RESUMO
Prostate cancer is a common type of cancer in men with high incidence and mortality. Our aim was to investigate the effects of oxalipalladium (ox-Pd) on metastatic human prostate cancer PC3 cells and compare them with the effects of oxaliplatin (ox-Pt) (as an approved cancer drug). We synthesized ox-Pd through a new chemical method and used FT-IR, 1H NMR, 13C NMR, and MS analyzes to characterize it. The effects of ox-Pd on PC3 cells viability, apoptosis, cell cycle, migration, and gene expression were examined. Inhibition of topoisomerase IIα activity was investigated by pHOT1 plasmid relaxation and kDNA decatenation assays. Chemical tests showed ox-Pd with the correct composition and structure. For the first time, the exact fragmentation pathway of ox-Pd and its difference with ox-Pt was obtained by MS analysis. Ox-Pd significantly decreased PC3 cell viability with less/no toxicity effect on MHFB-1 normal skin fibroblasts. Wound scratch assay confirmed the strong anti-migratory activity of ox-Pd. According to flow cytometry analysis, this drug increased the number of PC3 cells in late apoptosis and decreased DNA replication and mitosis. Furthermore, pHOT1 plasmid relaxation and kDNA decatenation assays showed that ox-Pd strongly inhibited the catalytic activity of topoisomerase IIα. The expression of topoisomerase IIα, Bcl-2, P21, and survivin was decreased while the expression of Bax and p53 was increased under ox-Pd treatment. We provide the first evidence that ox-Pd exhibits more selective anticancer effects on PC3 cells compared to ox-Pt. Taken together, these data strongly suggest a therapeutic window for ox-Pd in cancer.
Assuntos
Antineoplásicos , Apoptose , Sobrevivência Celular , Neoplasias da Próstata , Humanos , Masculino , Antineoplásicos/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Células PC-3 , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Paládio/farmacologia , Paládio/química , Oxaliplatina/farmacologia , Ciclo Celular/efeitos dos fármacosRESUMO
The spontaneous aggregation of infectious or misfolded forms of prion protein is known to be responsible for neurotoxicity in brain cells, which ultimately leads to the progression of prion disorders. Bovine spongiform encephalopathy (BSE) in animals and Creutzfeldt-Jakob disease (CJD) in humans are glaring examples in this regard. Square-planar complexes with labile ligands and indole-based compounds are found to be efficiently inhibitory against protein aggregation. Herein, we report the synthesis of an indole-based cyclometallated palladium complex. The ligand and complex were characterized by various spectroscopic techniques such as UV-visible, NMR, IR, and HRMS. The molecular structure of the complex was confirmed by single-crystal X-ray crystallography. The interaction of the complex with PrP106-126 was studied using UV-visible spectroscopy, CD spectroscopy, MALDI-TOF MS, and molecular docking. The inhibition effects of the complex on the PrP106-126 aggregation, fibrillization and amyloid formation phenomena were analysed through the ThT assay, CD, TEM and AFM. The effect of the complex on the aggregation process of PrP106-126 was determined kinetically through the ThT assay. The complex presented high binding affinity with the peptide and influenced the peptide's conformation and aggregation in different modes of binding. Furthermore, the MTT assay on neuronal HT-22 cells showed considerable protective properties of the complex against PrP106-126-mediated cytotoxicity. These findings suggest that the compound influences peptide aggregation in different ways, and the anti-aggregation action is primarily associated with the metal's physicochemical properties and the reactivity rather than the ligand. As a result, we propose that this compound be investigated as a potential therapeutic molecule in metallopharmaceutical research to treat prion disease (PD).
Assuntos
Complexos de Coordenação , Indóis , Paládio , Agregados Proteicos , Paládio/química , Paládio/farmacologia , Humanos , Indóis/química , Indóis/farmacologia , Agregados Proteicos/efeitos dos fármacos , Complexos de Coordenação/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/síntese química , Simulação de Acoplamento Molecular , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/farmacologia , Fragmentos de Peptídeos/metabolismo , Proteínas Priônicas/química , Proteínas Priônicas/metabolismo , Proteínas Priônicas/antagonistas & inibidores , PríonsRESUMO
Currently, there are many uses of metal complexes, especially in the fields of medicinal chemistry and catalysis. Thus, fabrication of new complexes which perform as a catalyst and chemotherapeutic drug is always a beneficial addition to the literature. Herein, we report three heterocyclic thiosemicarbazone-based Pd(II) complexes [Pd(HL1)Cl] (C1), [Pd(L2)(PPh3)] (C2) and [Pd(L3)(PPh3)]Cl (C3) having coligands Cl and PPh3. Thiosemicarbazone ligands (H2L1, H2L2 and HL3) and the complexes (C1-C3) were characterized methodically using several spectroscopic techniques. Single-crystal X-ray diffraction methods reveal that the structural environment around the metal center of C2 is square planar, while for C1 and C3 it is a slighty distorted square plane. The supramolecular network of compounds was built via hydrogen bonds, C-Hâ¯π and πâ¯π interactions. Density functional theory (DFT) study of the structure of the complexes supports experimental findings. The application of these complexes as catalysts toward Suzuki-Miyaura coupling reactions has been examined with various aryl halides and phenyl boronic acid in PEG 400 solvent. The complexes displayed good biomolecular interactions with DNA/protein, with a binding constant value of the order of 105 M-1. C3 showed greater binding efficacy toward these biomolecules than the other complexes, which might be due to the cationic nature of C3. Furthermore, antitumor activity of the complexes was studied against the human triple-negative breast cancer (TNBC) cell line MDA-MB-231. It was found that C3 was more toxic (IC50 = 10 ± 2.90 µM) toward MDA-MB-231 cells than the other complexes. A known chemotherapeutic drug, 5-fluorouracil, was included as positive control. The programmed cell death mechanism of C3 was confirmed. Additionally, complex-induced apoptosis was confirmed and occurred via a mitochondria-dependent (intrinsic) pathway.
Assuntos
Antineoplásicos , Complexos de Coordenação , Paládio , Tiossemicarbazonas , Paládio/química , Paládio/farmacologia , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Tiossemicarbazonas/química , Tiossemicarbazonas/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Complexos de Coordenação/síntese química , Catálise , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Estrutura Molecular , Proliferação de Células/efeitos dos fármacos , Teoria da Densidade Funcional , Modelos Moleculares , Apoptose/efeitos dos fármacosRESUMO
Deafness mainly results from irreversible impairment of hair cells (HCs), which may relate to oxidative stress, yet therapeutical solutions is lacked due to limited understanding on the exact molecular mechanism. Herein, mimicking the molecular structure of natural enzymes, a palladium (Pd) single-atom nanozyme (SAN) was fabricated, exhibiting superoxide dismutase and catalase activity, transforming reactive oxygen species (ROS) into O2 and H2O. We examined the involvement of Pd in neomycin-induced HCs loss in vitro and in vivo over zebrafish. Our results revealed that neomycin treatment induced apoptosis in HCs, resulting in substantial of ROS elevation in HEI-OC1 cells, decrease in mitochondrial membrane potential, and increase in lipid peroxidation and iron accumulation, ultimately leading to iron-mediated cell death. Noteworthy, Pd SAN treatment exhibited significant protective effects against HCs damage and impaired HCs function in zebrafish by inhibiting ferroptosis. Furthermore, the application of iron death inducer RSL3 resulted in notable exacerbation of neomycin-induced harm, which was mitigated by Pd administration. Our investigation demonstrates that antioxidants is promising for inhibiting ferroptosis and repairing of mitochondrial function in HCs and the enzyme-mimic SAN provides a good strategy for designing drugs alleviating neomycin-induced ototoxicity.
Assuntos
Ferroptose , Células Ciliadas Auditivas , Perda Auditiva , Neomicina , Paládio , Espécies Reativas de Oxigênio , Peixe-Zebra , Animais , Neomicina/farmacologia , Paládio/química , Paládio/farmacologia , Ferroptose/efeitos dos fármacos , Perda Auditiva/induzido quimicamente , Perda Auditiva/prevenção & controle , Perda Auditiva/tratamento farmacológico , Células Ciliadas Auditivas/efeitos dos fármacos , Células Ciliadas Auditivas/metabolismo , Células Ciliadas Auditivas/patologia , Espécies Reativas de Oxigênio/metabolismo , Linhagem Celular , Apoptose/efeitos dos fármacos , Potencial da Membrana Mitocondrial/efeitos dos fármacosRESUMO
Metal peroxide nanomaterials as efficient hydrogen peroxide (H2O2) self-supplying agents have attracted the attention of researchers for antitumor treatment. However, relying solely on metal peroxides to provide H2O2 is undoubtedly insufficient to achieve optimal antitumor effects. Herein, we construct novel hyaluronic acid (HA)-modified nanocomposites (MgO2/Pd@HA NCs) formed by decorating palladium nanoparticles (Pd NPs) onto the surfaces of a magnesium peroxide (MgO2) nanoflower as a highly effective nanoplatform for the tumor microenvironment (TME)-responsive induction of ferroptosis in tumor cells and tumor photothermal therapy (PTT). MgO2/Pd@HA NC could be well endocytosed into tumor cells with CD44 expression depending on the specific recognition of HA with CD44, and then, the nanocomposites can be rapidly decomposed in mild acid and hyaluronidase overexpressed TME, and plenty of H2O2 was released. Simultaneously, Pd NPs catalyze self-supplied H2O2 to generate abundant hydroxyl radicals (â¢OH) and catalyze glutathione (GSH) into glutathione disulfide owing to its peroxidase and glutathione oxidase mimic enzyme activities, while the abundant â¢OH could also consume GSH in tumor cells and disturb the defense pathways of ferroptosis leading to the accumulation of lipid peroxidation and resulting in the occurrence of ferroptosis. Additionally, the superior photothermal conversion performance of Pd NPs in near-infrared II could also be used for PTT, synergistically cooperating with nanocomposite-induced ferroptosis for tumor inhibition. Consequently, the successfully prepared TME-responsive MgO2/Pd@HA NCs exhibited marked antitumor effect without obvious biotoxicity, contributing to thoroughly explore the nanocomposites as a novel and promising treatment for tumor therapy.
Assuntos
Ferroptose , Ácido Hialurônico , Óxido de Magnésio , Nanocompostos , Paládio , Terapia Fototérmica , Microambiente Tumoral , Ácido Hialurônico/química , Ácido Hialurônico/farmacologia , Ferroptose/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos , Óxido de Magnésio/química , Óxido de Magnésio/farmacologia , Nanocompostos/química , Nanocompostos/uso terapêutico , Terapia Fototérmica/métodos , Animais , Humanos , Paládio/química , Paládio/farmacologia , Paládio/uso terapêutico , Camundongos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Peróxido de HidrogênioRESUMO
In order to investigate the structural features and antiproliferative activity of Pd(II) complexes containing halogenated ligands with different flexibility, several Schiff base and reduced Schiff base Pd(II) complexes, namely X1X2PicPd, X1X2PyPd, X1X2Pic(R)Pd, and X1X2Py(R)Pd (where X1 = X2 = Cl, Br and I; Pic: 2-picolylamine; Py = 2-(2-pyridyl)ethylamine), were synthesized and characterized by spectroscopic methods and, in the case of Br2PyPd, Cl2Py(R)Pd and ClBrPy(R)Pd, also by X-ray crystallography. The results of the X-ray crystallography showed that in both series of complexes the Pd(II) ion has a distorted square-planar geometry, although the coordination modes of the two ligands are different. In the Schiff base-type complexes the ligand acts as a tridentate chelate with NN'O donor atoms, whereas in the reduced Schiff base-type complexes the ligand acts as a bidentate chelate with NN' donor atoms. In both series of complexes, the chloride ions occupy the residual coordination sites of the Pd(II) ion. TD-DFT calculations were performed for a better understanding of the UV-Vis spectra. From these calculations it was found that the signal appearing at â¼400 nm in the complexes with reduced Schiff base ligands (X1X2Pic(R)Pd and X1X2Py(R)Pd) is mainly due to a HOMO â LUMO transition, while for the Schiff base complex ClBrPyPd the signal is due to a HOMO â LUMO+1 transition. For the complex I2PicPd, combinations of HOMO-4 â LUMO and HOMO-2 â LUMO transitions were found to be responsible for that signal. In regard to the biological activity profile, all complexes were first investigated as proteasome inhibitors by fluorometric methods. From these enzymatic assays, it emerged that they are good inhibitors with IC50 values in the low-micromolar range and that their inhibitory activity is strictly related to the presence of the metal ion. Subsequently they were also subjected to cell-based assays (the resazurin method) to assess their antiproliferative properties by using two leukemic cell lines, namely the drug-sensitive CCRF-CEM cell line and its multidrug-resistant sub-cell line CEM/ADR5000. In this test they displayed IC50 values in the sub-micromolar and low-micromolar range determined for a selected metal complex (Br2Pic(R)Pd) and ligand (Cl2Pic(R)), respectively. Moreover, docking studies were performed on the two expected molecular targets, i.e. proteasome and DNA, to shed light on the mechanisms of action of these types of Pd(II) complexes.
Assuntos
Antineoplásicos , Proliferação de Células , Complexos de Coordenação , Paládio , Bases de Schiff , Bases de Schiff/química , Bases de Schiff/farmacologia , Humanos , Paládio/química , Paládio/farmacologia , Proliferação de Células/efeitos dos fármacos , Ligantes , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Complexos de Coordenação/síntese química , Cristalografia por Raios X , Linhagem Celular Tumoral , Halogenação , Estrutura Molecular , Ensaios de Seleção de Medicamentos Antitumorais , Modelos MolecularesRESUMO
Hybrid nanomaterials have attracted considerable interest in biomedicine because of their fascinating characteristics and wide range of applications in targeted drug delivery, antibacterial activity, and cancer treatment. This study developed a gelatin-coated Titanium oxide/palladium (TiO2/Pd) hybrid nanomaterial to enhance the antibacterial and anticancer capabilities. Morphological and structural analyses were conducted to characterize the synthesized hybrid nanomaterial. The surface texture of the hybrid nanomaterials was examined by high-resolution transmission electron microscopy (HR-TEM) and field-emission scanning electron microscopy (FE-SEM). The FE-SEM image revealed the bulk of the spherically shaped particles and the aggregated tiny granules. Energy dispersive X-ray spectroscopy (EDS) revealed Ti, Pd, C, and O. X-ray diffraction (XRD) revealed the gelatin-coated TiO2/Pd to be in the anatase form. Fourier transform infrared spectroscopy examined the interactions among the gelatin-coated TiO2/Pd nanoparticles. The gelatin-coated TiO2/Pd nanomaterials exhibited high antibacterial activity against Escherichia coli (22 mm) and Bacillus subtilis (17 mm) compared to individual nanoparticles, confirming the synergistic effect. More importantly, the gelatin-coated TiO2/Pd hybrid nanomaterial exhibited remarkable cytotoxic effects on A549 lung cancer cells which shows a linear increase with the concentration of the nanomaterial. The hybrid nanomaterials displayed higher toxicity to cancer cells than the nanoparticles alone. Furthermore, the cytotoxic activity against human cancer cells was verified by the generation of reactive oxygen species and nuclear damage. Therefore, gelatin-coated TiO2/Pd nanomaterials have potential uses in treating cancer and bacterial infections.
Assuntos
Antibacterianos , Antineoplásicos , Escherichia coli , Gelatina , Nanoestruturas , Paládio , Titânio , Titânio/química , Titânio/farmacologia , Antibacterianos/farmacologia , Antibacterianos/química , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/química , Gelatina/química , Paládio/química , Paládio/farmacologia , Escherichia coli/efeitos dos fármacos , Nanoestruturas/química , Células A549 , Bacillus subtilis/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Difração de Raios X , Nanopartículas Metálicas/químicaRESUMO
To investigate the structure and bioactivity relationship, six Pd(II)/Pt(II) complexes with N-isobutylglycine (L1) and cyclohexylglycine (L2) as N^O amino acid bidentate ligands, 1,10'-phenanthroline (phen) and 2,2'-bipyridine (bipy) as N^N donor ligands, and [Pd(L1)(bipy)]NO3 (1), [Pd(L2)(bipy)]NO3 (2), [Pd(L1)(phen)]NO3 (3), [Pd(L2)(phen)]NO3·2H2O (4), [Pt(L1)(phen)]NO3 (5), along with [Pt(L2)(phen)]NO3 (6) were prepared and then characterized. The geometry of each compound was validated by doing a DFT calculation. Furthermore, tests were conducted on the complexes' water solubilities and lipophilicity. All bipy complexes had superior aqueous solubility and less lipophilicity in comparison with phen complexes, as well as complexes containing cyclohexyl-glycine compared to isobutyl-glycine complexes, probably because of the steric effects and polarity of cyclohexylglycine. The in-vitro anticancer activities of these compounds were examined against HCT116, A549, and MCF7 cancerous cell lines. Data revealed that all Pd/Pt complexes demonstrate higher anticancer activity than carboplatin, and complexes 3 and 4 are more cytotoxic than cisplatin against the HCT116 cell line, particularly against MCF7 cancerous cells. In addition, among all compounds, complex 4 has more anticancer ability than oxaliplatin. Due to different solubility and lipophilicity behavior, the accumulation of Pt complexes and clinical Pt drugs in each cancerous cell was investigated. The binding capabilities of these complexes to DNA, as the main target in chemotherapy, occur through minor grooves and intercalate into DNA, which was done using absorption, fluorescence, and circular dichroism spectroscopy. Finally, the docking simulation study showed the mode of DNA bindings is in good agreement with the spectral binding data.
Assuntos
Antineoplásicos , Complexos de Coordenação , Glicina , Paládio , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/química , Glicina/química , Glicina/análogos & derivados , Glicina/farmacologia , Paládio/química , Paládio/farmacologia , Ligantes , Relação Estrutura-Atividade , Linhagem Celular Tumoral , Complexos de Coordenação/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/síntese química , Platina/química , Platina/farmacologia , DNA/metabolismo , DNA/química , SolubilidadeRESUMO
The effect of strong metal-support interaction (SMSI) has never been systematically studied in the field of nanozyme-based catalysis before. Herein, by coupling two different Pd crystal facets with MnO2, i.e., (100) by Pd cube (Pdc) and (111) by Pd icosahedron (Pdi), we observed the reconstruction of Pd atomic structure within the Pd-MnO2 interface, with the reconstructed Pdc (100) facet more disordered than Pdi (111), verifying the existence of SMSI in such coupled system. The rearranged Pd atoms in the interface resulted in enhanced uricase-like catalytic activity, with Pdc@MnO2 demonstrating the best catalytic performance. Theoretical calculations suggested that a more disordered Pd interface led to stronger interactions with intermediates during the uricolytic process. In vitro cell experiments and in vivo therapy results demonstrated excellent biocompatibility, therapeutic effect, and biosafety for their potential hyperuricemia treatment. Our work provides a brand-new perspective for the design of highly efficient uricase-mimic catalysts.
Assuntos
Hiperuricemia , Compostos de Manganês , Óxidos , Urato Oxidase , Hiperuricemia/tratamento farmacológico , Urato Oxidase/química , Urato Oxidase/uso terapêutico , Urato Oxidase/metabolismo , Óxidos/química , Compostos de Manganês/química , Compostos de Manganês/farmacologia , Humanos , Paládio/química , Paládio/farmacologia , Animais , Catálise , Ácido Úrico/química , CamundongosRESUMO
The continuously increasing rate of breast cancer is one of the major threats to female health worldwide. Recently, palladium complexes have emerged as impressive candidates with effective biocompatibility and anticancer activities. Hence, in the present study, we report a new series of palladium complexes bearing NNS pincer ligands for cytotoxicity studies. The reaction of thiophenol/4-chlorothiophenol/4-methylthiophenol/4-methoxythiophenol with 2-bromo-N-quinolin-8-yl-acetamide in the presence of sodium hydroxide in ethanol at 80 °C gave [C9H6N-NH-C(O)-CH2-S-Ar] [Ar = C6H5 (L1), C6H4Cl-4 (L2), C6H4Me-4 (L3), and C6H4-OMe-4 (L4)]. The corresponding reaction of L1-L4 with Na2PdCl4 in methanol at room temperature for 3 h resulted in complexes [(L1-H)PdCl] (C1), [(L2-H)PdCl] (C2), [(L3-H)PdCl] (C3), and [(L4-H)PdCl] (C4). All new compounds have been characterized by spectroscopic analyses. The structures of complexes C1, C3, and C4 have also been determined from single-crystal X-ray diffraction data. The cytotoxicities of L1-L4 and C1-C4 have been investigated for breast cancer 4T1 and pancreatic cancer MIA-PaCa-2 cells. The IC50 values for complexes C2 and C3 were observed to be comparable to or higher than those of cisplatin. The stressed morphology and cell death of cancerous cells were successfully observed through cellular morphology analysis and the assessment of cytoskeleton damage.
Assuntos
Antineoplásicos , Neoplasias da Mama , Complexos de Coordenação , Ensaios de Seleção de Medicamentos Antitumorais , Paládio , Neoplasias Pancreáticas , Paládio/química , Paládio/farmacologia , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Ligantes , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Complexos de Coordenação/síntese química , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Linhagem Celular Tumoral , Feminino , Proliferação de Células/efeitos dos fármacos , Estrutura Molecular , Sobrevivência Celular/efeitos dos fármacos , Relação Estrutura-Atividade , Cristalografia por Raios XRESUMO
The search for novel anticancer agents to replace the current platinum-based treatments remains an ongoing process. Palladacycles have shown excellent promise as demonstrated by our previous work which yielded BTC2, a binuclear palladadycle with a non-ionisable polyethylene glycol (PEG) tether. Here, we explore the importance of the PEG-tether length on the anticancer activity of the binuclear palladacycles by comparing three analogous binuclear palladacycles, BTC2, BTC5 and BTC6, in the oestrogen receptor positive MCF7 and triple-negative MDA-MB-231 breast cancer cell lines. In addition, these are compared to another analogue with an ionisable morpholine tether, BTC7. Potent anticancer activity was revealed through cell viability studies (MTT assays) revealed that while BTC6 showed similar potent anticancer activity as BTC2, it was less toxic towards non-cancerous cell lines. Interestingly, BTC7 and BTCF were less potent than the PEGylated palladacycles but showed significantly improved selectivity towards the triple-negative breast cancer cells. Cell death analysis showed that BTC7 and BTCF significantly induced apoptosis in both the cancer cell lines while the PEGylated complexes induced both apoptosis and secondary necrosis. Furthermore, experimental and computational DNA binding studies indicated partial intercalation and groove binding as the modes of action for the PEGylated palladacycles. Similarly, experimental and computational BSA binding studies indicated and specific binding sites in BSA dependent on the nature of the tethers on the complexes.
Assuntos
Antineoplásicos , Apoptose , Complexos de Coordenação , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Complexos de Coordenação/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/síntese química , Apoptose/efeitos dos fármacos , Polietilenoglicóis/química , Polietilenoglicóis/farmacologia , Linhagem Celular Tumoral , Paládio/química , Paládio/farmacologia , Células MCF-7 , Sobrevivência Celular/efeitos dos fármacos , DNA/metabolismo , DNA/química , FemininoRESUMO
Triple-negative breast cancer (TNBC) poses challenges in therapy due to the absence of target expression such as estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Frequently, the treatment of TNBC involves the combination of several therapeutics. However, an enhanced therapeutic effect can be also achieved within a single molecule. The efficacy of raloxifene can be improved by designing a raloxifene-based hybrid drug bearing a 2,2'-bipyridine moiety (2). Integration of platinum(II), palladium(II), and nickel(II) complexes into this structure dramatically changed the cytotoxicity. The platinum(II) dichloride complexâ 3 did not demonstrate any activity, while palladium(II) and nickel(II) dichloride complexesâ 4 and 5 exhibited various cytotoxic behavior towards different types of hormone-receptor positive (HR+) cancer and TNBCâ cell lines. The replacement of the two chlorido ligands in 3-5 with a dicarbollide (carborate) ion [C2B9H11]2- resulted in reduced activity of compoundsâ 6, 7, and 8. However, the palladacarborane complex 7 demonstrated higher selectivity towards TNBC. Furthermore, the mechanism of action was shifted from cytotoxic to explicitly cytostatic with detectable proliferation arrest and accelerated aging, characterized by senescence-associated phenotype of TNBCâ cells. This study provides valuable insights into the development of hybrid therapeutics against TNBC.
Assuntos
Antineoplásicos , Proliferação de Células , Complexos de Coordenação , Ensaios de Seleção de Medicamentos Antitumorais , Níquel , Paládio , Platina , Cloridrato de Raloxifeno , Neoplasias de Mama Triplo Negativas , Humanos , Paládio/química , Paládio/farmacologia , Níquel/química , Níquel/farmacologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Platina/química , Platina/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Complexos de Coordenação/síntese química , Proliferação de Células/efeitos dos fármacos , Cloridrato de Raloxifeno/química , Cloridrato de Raloxifeno/farmacologia , Linhagem Celular Tumoral , Relação Estrutura-Atividade , Estrutura Molecular , Relação Dose-Resposta a Droga , FemininoRESUMO
In continuation of our previous works on the cytotoxic properties of organopalladium compounds, in this contribution we describe the first systematic study of the anticancer activity of Pd(II)-aryl complexes. To this end, we have prepared and thoroughly characterized a wide range of palladium derivatives bearing different diphosphine, aryl and halide ligands, developing, when necessary, specific synthetic protocols. Most of the synthesized compounds showed remarkable cytotoxicity towards ovarian and breast cancer cell lines, with IC50 values often comparable to or lower than that of cisplatin. The most promising complexes ([PdI(Ph)(dppe)] and [PdI(p-CH3-Ph)(dppe)]), characterized by a diphosphine ligand with a low bite angle, exhibited, in addition to excellent cytotoxicity towards cancer cells, low activity on normal cells (MRC5 human lung fibroblasts). Specific immunofluorescence tests (cytochrome c and H2AX assays), performed to clarify the possible mechanism of action of this class of organopalladium derivatives, seemed to indicate DNA as the primary cellular target, whereas caspase 3/7 assays proved that the complex [PdI(Ph)(dppe)] was able to promote intrinsic apoptotic cell death. A detailed molecular docking analysis confirmed the importance of a diphosphine ligand with a reduced bite angle to ensure a strong DNA-complex interaction. Finally, one of the most promising complexes was tested towards patient-derived organoids, showing promising ex vivo cytotoxicity.
Assuntos
Antineoplásicos , Complexos de Coordenação , Simulação de Acoplamento Molecular , Paládio , Fosfinas , Humanos , Paládio/química , Paládio/farmacologia , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Fosfinas/química , Fosfinas/farmacologia , Ligantes , Relação Estrutura-Atividade , Complexos de Coordenação/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/síntese química , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Estrutura MolecularRESUMO
This research introduces a novel method that leverages Spirulina extract (S.E) as a bio-surfactant in the ultrasound-assisted synthesis (UAS) of Pd3+ (0.25-10 mol%) doped tin oxide (SnO2) self-assembled superstructures. Nanotechnology has witnessed significant advancements in recent years, driven by the exploration of novel synthesis methods and the development of advanced nanomaterials tailored for specific applications. Metal oxide nanoparticles, particularly SnO2, have garnered considerable attention due to their versatile properties and potential applications in various fields, including gas sensing, catalysis, and biomedical engineering. The study explores how varying influential parameters like S.E concentration, sonication time, pH, and sonication power can influence the resulting superstructures' morphology, size, and shape. A theoretical model for forming different hierarchical superstructures (HS) is proposed. X-ray diffraction (XRD) analysis confirms the crystalline tetragonal rutile phase of the SnO2:Pd HS. Raman spectroscopy reveals a red shift in the A1g mode, indicating phonon confinement due to various defects in the SnO2 structure. Further characterization using transmission electron microscopy (TEM), scanning electron microscopy (SEM), and X-ray photoelectron spectroscopy (XPS) provides insights into particle size, surface morphology, elemental composition, and binding energy. The study also demonstrates the application of optimized SnO2:3Pd HS in developing latent fingerprints (LFPs) on different surfaces using a simple powder dusting (PD) method, with the fingerprints (FPs) visualized under normal light. A mathematical model developed in Python-based software is used to analyze various features of the developed FPs, including pore properties such as number, position, inter-spacing, area, and shape. Additionally, an in vitro MTT assay shows concentration-dependent anticancer activity of SnO2:3Pd nanoparticles (NPs) on MCF7 cell lines, highlighting their potential as a promising cancer treatment option. Overall, the study suggests that the optimized HS can serve as multifunctional platforms for biomedical and dermatoglyphics applications, demonstrating the versatility and potential of the synthesized materials.
Assuntos
Antineoplásicos , Paládio , Compostos de Estanho , Compostos de Estanho/química , Compostos de Estanho/farmacologia , Humanos , Paládio/química , Paládio/farmacologia , Antineoplásicos/farmacologia , Antineoplásicos/química , Nanopartículas Metálicas/química , Células MCF-7RESUMO
The four new ligands, dialkyl esters of (S,S)-propylenediamine-N,N'-di-(2,2'-di-(4-hydroxy-benzil))acetic acid (R2-S,S-pddtyr·2HCl) (R = ethyl (L1), propyl (L2), butyl (L3), and pentyl (L4)) and corresponding palladium(II) complexes have been synthesized and characterized by microanalysis, infrared, 1H NMR and 13C NMR spectroscopy. In vitro cytotoxicity was evaluated using the MTT assay on four tumor cell lines, including mouse mammary (4T1) and colon (CT26), and human mammary (MDA-MD-468) and colon (HCT116), as well as non-tumor mouse mesenchymal stem cells. Using fluorescence spectroscopy were investigated the interactions of new palladium(II) complexes [PdCl2(R2-S,S-pddtyr)]; (R = ethyl (C1), propyl (C2), butyl (C3), and pentyl (C4)) with calf thymus human serum albumin (HSA) and DNA (CT-DNA). The high values of the binding constants, Kb, and the Stern-Volmer quenching constant, KSV, show the good binding of all complexes for HSA and CT-DNA. The mentioned ligands and complexes were also tested on in vitro antimicrobial activity against 11 microorganisms. Testing was performed by the microdilution method, where the minimum inhibitory concentration (MMC) and the minimum microbicidal concentration (MMC) were determined.
Assuntos
Complexos de Coordenação , DNA , Ésteres , Paládio , Albumina Sérica Humana , Animais , Humanos , Camundongos , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/síntese química , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Complexos de Coordenação/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/síntese química , DNA/metabolismo , Ésteres/química , Ésteres/farmacologia , Testes de Sensibilidade Microbiana , Estrutura Molecular , Paládio/química , Paládio/farmacologia , Ligação Proteica , Albumina Sérica Humana/metabolismoRESUMO
Cisplatin (cDDP) resistance is a matter of concern in triple-negative breast cancer therapeutics. We measured the metabolic response of cDDP-sensitive (S) and -resistant (R) MDA-MB-231 cells to Pd2Spermine(Spm) (a possible alternative to cDDP) compared to cDDP to investigate (i) intrinsic response/resistance mechanisms and (ii) the potential cytotoxic role of Pd2Spm. Cell extracts were analyzed by untargeted nuclear magnetic resonance metabolomics, and cell media were analyzed for particular metabolites. CDDP-exposed S cells experienced enhanced antioxidant protection and small deviations in the tricarboxylic acid cycle (TCA), pyrimidine metabolism, and lipid oxidation (proposed cytotoxicity signature). R cells responded more strongly to cDDP, suggesting a resistance signature of activated TCA cycle, altered AMP/ADP/ATP and adenine/uracil fingerprints, and phospholipid biosynthesis (without significant antioxidant protection). Pd2Spm impacted more markedly on R/S cell metabolisms, inducing similarities to cDDP/S cells (probably reflecting high cytotoxicity) and strong additional effects indicative of amino acid depletion, membrane degradation, energy/nucleotide adaptations, and a possible beneficial intracellular γ-aminobutyrate/glutathione-mediated antioxidant mechanism.
Assuntos
Antineoplásicos , Cisplatino , Resistencia a Medicamentos Antineoplásicos , Neoplasias de Mama Triplo Negativas , Humanos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/metabolismo , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Antineoplásicos/farmacologia , Antineoplásicos/química , Linhagem Celular Tumoral , Feminino , Espermina/farmacologia , Espermina/metabolismo , Paládio/química , Paládio/farmacologiaRESUMO
Reactions between sodium tetrachloropalladate and 2- (or 4-) substituted 4-phenyl-3-thiosemicarbazone ligands (HLR), with various electron-donating and electron-withdrawing substituents (R = OCH3, NO2, and Cl), afford square-planar complexes of the general formula [Pd(LR)2]. Ground-state geometry optimization and the vibrational analysis of cis- and trans-isomers of the complexes were carried out to get an insight into the stereochemistry of the complexes. Natural bond orbital analysis was used to analyze how the nature of the substituent affects the natural charge of the metal center, the type of hybridization, and the strength of the M-N and M-S bonds. Using spectrophotometry, the stability of the complexes, and their DNA binding abilities were assessed. The Pd(II) complexes showed moderate cytotoxicity against MCF-7 and Caco-2â cell lines, two of the assessed malignant cell lines, resulting in all known cell death types, including early apoptotic bodies and late apoptotic vacuoles as well as evident necrotic bodies.
Assuntos
Antineoplásicos , Complexos de Coordenação , Paládio , Tiossemicarbazonas , Humanos , Paládio/química , Paládio/farmacologia , Tiossemicarbazonas/química , Tiossemicarbazonas/farmacologia , Ligantes , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Complexos de Coordenação/síntese química , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Ensaios de Seleção de Medicamentos Antitumorais , Células CACO-2 , Proliferação de Células/efeitos dos fármacos , Células MCF-7 , Estrutura Molecular , Apoptose/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Relação Estrutura-Atividade , DNA/química , DNA/metabolismo , DNA/efeitos dos fármacosRESUMO
Antibiotic resistance represents a pressing global health challenge, now acknowledged as a critical concern within the framework of One Health. Photodynamic inactivation of microorganisms (PDI) offers an attractive, non-invasive approach known for its flexibility, independence from microbial resistance patterns, broad-spectrum efficacy, and minimal risk of inducing resistance. Various photosensitizers, including porphyrin derivatives have been explored for pathogen eradication. In this context, we present the synthesis, spectroscopic and photophysical characteristics as well as antimicrobial properties of a palladium(II)-porphyrin derivative (PdF2POH), along with its zinc(II)- and free-base counterparts (ZnF2POH and F2POH, respectively). Our findings reveal that the palladium(II)-porphyrin complex can be classified as an excellent generator of reactive oxygen species (ROS), encompassing both singlet oxygen (Φâ³ = 0.93) and oxygen-centered radicals. The ability of photosensitizers to generate ROS was assessed using a variety of direct (luminescence measurements) and indirect techniques, including specific fluorescent probes both in solution and in microorganisms during the PDI procedure. We investigated the PDI efficacy of F2POH, ZnF2POH, and PdF2POH against both Gram-negative and Gram-positive bacteria. All tested compounds proved high activity against Gram-positive species, with PdF2POH exhibiting superior efficacy, leading to up to a 6-log reduction in S. aureus viability. Notably, PdF2POH-mediated PDI displayed remarkable effectiveness against S. aureus biofilm, a challenging target due to its complex structure and increased resistance to conventional treatments. Furthermore, our results show that PDI with PdF2POH is more selective for bacterial than for mammalian cells, particularly at lower light doses (up to 5 J/cm2 of blue light illumination). This enhanced efficacy of PdF2POH-mediated PDI as compared to ZnF2POH and F2POH can be attributed to more pronounced ROS generation by palladium derivative via both types of photochemical mechanisms (high yields of singlet oxygen generation as well as oxygen-centered radicals). Additionally, PDI proved effective in eliminating bacteria within S. aureus-infected human keratinocytes, inhibiting infection progression while preserving the viability and integrity of infected HaCaT cells. These findings underscore the potential of metalloporphyrins, particularly the Pd(II)-porphyrin complex, as promising photosensitizers for PDI in various bacterial infections, warranting further investigation in advanced infection models.
Assuntos
Anti-Infecciosos , Fotoquimioterapia , Porfirinas , Animais , Humanos , Porfirinas/farmacologia , Porfirinas/química , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/química , Espécies Reativas de Oxigênio , Staphylococcus aureus , Oxigênio Singlete/química , Plâncton , Paládio/farmacologia , Fotoquimioterapia/métodos , Anti-Infecciosos/química , Biofilmes , Oxigênio , MamíferosRESUMO
Palladium and platinum complexes, especially those that include cisplatin, can be useful chemotherapeutic drugs. Alternatives that have less adverse effects and require lower dosages of treatment could be provided by complexes containing pyridine bases. The complexes [Pd(SCN)2(4-Acpy)2] (1), [Pd(N3)2(4-Acpy)2] (2) [Pd(paOH)2].2Cl (3) and [Pt(SCN)2(paO)2] (4) were prepared by self-assembly method at ambient temperature; (4-Acpy = 4-acetylpyridine and paOH = pyridine-2-carbaldehyde-oxime). The structure of complexes 1-4 was confirmed using spectroscopic and X-ray crystallography methods. Complexes 1-4 have similar features in isomerism that include the trans coordination geometry of pyridine ligands with Pd or Pt ion. The 3D network structure of complexes 1-4 was constructed by an infinite number of discrete mononuclear molecules extending via H-bonds. The Pd and Pt complexes 1-4 with pyridine ligands were assessed on MCF-7, T47D breast cancer cells and HCT116 colon cancer cells. The study evaluated cell death through apoptosis and cell cycle phases in MCF-7 cells treated with palladium or platinum conjugated with pyridine base. Upon treatment of MCF-7 with these complexes, the expression of apoptotic signals (Bcl2, p53, Bax and c-Myc) and cell cycle signals (p16, CDK1A, CDK1B) were evaluated. Compared to other complexes and cisplatin, IC50 of complex 1 was lowest in MCF-7 cells and complex 2 in T47D cells. Complex 4 has the highest effectiveness on HCT116. The selective index (SI) of complexes 1-4 has a value of more than two for all cancer cell lines, indicating that the complexes were less toxic to normal cells when given the same dose. MCF-7 cells treated with complex 2 and platinum complex 4 exhibited the highest level of early apoptosis. p16 may be signal arrest cells in Sub G, which was observed in cells treated with palladium complexes that suppress excessive cell proliferation. High c-Myc expression of treated cells with four complexes 1-4 and cisplatin could induce p53. All complexes 1-4 elevated the expression of Bax and triggered by the tumor suppressor gene p53. p53 was downregulating the expression of Bcl2.
Assuntos
Antineoplásicos , Apoptose , Complexos de Coordenação , Paládio , Piridinas , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Paládio/química , Paládio/farmacologia , Piridinas/química , Piridinas/farmacologia , Apoptose/efeitos dos fármacos , Complexos de Coordenação/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/síntese química , Transdução de Sinais/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Platina/química , Platina/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Linhagem Celular Tumoral , Compostos Organoplatínicos/farmacologia , Compostos Organoplatínicos/química , Compostos Organoplatínicos/síntese química , Cristalografia por Raios X , Estrutura Molecular , Relação Dose-Resposta a DrogaRESUMO
Herein, we report the synthesis and biological evaluation of [Pd(L)(OH2)Cl] complex (where L = 2,2'-(pyridin-2-ylmethylene)bis(5,5-dimethylcyclohexane-1,3-dione) as a novel promising anticancer candidate. The complex was characterized by single-crystal X-ray diffraction and other various spectroscopic techniques. Besides, the optimized structure was determined through DFT calculations revealing that the coordination geometry of [Pd(L)(OH2)Cl] complex is square planar. The binding propensity of [Pd(L)(OH2)Cl] complex with DNA and BSA was assessed by the spectrophotometric method. The antimicrobial profile of the ligand and its [Pd(L)(OH2)Cl] complex was screened against clinically important bacterial strains. [Pd(L)(OH2)Cl] complex showed promising activity against these microorganisms. Pd(L)(OH2)Cl] complex exhibited a potent antiproliferative potential compared to its ligand against different human cancer cells (A549, HCT116, MDA-MB-231, and HepG2) with less toxic effect against normal cells (WI-38). Additionally, [Pd(L)(OH2)Cl] complex exerted its anticancer effects against the most responsive cells (HCT116 cells; IC50 = 11 ± 1 µM) through suppressing their colony-forming capabilities and triggering apoptosis and cell cycle arrest at S phase. Quantitative PCR analysis revealed a remarkable upregulation of the mRNA expression level of p53 and caspase-3 by 4.8- and 5.9-fold, respectively, relative to control. Remarkable binding properties and non-covalent interactions between L and its [Pd(L)(OH2)Cl] complex with the binding sites of different receptors including CDK2, MurE ligase, DNA, and BSA were established using molecular docking. Based on our results, [Pd(L)(OH2)Cl] complex is an intriguing candidate for future investigations as a potential anticancer drug for the treatment of colon cancer.