Síntese, caracterização e bioatividade de complexos de cobre(II) com N-heterociclos

Orientador: André Luiz Barboza FormigaDissertação (mestrado) - Universidade Estadual de Campinas, Instituto de QuímicaResumo: Neste trabalho, foram investigadas a química de coordenação e bioatividade de complexos de cobre(II) com N-heterociclos contendo imidazol ou tetrazol em sua estrutura. A estrutura cristalina dos ligantes mostrou que a presença de ligações de hidrogênio entre os anéis imidazólicos ou tetrazólicos possui uma grande contribuição na determinação do seu empacotamento. Dados de difração de raios X mostraram que a geometria quadrada planar é adotada pelos complexos contendo ligantes bidentados ou monodentados, com fórmulas de coordenação [CuCl2(L)] e [CuCl2(X)2], L = impy, impm and impz e X = thim, respectivamente. Análises elementares e de espectrometria de massas concordaram com as estequiometrias propostas. Técnicas espectroscópicas mostraram que a mudança do número ou posição de átomos de nitrogênio em um anel pode resultar em mudanças significativas nas propriedades eletrônicas e vibracionais tanto dos ligantes isolados quanto dos complexos. Os ligantes impy, impm e impz não mostraram atividade sobre E. coli e S. aureus, enquanto seus respectivos complexos, [CuCl2(impy)], [CuCl2(impm)] e [CuCl2(impz)], foram ativos contra estas cepas (MIC = 17.8 µmol¿mL-1), mas sem distinção entre os complexos e a cepa testada, o que pode ser relacionado à carga dos complexos após a hidrólise dos cloretos. Experimentos biofísicos indicaram que o complexo trans [CuCl2(thim)2] interage covalentemente com o DNA, um possível alvo molecular dos complexos e também mostrou atividade antifúngica sobre Trichophyton mentagrophytesAbstract: The coordination chemistry and bioactivity profiles of copper(II) complexes with N-heterocycles containing imidazole and tetrazole in their structures have been investigated. The crystal structures of the ligands showed that hydrogen bonding between either the imidazole or the tetrazole rings has an important effect on determining their packing. Based on X-ray diffraction data, square planar geometry was proposed for the complexes containing bidentate or monodentate ligands with coordination formulas [CuCl2(L)] and [CuCl2(X)2], L = impy, impm and impz and X = thim, respectively. Elemental analysis and mass spectrometry results were in agreement with the proposed stoichiometries. Spectroscopic techniques showed that changing either the number or position of nitrogen atoms in a ring can result in significant changes in the electronic and vibrational properties of both the isolated ligands and the complexes. The imidazolic ligands impy, impm and impz showed no activity over E. coli and S. aureus, whereas their respective complexes, [CuCl2(impy)], [CuCl2(impm)] and [CuCl2(impz)], showed some activity towards these strains (MIC = 17.8 µmol¿mL-1), but with no distinction between the complexes and the tested strain, which may be due to the charge of the complexes after hydrolysis. Biophysical experiments showed that the trans complex [CuCl2(thim)2] interacts covalently with DNA, a possible molecular target for this complex, and it also showed antifungal activity over the Trichophyton mentagrophytes strainMestradoQuimica InorganicaMestre em Química131013/2014-9CNP

Synthesis and crystal structure of di­chlorido­(1,10-phenanthroline-κ2N,N′)gold(III) hexa­fluorido­phosphate

FAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOCNPQ - CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICOA gold(III) salt of composition [AuCl2(C12H8N2)]PF6 was prepared and characterized by elemental and mass spectrometric analysis (ESI(+)–QTOF–MS), 1H nuclear magnetic resonance measurements and by single-crystal X-ray diffraction. The square-planar coordin73710481051FAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOCNPQ - CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICOFAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOCNPQ - CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO2015/25114-42015/20882-3140466/2014-2The authors are grateful to Dr Déborah de Alencar Simoni, technician of the Institutional Single Crystal XRD facility – UNICAMP, Brazil, for the data collection and preliminary data refinement

Synthesis and crystal structure of dichlorido(1,10-phenanthroline-κ2N,N′)gold(III) hexafluoridophosphate

A gold(III) salt of composition [AuCl2(C12H8N2)]PF6 was prepared and characterized by elemental and mass spectrometric analysis (ESI(+)–QTOF–MS), 1H nuclear magnetic resonance measurements and by single-crystal X-ray diffraction. The square-planar coordination sphere of AuIII comprises the bidentate 1,10-phenanthroline ligand and two chloride ions, with the AuIII ion only slightly shifted from the least-squares plane of the ligating atoms (r.m.s. = 0.018 Å). In contrast to two other previously reported AuIII-phenantroline structures that are stabilized by interactions involving the chlorido ligands, the packing of the title compound does not present these features. Instead, the hexafluoridophosphate counter-ion gives rise to anion...π interactions that are a crucial factor for the crystal packing

N,N′,N′′ versus N,N′,O imine-containing coordination motifs: ligand-directed synthesis of mononuclear and binuclear cuII compounds

CNPQ - CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICOFAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOIt is demonstrated here that tridentate imine ligands can control the nuclearity of copper(II) complexes based on the donor atoms present in the ligand. The N,N′,N′′-donating imine ligand led to a mononuclear compound, namely di­chlorido­[N,N-dimethyl-N′-731015631567CNPQ - CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICOFAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOCNPQ - CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICOFAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO140466/2014-2140707/2013-12015/ 25114-42015/20882-3The authors are grateful to Dr Déborah de Alencar Simoni, technician of the Institutional Single-Crystal XRD Facility, UNICAMP, Brazil, for the data collectio

N,N′,N′′ versus N,N′,O imine-containing coordination motifs: ligand-directed synthesis of mononuclear and binuclear CuII compounds

It is demonstrated here that tridentate imine ligands can control the nuclearity of copper(II) complexes based on the donor atoms present in the ligand. The N,N′,N′′-donating imine ligand led to a mononuclear compound, namely dichlorido[N,N-dimethyl-N′-(pyridin-2-ylmethylidene)ethane-1,2-diamine]copper(II) monohydrate, [CuCl2(C10H15N3)]·H2O, 1, while the N,N′,O-donating imine ligand produced a binuclear metal complex, namely μ2-chlorido-dichlorido(μ2-2-{[2-(dimethylamino)ethyl]iminomethyl}phenolato)(N,N-dimethylethylenediamine)dicopper(II) 0.11-hydrate, [Cu2(C11H15N2O)Cl3(C4H12N2)]·0.11H2O, 2. The structure of 2 is a remarkable example of a binuclear copper(II) complex containing a single substituted 2-iminomethylphenolate ligand that has two copper(II) sites in square-pyramidal coordination

Synthesis, crystallographic studies, molecular modeling and in vitro biological studies of silver(I) complexes with aminoadamantane ligands

Silver(I) complexes with amantadine (atd) and memantine (mtn) were synthesized and characterized. Elemental, thermogravimetric and mass spectrometric analyses indicated a 1:2 metal/ligand ratio, with the molecular composition AgC20H34N2 center dot NO3 for Ag-atd and AgC24H42N2 center dot NO3 center dot H2O for Ag-mtn. The crystal structures of the silver(I) complexes were determined by single crystal X-ray diffractometric studies and show the coordination of amantadine and memantine to the Ag(I) ion by the nitrogen atom of the NH2 group. The spectral analysis by infrared and H-1, C-13 and {N-15, H-1} nuclear magnetic resonance (NMR) spectroscopies confirmed the coordination sites of the ligands to the silver ions. Computational studies revealed modes of vibration and bond lengths similar to those found experimentally. The in vitro antibacterial activity assays showed that amantadine is not active over the tested strains while memantine showed a low activity against Staphylococcus aureus and Pseudomonas aeruginosa. On the other hand, the complexes had a pronounced antibacterial activity over the same strains with minimum inhibitory concentration (MIC) values in the micromolar range. Biophysical assays based on fluorescence spectroscopy indicated that the silver(I) complexes interact weakly with bovine serum albumin, while agarose gel electrophoresis and competitive binding experiments revealed that the compounds interact with DNA by non-covalent interactions.173CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQCOORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL DE NÍVEL SUPERIOR - CAPESFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESP407012/2018-4; 164658/20181Sem informação2013/22127-2; 2014/50906-9; 2015/20882-3; 2017/25995-6; 2018/12062-4; 2018/12590-

Copper transporter 1 affinity as a delivery strategy to improve the cytotoxic profile of rationally designed copper(II) complexes for cancer treatment

Cisplatin is widely used to treat different types of cancer, but its severe side effects are the major disadvantage of this treatment. Therefore, other metals are currently the subject of research in the rational development of anticancer drugs, such as copper, that has been demonstrated to be promising in this scenario. Here, we evaluated the effects of two novel copper complexes against breast cancer cell lines, and also examined the influence of overexpressing copper transporter 1 (CTR1) on the cytotoxicity of these complexes. Complex (1) [Cu(sdmx−)2(phen)] showed low IC50 values, induced intense cell morphological changes and arrested the cell cycle at the sub-G1 phase in cancer cells. Complex (1) was tested in transfected cells overexpressing the CTR1 receptor in order to compare its steric effects with a less bulky ligand and more labile complex (2) [CuCl2(impy)]. A significant reduction of IC50 value was observed in CTR1 overexpressing cells for complex (2) (32 μM to 20 μM) as compared to (1) (2.78 μM to 3.41 μM), evidencing a possible uptake through copper reduction (Cu+2 → Cu+1) mediated by CTR1. Thus, considering that CTR1 is a mediator of metallodrugs uptake, the development of strategies that use rational drug design is important in order to improve the therapeutic efficacy through greater specificity and consecutive reduction of side effects. Here we show the example for the case of copper(II) complexes67FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESP2015/20882-3; 2017/19504-0; 2018/17170-0; 2013/07600-3; 2018/12062-