RESUMO
In the treatment of hormone-dependent cancers, aromatase inhibitors (AI) are receiving increased attention due to some undesirable effects such as the risk of endometrial cancer and thromboembolism of SERMs (selective estrogen receptor modulators). Letrozole is the most active AI with 99% aromatase inhibition. Unfortunately, this compound also exhibits some adverse effects such as hot flashes and fibromyalgias. Therefore, there is an urgent need to explore new types of AIs that retain the same-or even increased-antitumor ability. Inspired by the letrozole structure, a set of new derivatives has been synthesized that include a ferrocenyl moiety and different heterocycles. The derivative that contains a benzimidazole ring, namely compound 6, exhibits a higher aromatase inhibitory activity than letrozole and it also shows potent cytostatic behavior when compared to other well-established aromatase inhibitors, as demonstrated by dose-response, cell cycle, apoptosis and time course experiments. Furthermore, 6 promotes the inhibition of cell growth in both an aromatase-dependent and -independent fashion, as indicated by the study of A549 and MCF7 cell lines. Molecular docking and molecular dynamics calculations on the interaction of 6 or letrozole with the aromatase binding site revealed that the ferrocene moiety increases the van der Waals and hydrophobic interactions, thus resulting in an increase in binding affinity. Furthermore, the iron atom of the ferrocene fragment can form a metal-acceptor interaction with a propionate fragment, and this results in a stronger coupling with the heme group-a possibility that is consistent with the strong aromatase inhibition of 6.
Assuntos
Neoplasias da Mama , Citostáticos , Humanos , Feminino , Letrozol/farmacologia , Inibidores da Aromatase/farmacologia , Inibidores da Aromatase/química , Aromatase/metabolismo , Metalocenos , Simulação de Acoplamento Molecular , Nitrilas/farmacologia , Triazóis/farmacologia , Células MCF-7RESUMO
Photoredox catalysis constitutes a very powerful tool in organic synthesis, due to its versatility, efficiency, and the mild conditions required by photoinduced transformations. In this paper, we present an efficient and selective photocatalytic procedure for the aerobic oxidative dehydrogenation of partially saturated N-heterocycles to afford the respective N-heteroarenes (indoles, quinolines, acridines, and quinoxalines). The protocol involves the use of new Ir(III) biscyclometalated photocatalysts of the general formula [Ir(C^N)2(N^N')]Cl, where the C^N ligand is 2-(2,4-difluorophenyl)pyridinate, and N^N' are different ligands based on the 2-(2'-pyridyl)benzimidazole scaffold. In-depth electrochemical and photophysical studies as well as DFT calculations have allowed us to establish structure-activity relationships, which provide insights for the rational design of efficient metal-based dyes in photocatalytic oxidation reactions. In addition, we have formulated a dual mechanism, mediated by the radical anion superoxide, for the above-mentioned transformations.
Assuntos
Fármacos Fotossensibilizantes , Quinolinas , Benzimidazóis , Catálise , Fármacos Fotossensibilizantes/farmacologiaRESUMO
Five new RuII polypyridyl complexes bearing N-(arylsulfonyl)-8-amidoquinolate ligands and three of their biscyclometalated IrIII congeners have been prepared and employed as photocatalysts (PCs) in the photooxidation of benzylamines with O2 . In particular, the new RuII complexes do not exhibit photoluminescence, rather they harvest visible light efficiently and are very stable in solution under irradiation with blue light. Their non-emissive behavior has been related to the low electrochemical energy gaps and rationalized on the basis of theoretical calculations (DFT analysis) that predict low S0 âT1 energy values. Moreover, the RuII complexes, despite being non-emissive, display excellent activities in the selective photocatalytic transformation of benzylamines into the corresponding imines. The presence of an electron-withdrawing group (-CF3) on the arene ring of the N-(arylsulfonyl)-8-amidoquinolate ligand improves the photocatalytic activity of the corresponding photocatalyst. Furthermore, all the experimental evidence, including transient absorption spectroscopy measurements suggest that singlet oxygen is the actual oxidant. The IrIII analogues are considerably more photosensitive and consequently less efficient photosensitizers (PSs).
RESUMO
The importance of ion pairing in different fields of chemistry is widely recognized. In this work, we have synthesized a set of cationic p-cymene ruthenium complexes of general formula [(p-cym)Ru(L')(κ2-O^N-L)]X (p-cym = p-cymene; L' = N-methylimidazole (MeIm), N-ethylpiperidylimidazole (EpipIm), 1,3,5-triaza-7-phosphaadamantane (PTA); L = 2-(1H-benzimidazol-2-yl)phenolato (L1), 2-(1,3-benzothiazol-2-yl)phenolato (L2); X = Cl-, BF4-, OTf-, BPh4-). X-ray diffraction studies on selected complexes revealed relatively strong anion-cation interactions in the solid state mainly based on N-H···X (X = Cl, F, O) and C-H···π interactions, also observed in the DFT-modeled complexes in the gas phase. Moreover, NMR studies showed that they exist as intimate ion pairs in solution and, remarkably, as head-to-tail quadruples in the particular case of the cation [(p-cym)Ru(MeIm)(κ2- O^N-L1)]+ ([1]+) with Cl- and BPh4- as counteranions. Furthermore, a value of ΔG = -2.9 kcal mol-1 at 299 K has been estimated for the equilibrium {[1]BPh4···[1]BPh4} â 2{[1]+···BPh4-} in concentrated CDCl3 solutions. In addition, preliminary studies concerning the cytotoxic properties against HeLa cell lines of the derivatives suggested a positive effect derived from the presence of the lipophilic BPh4- anion and also from the NH group of the benzimidazolyl fragment.
RESUMO
A new family of heteroleptic bis-cyclometalated IrIII complexes with formula [Ir(CN^ )2 (NN^ )]Cl (CN^ =2-phenylpyridinate and NN^ =2,2'-dipyridylamine or N-benzylated 2,2'-dipyridylamines, were synthesized, characterized, and successfully used as photosensitizers in the catalytic photooxidation of an array of dialkyl, dibenzyl, alkyl aryl, and diaryl sulfides, as well as sulfur-containing amino acids. Furthermore, the reactions proceeded with optimal chemoselectivity, and atom economy under mild conditions. Experimental observations support a dual mechanism in which singlet oxygen and superoxide are the actual oxidants.
RESUMO
In this paper, the synthesis, comprehensive characterization and biological and photocatalytic properties of two series of neutral IrIII biscyclometalated complexes of general formula [Ir(C^N)2 (N^O)], where the N^O ligands are 2-(benzimidazolyl)phenolate-N,O (L1, series a) and 2-(benzothiazolyl)phenolate-N,O (L2, series b), and the C^N ligands are 2-(phenyl)pyridinate or its derivatives, are described,. Complexes of types a and b exhibit dissimilar photophysical and biological properties. In vitro cytotoxicity tests conclusively prove that derivatives of series a are harmless in the dark against SW480 cancer cells (colon adenocarcinoma), but express enhanced cytotoxicity versus the same cells after stimulation with UV or blue light. In contrast, complexes of type b show a very high cytotoxic activity in the dark, but low photosensitizing ability. Thus, the ancillary N^O ligand is the main factor in terms of cytotoxic activity both in the dark and upon irradiation. However, the C^N ligands play a key role regarding cellular uptake. In particular, the complex of formula [Ir(dfppy)2 (L1)] (dfppy=2-(4,6-difluorophenyl)pyridinate) [3 a] has been identified as both an efficient photosensitizer for 1 O2 generation and a potential agent for photodynamic therapy. These capabilities are probably related to a combination of its notable cellular internalization, remarkable photostability, high photoluminescence quantum yield, and long triplet excited-state lifetime. Both types of complexes exhibit notable catalytic activity in the photooxidation of thioanisole and S-containing aminoacids with full selectivity.
Assuntos
Complexos de Coordenação/química , Irídio/química , Ligantes , Fármacos Fotossensibilizantes/síntese química , Azóis/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Neoplasias do Colo/diagnóstico por imagem , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/patologia , Cristalografia por Raios X , Estabilidade de Medicamentos , Técnicas Eletroquímicas , Humanos , Hidroxibenzoatos/química , Luz , Microscopia de Fluorescência , Conformação Molecular , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Teoria Quântica , Espécies Reativas de Oxigênio/metabolismo , Espectrometria de FluorescênciaRESUMO
A new family of neutral ruthenium(II) arene complexes of the type [Ru(η6-arene)X(κ2- O, N-L)] (η6-arene = p-cym, bz; X = Cl-, SCN-; HL1 = 2-(2'-hydroxyphenyl)benzimidazole, HL2 = 2-(2'-hydroxyphenyl)benzothiazole) has been synthesized and characterized. The cytotoxic activity of the Ru(II) complexes was evaluated in several tumor cell lines (A549, HepG2 and SW480) both in the dark and after soft irradiation with UV and blue light. None of the complexes bearing benzimidazole (HL1) as a ligand displayed phototoxicity, whereas the complexes with a benzothiazole ligand (HL2) exhibited photoactivation; the sensitivity observed for UV was higher than for blue light irradiation. The interesting results displayed by HL2 and [Ru(η6- p-cym)(NCS)(κ2- O, N-L2)], [3a], in terms of photo cytotoxicity prompted us to analyze their interaction with DNA, both in the dark and under irradiation conditions, in an effort to shed some light on their mechanism of action. The results of this study revealed that HL2 interacts with DNA by groove binding, whereas [3a] interacts by a dual mode of binding, an external groove binding, and covalent binding of the metal center to the guanine moiety. Interestingly, both HL2 and [3a] display a clear preference for AT base pairs, and this causes fluorescence enhancement. Additionally, cleavage of the pUC18 plasmid DNA by the complex is observed upon irradiation. The study of the irradiated form demonstrates that the arene ligand is released to yield species such as [Ru(κ2- O, N-L2)(κ1- S-DMSO)2(µ-SCN)]2 [3c] and [Ru(κ2- O, N-L2)(κ1- S-DMSO)3(SCN)] [3d]. Such photo dissociation occurs even in the absence of oxygen and leads to cytotoxicity enhancement, an effect attributed to the presence of [3d], thus revealing the potential of [3a] as a pro-drug for photoactivated anticancer chemotherapy (PACT).
Assuntos
Antineoplásicos/farmacologia , Benzimidazóis/farmacologia , Benzotiazóis/farmacologia , Complexos de Coordenação/farmacologia , Fármacos Fotossensibilizantes/farmacologia , Rutênio/química , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/efeitos da radiação , Benzimidazóis/síntese química , Benzimidazóis/química , Benzimidazóis/efeitos da radiação , Benzotiazóis/síntese química , Benzotiazóis/química , Benzotiazóis/efeitos da radiação , Bovinos , Linhagem Celular Tumoral , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Complexos de Coordenação/efeitos da radiação , DNA/química , Fluorescência , Humanos , Concentração de Íons de Hidrogênio , Substâncias Intercalantes/síntese química , Substâncias Intercalantes/química , Substâncias Intercalantes/farmacologia , Substâncias Intercalantes/efeitos da radiação , Ligantes , Estrutura Molecular , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/efeitos da radiação , Raios UltravioletaRESUMO
Considering the interest in processes related to hydrogen storage such as CO2 hydrogenation and formic acid (FA) decomposition, we have synthesized a set of Ir, Rh, or Ru complexes to be tested as versatile precatalysts in these reactions. In relation with the formation of H2 from FA, the possible applicability of these complexes in the transfer hydrogenation (TH) of challenging substrates as quinoline derivatives using FA/formate as hydrogen donor has also been addressed. Bearing in mind the importance of secondary coordination sphere interactions, N,N' ligands containing NH2 groups, coordinated or not to the metal center, were used. The general formula of the new complexes are [( p-cymene)RuCl(N,N')]X, X = Cl-, BF4- and [Cp*MCl(N,N')]Cl, M = Rh, Ir, where the N,N' ligands are 8-aminoquinoline (HL1), 6-pyridyl-2,4-diamine-1,3,5-triazine (L2) and 5-amino-1,10-phenanthroline (L3). Some complexes are not active or catalyze only one process. However, the complexes [Cp*MCl(HL1)]Cl with M = Rh, Ir are versatile catalysts that are active in hydrogenation of quinolines, FA decomposition, and also in CO2 hydrogenation with the iridium derivative being more active and robust. The CO2 hydrogenation takes place in mild conditions using only 5 bar of pressure of each gas (CO2 and H2). The behavior of some precatalysts in D2O and after the addition of 9 equiv of HCO2Na (pseudocatalytic conditions) has been studied in detail and mechanisms for the FA decomposition and the hydrogenation of CO2 have been proposed. For the Ru, Ir, or Rh complexes with ligand HL1, the amido species with the deprotonated ligand are observed. In the case of ruthenium, the formate complex is also detected. For the iridium derivative, both the amido intermediate and the hydrido species have been observed. This hydrido complex undergoes a process of umpolung D+â Ir-D. All in all, the results of this work reflect the active role of -NH2 in the transfer of H+.
RESUMO
Precursors of chelate pyridine-N-heterocyclic carbene (N^C:) ligands with methyl- or benzyl-substituted imidazolylidene fragments were synthesized. They were used to obtain 12 iridium bis-cyclometalated complexes of the type [Ir(C^N)2(N^C:)]+ (C^N = 2-(phenyl)pyridinato-C2,N, ppy, 2-(4,6-difluorophenyl)pyridinato-C2,N, dfppy). The ancillary N^C: ligands contain different structural modifications. The aim of the work was to analyze the effect that changes in the two types of ligands have on the photophysical and electrochemical properties and also on the behavior of these materials as photosensitizers. The X-ray crystal structures of five complexes were determined. The complexes emitted in the blue-green region. It was expected that the frontier orbitals and thus the photophysical and electrochemical properties would be controlled by the main C^N ligands, and it was demonstrated that the effect of the modifications in the N^C: ligand, especially the presence of a nitro group in the pyridine ring or the interruption of conjugation between the two rings, also affected these properties. The quenching with O2 and photostability studies were also performed. Density functional theory calculations were used to explain the behavior of some derivatives. The complexes and other previously reported compounds were employed as photosensitizers (PS) in preliminary studies on the production of H2 from water using [Co(bpy)3]Cl2 (bpy = 2,2'-bipyridine) as catalyst and triethanolamine (TEOA) as the sacrificial reductant. The absence of quenching of the PS with TEOA allowed us to propose an oxidative quenching mechanism.
RESUMO
Given the potent anticancer properties of cis-diamminedichloroplatinum(II) and knowing its mode of action, we synthesized four new cis-[PtCl2(N^N)] organoplatinum complexes, two with N-substituted pbi ligands (pbiR = 1-R-2-(2-pyridyl)benzimidazole) (namely, 1 and 2) and two more with 4,4'-disubstituted bpy ligands (bpy = 2,2'-bipyridine) (namely, 3 and 4). We explored their cytotoxicity and ability to bind to deoxyguanosine monophosphate (dGMP), DNA, and albumin models. By 1H NMR and UV-vis spectroscopies, circular dichroism, agarose gel electrophoresis, differential scanning calorimetry measurements, and density functional theory calculations, we verified that only 3 can form aquacomplex species after dimethyl sulfoxide solvation; surprisingly, 1, 2, and 3 can bind covalently to DNA, whereas 4 can form a noncovalent complex. Interestingly, only complexes 1 and 4 exhibit good cytotoxicity against human ovarian carcinoma (HeLa) cell line, whereas 2 and 3 are inactive. Although lung carcinoma (A549) cells are more resistant to the four platinum complexes than HeLa cells, when the protein concentration in the extracellular media is lower, the cytotoxicity becomes substantially enhanced. By native electrophoresis of bovine seroalbumin (BSA) and inductively coupled plasma mass spectrometry uptake studies we bear out, on one hand, that 2 and 3 can interact strongly with BSA and its cellular uptake is negligible and, on the other hand, that 1 and 4 can interact with BSA only weakly, its cellular uptake being higher by several orders. These results point up the important role of the protein binding features on their biological activity and cellular uptake of cis-"PtCl2" derivatives. Our results are valuable in the future rational design of new platinum complexes with improved biological properties, as they expose the importance not only of their DNA binding abilities but also of additional factors such as protein binding.
Assuntos
Complexos de Coordenação/química , Platina/química , Soroalbumina Bovina/química , Células A549 , Varredura Diferencial de Calorimetria , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/farmacologia , Complexos de Coordenação/toxicidade , DNA/química , Nucleotídeos de Desoxiguanina/química , Estabilidade de Medicamentos , Células HeLa , Humanos , Ligantes , Estrutura Molecular , Ligação ProteicaRESUMO
The synthesis and characterization of Pt(II) (1 and 2) and Ru(II) arene (3 and 4) or polypyridine (5 and 6) complexes is described. With the aim of having a functional group to form bioconjugates, one uncoordinated carboxyl group has been introduced in all complexes. Some of the complexes were selected for their potential in photodynamic therapy (PDT). The molecular structures of complexes 2 and 5, as well as that of the sodium salt of the 4'-(4-carboxyphenyl)-2,2':6',2â³-terpyridine ligand (cptpy), were determined by X-ray diffraction. Different techniques were used to evaluate the binding capacity to model DNA molecules, and MTT cytotoxicity assays were performed against four cell lines. Compounds 3, 4, and 5 showed little tendency to bind to DNA and exhibited poor biological activity. Compound 2 behaves as bonded to DNA probably through a covalent interaction, although its cytotoxicity was very low. Compound 1 and possibly 6, both of which contain a cptpy ligand, were able to intercalate with DNA, but toxicity was not observed for 6. However, compound 1 was active in all cell lines tested. Clonogenic assays and apoptosis induction studies were also performed on the PC-3 line for 1. The photodynamic behavior for complexes 1, 5, and 6 indicated that their nuclease activity was enhanced after irradiation at λ = 447 nm. The cell viability was significantly reduced only in the case of 5. The different behavior in the absence or presence of light makes complex 5 a potential prodrug of interest in PDT. Molecular docking studies followed by molecular dynamics simulations for 1 and the counterpart without the carboxyl group confirmed the experimental data that pointed to an intercalation mechanism. The cytotoxicity of 1 and the potential of 5 in PDT make them good candidates for subsequent conjugation, through the carboxyl group, to "selected peptides" which could facilitate the selective vectorization of the complex toward receptors that are overexpressed in neoplastic cell lines.
Assuntos
Antineoplásicos/farmacologia , Ácidos Carboxílicos/farmacologia , Complexos de Coordenação/farmacologia , Compostos Organoplatínicos/farmacologia , Rutênio/química , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/efeitos da radiação , Apoptose/efeitos dos fármacos , Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/química , Ácidos Carboxílicos/efeitos da radiação , Linhagem Celular Tumoral , Cisplatino/farmacologia , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Complexos de Coordenação/efeitos da radiação , DNA/química , Dano ao DNA , Humanos , Substâncias Intercalantes/síntese química , Substâncias Intercalantes/química , Substâncias Intercalantes/farmacologia , Substâncias Intercalantes/efeitos da radiação , Luz , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Compostos Organoplatínicos/síntese química , Compostos Organoplatínicos/química , Compostos Organoplatínicos/efeitos da radiação , PlasmídeosRESUMO
The ligands 2-pyridin-2-yl-1H-benzimidazole (HL(1)), 1-methyl-2-pyridin-2-ylbenzimidazole (HL(2)), and 2-(1H-imidazol-2-yl)pyridine (HL(3)) and the proligand 2-phenyl-1H-benzimidazole (HL(4)) have been used to prepare five different types of new ruthenium(II) arene compounds: (i) monocationic complexes with the general formula [(η(6)-arene)RuCl(κ(2)-N,N-HL)]Y [HL = HL(1), HL(2), or HL(3); Y = Cl or BF4; arene = 2-phenoxyethanol (phoxet), benzene (bz), or p-cymene (p-cym)]; (ii) dicationic aqua complexes of the formula [(η(6)-arene)Ru(OH2)(κ(2)-N,N-HL(1))](Y)2 (Y = Cl or TfO; arene = phoxet, bz, or p-cym); (iii) the nucleobase derivative [(η(6)-arene)Ru(9-MeG)(κ(2)-N,N-HL(1))](PF6)2 (9-MeG = 9-methylguanine); (iv) neutral complexes consistent with the formulation [(η(6)-arene)RuCl(κ(2)-N,N-L(1))] (arene = bz or p-cym); (v) the neutral cyclometalated complex [(η(6)-p-cym)RuCl(κ(2)-N,C-L(4))]. The cytototoxic activity of the new ruthenium(II) arene compounds has been evaluated in several cell lines (MCR-5, MCF-7, A2780, and A2780cis) in order to establish structure-activity relationships. Three of the compounds with the general formula [(η(6)-arene)RuCl(κ(2)-N,N-HL(1))]Cl differing in the arene moiety have been studied in depth in terms of thermodynamic dissociation constants, aquation kinetic constants, and DNA binding measurements. The biologically most active compound is the p-cym derivative, which strongly destabilizes the DNA double helix, whereas those with bz and phoxet have only a small effect on the stability of the DNA double helix. Moreover, the inhibitory activity of several compounds toward CDK1 has also been evaluated. The DNA binding ability of some of the studied compounds and their CDK1 inhibitory effect suggest a multitarget mechanism for their biological activity.
Assuntos
Antineoplásicos/farmacologia , Compostos Organometálicos/farmacologia , Oxidiazóis/química , Inibidores de Proteínas Quinases/farmacologia , Rutênio/química , Antineoplásicos/síntese química , Antineoplásicos/química , Proteína Quinase CDC2 , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Quinases Ciclina-Dependentes/antagonistas & inibidores , Quinases Ciclina-Dependentes/metabolismo , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Ligantes , Células MCF-7 , Modelos Moleculares , Conformação Molecular , Compostos Organometálicos/síntese química , Compostos Organometálicos/química , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-AtividadeRESUMO
One approach to reduce the side effects of chemotherapy in cancer treatment is photodynamic therapy (PDT), which allows spatiotemporal control of the cytotoxicity. We have used the strategy of coordinating π-expansive ligands to increase the excited state lifetimes of Ir(III) half-sandwich complexes in order to facilitate the generation of 1O2. We have obtained derivatives of formulas [Cp*Ir(Câ§N)Cl] and [Cp*Ir(Câ§N)L]BF4 with different degrees of π-expansion in the Câ§N ligands. Complexes with the more π-expansive ligand are very effective photosensitizers with phototoxic indexes PI > 2000. Furthermore, PI values of 63 were achieved with red light. Time-dependent density functional theory (TD-DFT) calculations nicely explain the effect of the π-expansion. The complexes produce reactive oxygen species (ROS) at the cellular level, causing mitochondrial membrane depolarization, cleavage of DNA, nicotinamide adenine dinucleotide (NADH) oxidation, as well as lysosomal damage. Consequently, cell death by apoptosis and secondary necrosis is activated. Thus, we describe the first class of half-sandwich iridium cyclometalated complexes active in PDT.
Assuntos
Antineoplásicos , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Antineoplásicos/farmacologia , Ligantes , Linhagem Celular Tumoral , Irídio/farmacologiaRESUMO
The synthesis and full characterization of the new aqua-complex [(η(6)-p-cymene)Ru(OH2)(κ(2)-N,N-2-pydaT)](BF4)2, [2](BF4)2, and the nucleobase derivative [(η(6)-p-cymene)Ru(9-MeG)(κ(2)-N,N-2-pydaT)](BF4)2, [4](PF6)2, where 2-pydaT = 2,4-diamino-6-(2-pyridyl)-1,3,5-triazine and 9-MeG = 9-methylguanine, are reported here. The crystal structures of both [4](PF6)2 and the chloro complex [(η(6)-p-cymene)RuCl(κ(2)-N,N-2-pydaT)](PF6), [1](PF6), have been elucidated by X-ray diffraction. The former provided relevant information regarding the interaction of the metallic fragment [(η(6)-p-cymene)Ru(κ(2)-N,N-2-pydaT)](2+) and a simple model of DNA. NMR and kinetic absorbance studies have proven that the aqua-complex [2](BF4)2 binds to the N7 site of guanine in nucleobases, nucleotides, or DNA. A stable bifunctional interaction (covalent and partially intercalated) between the [(η(6)-p-cymene)Ru(κ(2)-N,N-2-pydaT)](2+) fragment and CT-DNA has been corroborated by kinetic, circular dichroism, viscometry, and thermal denaturation experiments. The reaction mechanism entails the very fast formation of the Ru-O-(PO3) linkage prior to the fast intercalation of the 2-pydaT fragment. Then, a Ru-N7-(G) covalent bond is formed at the expense of the Ru-O-(PO3) bond, yielding a bifunctional complex. The dissociation rate of the intercalated fragment is slow, and this confers additional interest to [2](BF4)2 in view of the likely correlation between slow dissociation and biological activity, on the assumption that DNA is the only biotarget. Furthermore, [2](BF4)2 displays notable pH-dependent cytotoxic activity in human ovarian carcinoma cells (A2780, IC50 = 11.0 µM at pH = 7.4; IC50 = 6.58 µM at pH = 6.5). What is more, complex [2](BF4)2 is not cross-resistant with cisplatin, exhibiting a resistance factor, RF(A2780cis), of 0.28, and it shows moderate selectivity toward the cancer cell lines, in particular, A2780cis (IC50 = 3.0 5 ± 0.08 µM), relative to human lung fibroblast cells (MRC-5; IC50 = 24 µM), the model for healthy cells.
Assuntos
Antineoplásicos/química , Complexos de Coordenação/química , DNA/metabolismo , Substâncias Intercalantes/química , Rutênio/química , Triazinas/química , Animais , Antineoplásicos/farmacologia , Bovinos , Complexos de Coordenação/farmacologia , Cimenos , Feminino , Humanos , Substâncias Intercalantes/farmacologia , Modelos Moleculares , Monoterpenos/química , Monoterpenos/farmacologia , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Ovário/efeitos dos fármacos , Ovário/patologia , Rutênio/farmacologia , Triazinas/farmacologiaRESUMO
Despite their outstanding properties as potential photosensitizers for photodynamic therapy (PDT), Ir(III) biscyclometalated complexes need both further developments to overcome remaining limitations and in-depth investigations into their mechanisms of action to reach clinic application in the treatment of cancer. This work describes the synthesis of a family of Ir(III) complexes of general formula [Ir(C^N)2(N^N')]Cl (N^N' = thiabendazole-based ligands; C^N = ppy (2-phenylpyridinate) (Series A), or dfppy (2-(2,4-difluorophenyl)pyridinate) (Series B)) and their evaluation as potential PDT agents. These complexes are partially soluble in water and exhibit cytotoxic activity in the absence of light irradiation versus several cancer cell lines. Furthermore, the cytotoxic activity of derivatives of Series A is enhanced upon irradiation, particularly for complexes [1a]Cl and [3a]Cl, which show phototoxicity indexes (PI) above 20. Endocytosis was established as the uptake mechanism for [1a]Cl and [3a]Cl in prostate cancer cells by flow cytometry. These derivatives mainly accumulate in the mitochondria as shown by colocalization confocal microscopy experiments. Presumably, [1a]Cl and [3a]Cl induce death on cancer cells under irradiation through apoptosis triggered by a multimodal mechanism of action, which likely involves damage over mitochondrial DNA and mitochondrial membrane depolarization. Both processes seem to be the result of photocatalytic oxidation processes.
Assuntos
Antineoplásicos , Complexos de Coordenação , Neoplasias , Fotoquimioterapia , Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Irídio/farmacologia , Mitocôndrias , Neoplasias/tratamento farmacológico , Fármacos Fotossensibilizantes/farmacologia , TiabendazolRESUMO
Photodynamic therapy is an alternative to classical chemotherapy due to its potential to reduce side effects by a controlled activation of a photosensitizer through local irradiation with light. The photosensitizer then interacts with oxygen and generates reactive oxygen species. Iridium biscyclometallated complexes are very promising photosensitizers due to their exceptional photophysical properties and their ability to target mitochondria. Four Ir(III) biscyclometallated complexes of formula [Ir(C^N)2(N^N')]Cl, where N^N' is a ligand containing a benzimidazolyl fragment, have been synthesized and characterized. The C^N ligands were 2-phenylpyridinate (ppy) and 2-(2,4-difluorophenyl)pyridinate (dfppy). The complexes exhibited high photostability. The electrochemical and photophysical properties were modulated by both the cyclometallating and the ancillary ligands. The dfppy derivatives yielded the highest emission energy values, quantum yields of phosphorescence and excited state lifetimes. All complexes generated 1O2 in aerated solutions upon irradiation. Biological studies revealed that these complexes have a moderate cytotoxicity in the dark against different human cancer cell lines: prostate (PC-3), colon (CACO-2) and melanoma (SK-MEL-28), and against non-malignant fibroblasts (CCD-18Co). However, derivatives with ppy ligands ([1a]Cl, [2a]Cl) yielded a relevant photodynamic activity upon light irradiation (450 nm, 24.1 J cm-2), with phototoxicity indexes (EC50,dark/EC50,light) of 20.8 and 17.3, respectively, achieved in PC-3 cells. Mechanistic studies showed that these complexes are taken up by the cells through endocytosis and preferentially accumulate in mitochondria. Upon photoactivation, the complexes induced mitochondrial membrane depolarization and DNA damage, thus triggering cell death, mainly by apoptosis. Complex [1a]Cl is also able to oxidize NADH. This mitochondria-targeted photodynamic mechanism greatly inhibited the reproductive capacity of cancer cells and provides a valuable alternative to traditional chemotherapy for the controlled treatment of cancer.
RESUMO
An important challenge in the field of anticancer chemotherapy is the search for new species to overcome the resistance of standard drugs. An interesting approach is to link bioactive ligands to metal fragments. In this work, we have synthesized a set of p-cymene-Ru or cyclopentadienyl-M (M = Rh, Ir) complexes with four chrysin-derived pro-ligands with different -OR substituents at position 7 of ring A. The introduction of a piperidine ring on chrysin led to the highly cytotoxic pro-ligand HL4 and its metal complexes L4-M (SW480 and A549 cell lines, cytotoxic order: L4-Ir > L4-Ru ≈ L4-Rh). HL4 and its complexes induce apoptosis and can overcome cis-platinum resistance. However, HL4 turns out to be more cytotoxic in healthy than in tumor cells in contrast to its metal complexes which displayed higher selectivity than cisplatin towards cancer cells. All L4-M complexes interact with double stranded DNA. Nonetheless, the influence of the metal is clear because only complex L4-Ir causes DNA cleavage, through the generation of highly reactive oxygen species (1O2). This result supports the hypothesis of a potential dual mechanism consisting of two different chemical pathways: DNA binding and ROS generation. This behavior provides this complex with a great effectivity in terms of cytotoxicity.
RESUMO
The problems of resistance and side effects associated with cisplatin and other chemotherapeutic drugs have boosted research aimed at finding new compounds with improved properties. The use of platinum(IV) prodrugs is one alternative, although there is some controversy regarding the predictive ability of the peak reduction potentials. In the work described here a series of fourteen chloride Pt(II) and Pt(IV) compounds was synthesised and fully characterised. The compounds contain different bidentate arylazole heterocyclic ligands. Their cytotoxic properties against human lung carcinoma (A549), human breast carcinoma (MCF7) and human colon carcinoma (HCT116 and HT29) cell lines were studied. A clear relationship between the type of ligand and the anti-proliferative properties was found, with the best results obtained for the Pt(II) compound that contains an aniline fragment, (13), thus evidencing a positive effect of the NH2 group. Stability and aquation studies in DMSO, DMF and DMSO/water mixtures were carried out on the active complexes and an in-depth analysis of the two aquation processes, including DFT analysis, of 13 was undertaken. It was verified that DNA was the target and that cell death occurred by apoptosis in the case of 13. Furthermore, the cytotoxic derivatives did not exhibit haemolytic activity. The reduction of the Pt(IV) compounds whose Pt(II) congeners were active was studied by several techniques. It was concluded that the peak reduction potential was not useful to predict the ability for reduction. However, a correlation between the cytotoxic activity and the standard reduction potential was found.
Assuntos
Compostos de Anilina/química , Antineoplásicos/farmacologia , Neoplasias/tratamento farmacológico , Compostos Organoplatínicos/farmacologia , Platina/química , Pró-Fármacos/farmacologia , Células A549 , Antineoplásicos/química , Apoptose , Proliferação de Células , Células HCT116 , Humanos , Células MCF-7 , Neoplasias/patologia , Compostos Organoplatínicos/química , Pró-Fármacos/químicaRESUMO
The synthesis of several silver double helices containing bis(3,5dimethylpyrazolyl)-6-(R)-s-triazine ligands is described. The structure of two of them has been determined by X-ray difraction. Both derivatives represent the first reported examples of a new interaction mode for a triazine ring that involves a triazine N atom bridging two metal centers. Argentophilic contacts are also present. The Ag-N and Ag-Ag interactions have been demonstrated by theoretical studies, which also showed the clear influence of weak interactions with the counteranion and the effect of the symmetry of the triazine substituent. The different donor characters of these substituents allows a modulation of the strength of the bridging Ag-N(triazine) interaction. Double pi-pi stacking, anion-pi interactions, hydrogen bonds, and hydrophobic effects are observed in an unusual highly symmetrical interpenetrated three-dimensional superstructure.
RESUMO
Several complexes with a [2 × 2] grid structure have been obtained by the self-assembly of different copper(I) salts and ligands of the type 4,6-bis(pyrazol-1-yl)pyrimidine containing different substituents on the heterocycles. The main goal has been to evaluate the influence over the solid state and solution behavior of the functionalization of the pyrimidine ring with a primary amino substituent. The molecular and crystalline structures of some derivatives have been determined by X-ray diffraction. The grids contain two open voids formed by pairs of ligands facing one another on opposite sides of the grid in a somewhat divergent manner. One counteranion is hosted in each void interacting through hydrogen bonds and anion-π interactions. The presence of the amino group that points toward the inside of the cavity dominates the interactions in the void and apparently determines the orientation of the hosted counteranion and that of the ligands. With the exception of the derivative with chloride as the anion, the grid structure is preserved in solution (NMR and UV-vis) and some cation-anion interaction, increased by the presence of the amino group, exists also in solution (DOSY experiments). The experiments of anion interchange performed in solution indicate that a higher stability is found for the host-guest aggregates with OTs(-) (p-Me-C(6)H(4)SO(3)) and NO(3)(-). While for these anions a 1:2 stoichiometry is reached, for the rest of the anions tested (ReO(4)(-), OTf(-), and PF(6)(-)), only weaker 1:1 complexes are formed. Computational studies support the presence of anion-π interactions.