities of N(4)-phenyl-2-acetylpyridine thiosemicarbazone (H2Ac4Ph, 1), its derivatives were prepared withfluorine, chlorine, iodine and nitro substituents in the ortho, meta and para positions of the N(4)-phenyl group: H2Ac4oFPh (2), H2Ac4mFPh (3), H2Ac4pFPh (4), H2Ac4oClPh (5), H2Ac4mClPh (6), H2Ac4pClPh (7), H2Ac4oIPh (8), H2Ac4mIPh (9), H2Ac4pIPh (10), H2Ac4oNO2Ph (11), H2Ac4mNO2Ph (12) and H2Ac4pNO2Ph (13). Most of the compounds were more or as active as 1 against Staphylococcus aureus. Allthiosemicarbazones were more active than fluconazole against Candida albicans, 9-13 being more active than 1. Thiosemicarbazones 1-13 were cytotoxic at nanomolar doses against MCF-7 (breast adenocarcinoma), U87 (glioblastoma multiforme expressing wild-type pro-apoptotic p53 protein) and T98G (glioblastoma multiforme expressing mutant p53) tumor cell lines and demonstrated low hemolytic activity. According to structure-activity relationship studies, the cytotoxic activityof 1-13 is directly correlated to the energy of the HOMO orbital and to the partial charge of sulfur atom, and inversely correlated to the molecular surface area of thiosemicarbazones. The cytotoxic action of 1-13 may occur through pathways that are independent of p53 protein. Cells death on exposure to 1-13 occur by apoptosis and autophagy. Direct interaction with microtubules is not the main mechanism of apoptosis induction by 1-13. Complexes [Ga(2Ac4pFPh)2]NO3 (1), [Ga(2Ac4pClPh)2]NO3 (2), [Ga(2Ac4pIPh)2]NO3 (3), [Ga(2Ac4pNO2Ph)2]NO3·3H2O (4) and [Ga(2Ac4pT)2]NO3 (5) were obtained with H2Ac4pFPh, H2Ac4pClPh, H2Ac4pIPh, H2Ac4pNO2Ph and N(4)-para-tolyl 2-acetylpyridinethiosemicarbazone (H2Ac4pT). The structures of 1 and 5 were determined by X-ray diffraction and indicate the presence of a gallium(III) center, which is hexacoordinated to two anionic thiosemicarbazones which bind to the metal through the Npy-N-S chelating system. 1-5 were more active than free thiosemicarbazones against Pseudomonas aeruginosa and C. albicans, whereas coordination to gallium(III) did not result in more active compounds against S. aureus. The gallium(III) complexes were also not more cytotoxic than their thiosemicarbazones against the T98G, U87 e MCF-7 cells. Complexes [Au(H2Ac4DH)Cl]·MeOH (1), [Au(H22Ac4Me)Cl]Cl (2)[Au(H22Ac4Ph)Cl]Cl·2H2O (3) and [Au(H22Bz4Ph)Cl]Cl (4) were prepared with 2-acetylpyridine thiosemicarbazone (H2Ac4DH), its N(4)-methyl- (H2Ac4Me) and N(4)-phenyl-(H2Ac4Ph) derivatives, as well as with N(4)-phenyl 2-benzoylpyridine thiosemicarbazone (H2Bz4Ph). The compounds were cytotoxic to Jurkat (immortalized line of T lymphocyte), HL-60 (acute myeloid leukemia), MCF-7 (human breast adenocarcinoma) and HCT-116 (colorectal carcinoma) tumor cell lines. Jurkat and HL-60 cells were more sensitive to the compounds than the solid tumor cells. Upon coordinating to the Au(I) metal center in 2 and 4, the cytotoxicactivity of the H2Ac4Me and H2Bz4Ph ligands increases against the HL-60 and Jurkat tumor cell lines. 2 was more active than auranofin against both leukemia cells. All compounds induced DNAfragmentation in HL-60 and Jurkat cells indicating their pro-apoptotic potential. 2 strongly inhibited the activity of thioredoxin reductase (TrxR), which suggests inhibition of TrxR to be part of its mechanism of action.Complexes [Au(H2Gy3DH)]2Cl2 (1), [Au(H2Gy3Me)]Cl3 (2) and [Au(H2Gy3Et)]Cl3 (3) were synthesized with glyoxaldehyde bis(thiosemicarbazone) (H2Gy3DH) and its N(3)-methyl-(H2Gy3Me) and N(3)-ethyl- (H2Gy3Et) derivatives. The bis(thiosemicarbazones) and 1-3 showed cytotoxic effects against Jurkat, HL-60 and MCF-7 cells, but not against HCT-116 cells. 2inhibited the activity of TrxR, suggesting that the enzyme is a possible biologic target of its cytotoxic action. Complexes [Sb(2Fo4Ph)Cl2] (1), [Bi(2Fo4Ph)Cl2] (2) [Sb(2Ac4Ph)Cl2] (3) and [Bi(2Ac4Ph)Cl2] (4) were prepared with N(4)-phenyl-2-formylpyridine thiosemicarbazone(H2Fo4Ph) and H2Ac4Ph. Coordination to bismuth(III) resulted in compounds more active against S. aureus in comparison with coordination to antimony(III). Thiosemicarbazones and theirSb(III) complexes showed activity against Trypanosoma cruzi, but were highly cytotoxic to healthy cells. Complexes [Bi(H2Gy3DH)Cl3] (1), [Bi(H2Gy3Et)(OH)2Cl] (2) and [Bi(H2Gy3Ph)Cl3] (3)were obtained with H2Gy3DH, H2Gy3Et and N(3)-phenyl glyoxaldehyde bis(thiosemicarbazone) (H2Gy3Ph). The bis(thiosemicarbazones) were not active or demonstrated low activity against S. aureus, S. epidermidis and E. faecalis. Coordination to bismuth(III) significantly increased theantibacterial activity against S. aureus and E. faecalis, constituting an interesting strategy to reduce doses against these bacterial strains