Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.900
Filtrar
1.
Anticancer Res ; 40(9): 5001-5013, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878788

RESUMO

AIM: Newly synthesized platinum(IV) complexes with ethylenediamine-N,N'-diacetate ligands (EDDA-type) (butyl-Pt and pentyl-Pt) were investigated against two cancer (A549 lung, and HTB 140 melanoma) and one non-cancerous (MRC-5 embryonic lung fibroblast) human cell lines. MATERIALS AND METHODS: The effects of these agents were compared with those of cisplatin after 6-, 24- and 48-h treatment. Sulforhodamine-B (SRB) assay was performed to estimate the cytotoxic effect, while the inhibitory effect on cell proliferation was measured using 5-bromo-2,-deoxyuridine (BrdU) incorporation assay. Cell cycle analysis was performed by flow cytometry. Type of cell death induced by these agents was determined by electrophoretic analysis of DNA, flow cytometry and by western blot analysis of proteins involved in induction of apoptosis. The effects of gamma irradiation, alone and in combination with platinum-based compounds, were examined by clonogenic and SRB assays. RESULTS: All examined platinum-based compounds had inhibitory and antiproliferative effects on A549 cells, but not on HTB140 and MRC-5 cells. Butyl-Pt, pentyl-Pt and cisplatin arrested the cell cycle in the S-phase and induced apoptotic cell death via regulation of expression of B-cell lymphoma 2 (BCL2) and BCL2-associated X (BAX) proteins. Platinum-based compounds increased the sensitivity of A549 cells to gamma irradiation. Butyl-Pt and pentyl-Pt showed better antitumour effects against A549 cells than did cisplatin, by interfering in cell proliferation and the cell cycle, and by triggering apoptosis. CONCLUSION: The effects of gamma irradiation on tumour cells may be amplified by pre-treatment of cells with platinum-based compounds.


Assuntos
Antineoplásicos/farmacologia , Compostos Organoplatínicos/farmacologia , Radiossensibilizantes/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/efeitos da radiação , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Cisplatino/farmacologia , Relação Dose-Resposta a Droga , Ácido Edético/análogos & derivados , Ácido Edético/química , Raios gama , Humanos , Concentração Inibidora 50 , Compostos Organoplatínicos/síntese química , Compostos Organoplatínicos/química , Radiossensibilizantes/síntese química , Radiossensibilizantes/química
2.
Dalton Trans ; 49(8): 2547-2558, 2020 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-32022814

RESUMO

Pt(ii) drugs and nitrogen mustards show severe side effects, poor tumour selectivity and face growing resistance by cancer cells due to sequestration by thiol-containing molecules (viz. glutathione (GSH) and copper ATPases like ATP7A/7B). ATP7A and ATP7B-sequestered Pt(ii) complexes show dose inefficacy and resistance. The incorporation of bulky ligands and chelating leaving groups may prevent deactivation by thiols. In this work, we have synthesised four new Pt(ii) complexes (3-6) of two carrier ligands, bis(2-hydroxyethyl)pyridylmethylamine (L1) and bis(2-chloroethyl)pyridylmethylamine (L2) with oxalato and cyclobutanedicarboxylato leaving groups. Among these four new complexes, the Pt(ii) complex of L2 with the oxalato leaving group (5, termed "oxamusplatin") is cytotoxic. Oxamusplatin is more resistant than cisplatin or oxaliplatin towards hydrolysis, thiol binding and sequestration by ATP7B. It targets cellular DNA and is capable of disrupting the microtubule network in the cytoskeleton. Oxamusplatin demonstrates better selectivity than oxaliplatin towards cancerous cells. It is ca. 4-10 times more cytotoxic towards metastatic prostate carcinoma (DU-145, IC50 = 21 ± 1 µM) and ca. 10-24 times more cytotoxic towards breast adenocarcinoma (MCF-7, IC50 = 8.1 ± 0.8 µM) compared to the three noncancerous cells investigated.


Assuntos
Antineoplásicos/farmacologia , ATPases Transportadoras de Cobre/metabolismo , Cobre/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Glutationa/metabolismo , Neoplasias/tratamento farmacológico , Compostos Organoplatínicos/farmacologia , Antineoplásicos/química , Apoptose , Ciclo Celular , Proliferação de Células , Humanos , Neoplasias/metabolismo , Neoplasias/patologia , Compostos Organoplatínicos/química , Células Tumorais Cultivadas
3.
Chem Commun (Camb) ; 56(15): 2320-2323, 2020 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-31990000

RESUMO

Novel biotinylated diazido-Pt(iv) complexes exhibit high visible light photocytotoxicity while being stable in the dark. Photocytotoxicity and cellular accumulation of all-trans-[Pt(py)2(N3)2(biotin)(OH)] (2a) were enhanced significantly when bound to avidin; irradiation induced dramatic cellular morphological changes in human ovarian cancer cells treated with 2a.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Biotinilação , Compostos Organoplatínicos/química , Compostos Organoplatínicos/farmacologia , Neoplasias Ovarianas/tratamento farmacológico , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Estrutura Molecular , Imagem Óptica , Compostos Organoplatínicos/síntese química , Neoplasias Ovarianas/diagnóstico por imagem , Neoplasias Ovarianas/patologia , Processos Fotoquímicos , Relação Estrutura-Atividade
4.
Dalton Trans ; 49(6): 1736-1741, 2020 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-31967147

RESUMO

Platinum(iv) complexes with a heterocyclic ligand and an ancillary ligand have been investigated and applied for treating various tumour cell lines. Another application of the Pt(iv) complexes in forming peptide disulfide bonds was investigated in this work. For development of Pt(iv) complex chemistry for disulfide bond formation in peptides, two Pt(iv) complexes, [PtCl2(phen)(en)]Cl2 and [PtCl2(bpy)(en)]Cl2, were synthesized and characterized using elemental analysis, ESI-MS and NMR. Subsequently, they were investigated as oxidants for the formation of disulfide bonds in various peptides. Excellent purities and yields of disulfide-containing peptides were achieved when the reactions were carried out in aqueous solution. The reactions were completed rapidly in a wide range of pH values even in acidic medium at room temperature. An intramolecular disulfide bond was formed in each of the peptides in a solution containing two dithiol-containing peptides, making the Pt(iv) complexes useful for generating disulfide-containing peptide libraries. In addition, the two Pt(iv) complexes can be used as oxidants for the synthesis of disulfide bonds on a resin, which is a more convenient method to synthesize disulfide-containing peptides through automation.


Assuntos
Complexos de Coordenação/química , Dissulfetos/química , Compostos Organoplatínicos/química , Peptídeos/química , Técnicas de Química Sintética , Complexos de Coordenação/síntese química , Dissulfetos/síntese química , Ligantes , Compostos Organoplatínicos/síntese química , Peptídeos/síntese química , Platina/química
5.
Dalton Trans ; 49(5): 1613-1619, 2020 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-31942585

RESUMO

We herein designed two new PtIV prodrugs of oxoplatin (cis,cis,cis-[PtCl2(NH3)2(OH)2]), [PtIVCl2(NH3)2(O2C-FA)2] (Pt-2) and [PtIVCl2(NH3)2(O2C-RH)2] (Pt-3), by conjugating with ferulic acid (FA-COOH) and rhein (RH-COOH) which have well-known biological activities. Three other Pt(iv) complexes of [PtIVCl2(NH3)2(O2C-BA)2] (Pt-1), [PtIVCl2(NH3)2(O2C-CA)2] (Pt-4) and [PtIVCl2(NH3)2(O2C-TCA)2] (Pt-5) (where BA-COOH = benzoic acid, CA-COOH = crotonic acid and TCA-COOH = trans-cinnamic acid) were also prepared for the comparative study. Like most PtIV prodrug complexes, the cytotoxicity of Pt-3 containing the biologically active rhein (RH-COOH) ligand against lung carcinoma (A549 and A549/DDP) cells was higher than those of Pt-1, Pt-2, Pt-4, cisplatin and Pt-5. Moreover, the cytotoxicity of Pt-3 in HL-7702 normal cells was lower than those of PtIV derivatives bearing BA-COOH, FA-COOH, TCA-COOH and CA-COOH ligands. The highly efficacious Pt-2 and Pt-3 were found to accumulate strongly in the A549/DDP cells, with the prodrug Pt-3 showing highest levels of penetration into the mitochondria. The prodrug Pt-3 effectively entered the A549/DDP cells and caused mitochondrial damage, significantly greater than Pt-2. In addition, the prodrug Pt-3 exhibited higher antitumor efficacy (inhibition rates (IR) = 67.45%) than Pt-2 (28.12%) and cisplatin (33.05%) in the A549/DDP xenograft mouse model. Thus, the prodrug Pt-3 containing the rhein (RH-COOH) ligand is a promising candidate drug targeting the mitochondria.


Assuntos
Antraquinonas/farmacologia , Antineoplásicos/farmacologia , Cisplatino/análogos & derivados , Ácidos Cumáricos/farmacologia , Compostos Organoplatínicos/farmacologia , Pró-Fármacos/farmacologia , Células A549 , Animais , Antraquinonas/química , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cisplatino/química , Cisplatino/farmacologia , Ácidos Cumáricos/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Ligantes , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Compostos Organoplatínicos/síntese química , Compostos Organoplatínicos/química , Pró-Fármacos/síntese química , Pró-Fármacos/química , Relação Estrutura-Atividade
6.
Appl Biochem Biotechnol ; 190(2): 506-528, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31388926

RESUMO

In this paper, a new anticancer Pt (II) complex, cis-[Pt (NH3)2(tertpentylgly)]NO3, was synthesized with glycine-derivative ligand and characterized. Cytotoxicity of this water-soluble Pt complex was studied against human cancer breast cell line of MCF-7. The interaction of human serum albumin (HSA) with Pt complex was studied by using UV-Vis, fluorescence spectroscopy methods, and molecular docking at 27 and 37 °C in the physiological situation (I = 10 mM, pH = 7.4). The negative [Formula: see text] and positive [Formula: see text] indicated that electrostatic force may be a major mode in the binding between Pt complex and HSA. Binding constant values were obtained through UV-Vis and fluorescence spectroscopy that reveal strong interaction. The negative Gibbs free energy that was obtained by using the UV-Vis method offers spontaneous interaction. Fluorescence quenching the intensity of HSA by adding Pt complex confirms the static mode of interaction is effective for this binding process. Hill coefficients, nH, Hill constant, kH, complex aggregation number around HSA, , number of binding sites, g, HSA melting temperature, Tm, and Stern-Volmer constant, kSV, were also obtained. The kinetics of the interaction was studied, which showed a second-order kinetic. The results of molecular docking demonstrate the position of binding of Pt complex on HSA is the site I in the subdomain IIA.


Assuntos
Glicina/química , Compostos Organoplatínicos/metabolismo , Albumina Sérica Humana/metabolismo , Termodinâmica , Humanos , Cinética , Células MCF-7 , Simulação de Acoplamento Molecular , Compostos Organoplatínicos/química , Ligação Proteica
7.
Chemistry ; 26(1): 259-268, 2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31614021

RESUMO

In the effort to overcome issues of toxicity and resistance inherent to treatment by the approved platinum anticancer agents, a large number of cisplatin variants continues today to be prepared and tested. One of the applied strategies is to use monofunctional platinum complexes that, unlike traditional bifunctional compounds, are able to form only a single covalent bond with nuclear DNA. Chirality, aquation reaction, interaction with guanine and N-acetyl methionine as well as, intercalation into, binding to and distortion of DNA have been investigated by using both quantum mechanical DFT and molecular dynamics computations aiming at contributing to the elucidation of the molecular mechanism underlying the significantly enhanced spectrum of activity of the monofunctional PtII drug phenanthriplatin. Analogous calculations have been performed in parallel for other two less potent monofunctional PtII drugs, pyriplatin and enpyriplatin, which show very different cytotoxic effects.


Assuntos
Antineoplásicos/química , Teoria da Densidade Funcional , Simulação de Dinâmica Molecular , Compostos Organoplatínicos/química , Fenantridinas/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , DNA/química , DNA/metabolismo , Humanos , Substâncias Intercalantes/química , Metionina/química , Conformação de Ácido Nucleico , Compostos Organoplatínicos/farmacologia , Fenantridinas/farmacologia , Termodinâmica , Transcrição Genética/efeitos dos fármacos
8.
Molecules ; 24(23)2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31805648

RESUMO

Switchable luminescent bioprobes whose emission can be turned on as a function of specific enzymatic activity are emerging as important tools in chemical biology. We report a promising platform for the development of label-free and continuous enzymatic assays in high-throughput mode based on the reversible solvent-induced self-assembly of a neutral dinuclear Pt(II) complex. To demonstrate the utility of this strategy, the switchable luminescence of a dinuclear Pt(II) complex was utilized in developing an experimentally simple, fast (10 min), low cost, and label-free turn-on luminescence assay for the endonuclease enzyme DNAse I. The complex displays a near-IR (NIR) aggregation-induced emission at 785 nm in aqueous solution that is completely quenched upon binding to G-quadruplex DNA from the human c-myc oncogene. Luminescence is restored upon DNA degradation elicited by exposure to DNAse I. Correlation between near-IR luminescence intensity and DNAse I concentration in human serum samples allows for fast and label-free detection of DNAse I down to 0.002 U/mL. The Pt(II) complex/DNA assembly is also effective for identification of DNAse I inhibitors, and assays can be performed in multiwell plates compatible with high-throughput screening. The combination of sensitivity, speed, convenience, and cost render this method superior to all other reported luminescence-based DNAse I assays. The versatile response of the Pt(II) complex to DNA structures promises broad potential applications in developing real-time and label-free assays for other nucleases as well as enzymes that regulate DNA topology.


Assuntos
Ensaios Enzimáticos/métodos , Compostos Organoplatínicos/química , Platina/química , Quadruplex G , Luminescência , Estrutura Molecular
9.
Inorg Chem ; 58(23): 16154-16170, 2019 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-31721562

RESUMO

In this study, two new bis-cyclometalated Pt(II) complexes, [Pt(C^N)(S^N)] [S^N = deprotonated 6-mercaptopurine (6-MP) and C^N = deprotonated 2-phenylpyridine (ppy), 2a; C^N = deprotonated benzo[h]quinoline (bhq), 2b], are synthesized by the reaction of [PtR(SMe2)(C^N)] (R = Me or p-MeC6H4) with 1 equiv of 6-mercaptopurine (6-HMP) at room temperature. The complexes are fully characterized using 1H and 13C NMR spectroscopies, electrospray ionization mass spectrometry, and elemental analysis. Biomolecular interaction of complex 2a with human serum albumin (HSA) is studied by fluorescence, UV-vis, and circular dichroism (CD) spectroscopies. The binding constants (Kb) and number of binding sites (n) are evaluated using the Stern-Volmer equation. The intrinsic fluorescence of protein is quenched by a static quenching mechanism, with a binding constant of Kb ∼ 105 reflecting a high affinity of complex 2a for HSA. The thermodynamic parameters (ΔH°, ΔG°, and ΔS°) indicate that the interaction is a spontaneous process and hydrophobic forces play a main role in the reaction. The displacement experiments demonstrate that the reactive binding sites of HSA to complex 2a are mainly located within its hydrophobic cavity in subdomain IIA (site I). Synchronous fluorescence spectra reveal that complex 2a affected the microenvironment of tryptophan-214 residues in subdomain IIA of HSA. In the case of interaction of complex 2b and HSA, because of overlapping of the emission spectra of complex 2b with HSA, chemometric approaches are applied. The results indicate significant interaction between the tryptophan residue of HSA and complex 2b. Moreover, the binding of Pt(II) complexes 2a and 2b causes a reduction of the α-helix content of HSA, as obtained by far-UV CD spectroscopy. The average binding distance (r) between Pt(II) complexes and HSA is obtained by Förster's resonance energy-transfer theory. Also, a molecular docking simulation reveals that π-π-stacking and hydrophobic interactions between these complexes and HSA are significant. Furthermore, the interactions of platinum complexes, 2, with calf-thymus DNA (CT-DNA) are investigated. The UV-vis results and ethidium bromide competitive studies support an intercalative interaction of both Pt(II) complexes with DNA. The new complexes 2 are also screened for anticancer activities. The results show that complexes 2 exhibit significant anticancer activity against the K562 (chronic myelogenous leukemia) cell line.


Assuntos
Antineoplásicos/farmacologia , DNA/efeitos dos fármacos , Mercaptopurina/farmacologia , Compostos Organoplatínicos/farmacologia , Albumina Sérica Humana/efeitos dos fármacos , Antineoplásicos/síntese química , Antineoplásicos/química , Sítios de Ligação/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , DNA/química , Teoria da Densidade Funcional , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Células K562 , Mercaptopurina/química , Simulação de Acoplamento Molecular , Estrutura Molecular , Compostos Organoplatínicos/síntese química , Compostos Organoplatínicos/química , Albumina Sérica Humana/química , Relação Estrutura-Atividade , Termodinâmica
10.
Dalton Trans ; 48(47): 17556-17565, 2019 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-31748772

RESUMO

Mixed-ligand platinum(ii) complexes, [Pt(phen)(pacac)](NO3) (1), [Pt(phen)(cur)](NO3) (2), [Pt(bt-phen)(cur)](NO3) (3) and [Pt(phen)(scur)](NO3) (4), where phen is 1,10-phenanthroline, bt-phen is 5-biotin-1,10-phenanthroline, pacac is 1,3-diphenyl-1,3-propanedioate anion, Hcur is curcumin and Hscur is diglucosylcurcumin, were prepared, characterized and their anticancer activity studied. Complexes 2-4 showed absorption bands within 410-430 nm (ε, 2.1 × 104 to 2.8 × 104 M-1 cm-1) in 10% DMSO-DPBS (Dulbecco's phosphate-buffered saline) and emission bands near 530 nm (λex = 410-430 nm) with a fluorescence quantum yield (ΦF) value of ∼0.02. The curcumin complexes showed stability over a study period of 48 h. The photocytotoxicity was studied using human cervical HeLa, human liver HepG2, human breast cancer MDA-MB 231 and human lung adenocarcinoma A549 cancer cells along with human immortalized lung epithelial HPL1D as normal cells. Complexes 2-4 showed apoptotic photo-induced cell death in light of wavelength 400-700 nm (IC50, half maximal inhibitory concentration: 6-28 µM) by reactive oxygen species (ROS), while remaining inactive in the dark (IC50: 43-95 µM). The selectivity of the complexes 3 and 4 was enhanced significantly towards the cancer cells than towards the normal cells, thus making them targeted photochemotherapeutic agents. The ROS formation and mode of cell death were studied from 2',7'-dichlorofluorescein diacetate (DCFDA) and annexin-V/FITC (fluorescein isothiocyanate)-PI assays, respectively. Preferential nuclear and mitochondrial localization was evidenced from inductively coupled plasma mass spectrometry (ICP-MS) studies.


Assuntos
Antineoplásicos/farmacologia , Curcumina/química , Sistemas de Liberação de Medicamentos , Glucose/química , Compostos Organoplatínicos/farmacologia , Fenantrolinas/química , Fármacos Fotossensibilizantes/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Biotinilação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cristalografia por Raios X , Teoria da Densidade Funcional , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Modelos Moleculares , Estrutura Molecular , Compostos Organoplatínicos/síntese química , Compostos Organoplatínicos/química , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/química , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-Atividade
11.
Inorg Chem ; 58(23): 16279-16291, 2019 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-31738050

RESUMO

Many clinical trials using combinations of platinum drugs and PARP-1 inhibitors (PARPi) have been carried out, with the hope that such combinations will lead to enhanced therapeutic outcomes against tumors. Herein, we obtained seven potential PARPi with structural diversity and then conjugated them with cisplatin-based platinum(IV) complexes. Both the synthesized PARPi ligands and PARPi-Pt conjugates [PARPi-Pt(IV)] show inhibitory effects against PARP-1's catalytic activity. The PARPi-Pt(IV) conjugates are cytotoxic in a panel of human cancer cell lines, and the leading ones display the ability to overcome cisplatin resistance. A mechanistic investigation reveals that the representative PARPi-Pt(IV) conjugates efficiently enter cells, bind to genomic DNA, disturb cell cycle distribution, and induce apoptotic cell death in both cisplatin-sensitive and -resistant cells. Our study provides a strategy to improve the cytotoxicity of platinum(IV)-based anticancer complexes and overcome cisplatin resistance by using a small-molecule anticancer complex that simultaneously damages DNA and inhibits PARP.


Assuntos
Antineoplásicos/farmacologia , Compostos Organoplatínicos/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Poli(ADP-Ribose) Polimerases/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cisplatino/farmacologia , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Compostos Organoplatínicos/síntese química , Compostos Organoplatínicos/química , Inibidores de Poli(ADP-Ribose) Polimerases/síntese química , Inibidores de Poli(ADP-Ribose) Polimerases/química , Relação Estrutura-Atividade
12.
Dalton Trans ; 48(46): 17228-17240, 2019 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-31728483

RESUMO

Lipophilic platinum(iv) complexes were synthesised of the type [Pt(HL)(AL)(OH)(R)]2+ and [Pt(HL)(AL)(R)2]2+ (HL = 5,6-dimethyl-1,10-phenanthroline or 1,10-phenanthroline; AL = 1S,2S-diaminocyclohexane and R = increasingly lipophilic carboxylate axial ligands (C10-18)) from hydrophilic platinum(ii) precursors that exhibit exceptional anticancer activity. The increased overall lipophilicity of the complexes suggested the formation of spontaneously self-assembled structures in an aqueous environment. The anti-proliferative properties were assessed against one non-cancerous and a panel of cancerous cell lines. Nanomolar levels of activity were observed against several cell lines, with the lowest GI50 of 3.4 nm against the Du145 prostate cancer cell line and over 1100-fold greater activity than cisplatin against HT29 colon carcinoma. RP-HPLC was utilised to establish the relative lipophilicities of each complex. While there seemed to be an increase in cellular accumulation for the lipophilic derivatives in some instances, ICP-MS studies showed no clear correlation between increasing lipophilicity, cellular accumulation and cytotoxicity.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Compostos Organoplatínicos/síntese química , Compostos Organoplatínicos/farmacologia , Pró-Fármacos/metabolismo , Antineoplásicos/química , Antineoplásicos/metabolismo , Técnicas de Química Sintética , Células HT29 , Humanos , Interações Hidrofóbicas e Hidrofílicas , Modelos Moleculares , Conformação Molecular , Compostos Organoplatínicos/química , Compostos Organoplatínicos/metabolismo , Fenantrolinas/química
13.
Dalton Trans ; 48(46): 17217-17227, 2019 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-31729519

RESUMO

Novel platinum(iv) complexes were synthesised to examine the facile modulation of the lipophilicity of the complex by incorporating axial ligands of increasing length, ranging from 2-6 carbons. RP-HPLC was used to establish the lipophilicity of each complex. The in vitro cytotoxicities of all complexes were determined against a panel of malignant cell lines and a non-cancerous cell line. While there was no clear correlation between lipophilicity and cytotoxicity, all complexes demonstrated nanomolar activity against all cell lines. The most potent complexes exhibited 850-fold greater activity than cisplatin against HT29 colon carcinoma with GI50 values of 13 nM.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Interações Hidrofóbicas e Hidrofílicas , Compostos Organoplatínicos/síntese química , Compostos Organoplatínicos/farmacologia , Antineoplásicos/química , Linhagem Celular Tumoral , Técnicas de Química Sintética , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Modelos Moleculares , Conformação Molecular , Compostos Organoplatínicos/química , Relação Estrutura-Atividade
14.
Eur J Med Chem ; 184: 111751, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31593828

RESUMO

A series of novel organoplatinum(II) complexes, [PtII(QC1)(H-QC1)Cl] (Pt1), [PtII(QC2)(H-QC2)Cl] (Pt2), [PtII(QC3)(H-QC3)Cl] (Pt3), [PtII(QC4)(H-QC4)Cl]⋅CH3OH (Pt4), [PtII(QC5)(H-QC5)Cl] (Pt5), [PtII(H-QC6)(DMSO)Cl2] (Pt6), [PtII(H-QC7)(DMSO)Cl2]⋅H2O (Pt7), [PtII(H-QC8)(DMSO)Cl2] (Pt8), [PtII(H-QC9)(DMSO)Cl2]⋅CH3OH (Pt9), [PtII(H-QC10)(DMSO)Cl2] (Pt10) and [PtII(H-QC11)(DMSO)Cl2] (Pt11), bearing quinoline-coumarin derivatives (H-QC1-H-QC11) have been first designed. Complexes Pt1-Pt11 selectively displayed obvious cytotoxicities in comparison to cisplatin for A549/DDP (cisplatin-resistant human lung adenocarcinoma) cells and HeLa cervical carcinoma cells, with IC50 values as low as 100 nM-10.33 µM. In addition, Pt4 and Pt5 display a green-colored luminescent properties, targeted mitochondrial membrane and, thereby induced mainly mitochondria-mediated cell apoptosis was in the following order: Pt4 > Pt5. The different anti-cancer activity of quinoline-coumarin complexes Pt4 (100 nM) and Pt5 (250 nM) were correlate with the presence of 3-(2'-quinolyl)-6-hydroxy-coumarin (H-QC4) ligand. The quinoline-coumarin complex Pt4 (2.0 mg/kg per 2 days) also displayed potent in vivo anti-tumor effect after 21 days-treated. In contrast, the H-QC4 ligand highly enhances the anti-tumor activity and selectivity of organoplatinum(II) complexes in comparison to other previously reported coumarin derivatives metal complexes.


Assuntos
Antineoplásicos/farmacologia , Cumarínicos/farmacologia , Compostos Organoplatínicos/farmacologia , Quinolinas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Cumarínicos/química , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Ligantes , Modelos Moleculares , Estrutura Molecular , Imagem Óptica , Compostos Organoplatínicos/síntese química , Compostos Organoplatínicos/química , Quinolinas/química , Relação Estrutura-Atividade
15.
Nat Commun ; 10(1): 4599, 2019 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-31601813

RESUMO

Host-guest interactions are of central importance in many biological and chemical processes. However, the investigation of the formation and decomplexation of host-guest systems at the single-molecule level has been a challenging task. Here we show that the single-molecule conductance of organoplatinum(II) metallocycle hosts can be enhanced by an order of magnitude by the incorporation of a C60 guest molecule. Mechanically stretching the metallocycle-C60 junction with a scanning tunneling microscopy break junction technique causes the release of the C60 guest from the metallocycle, and consequently the conductance switches back to the free-host level. Metallocycle hosts with different shapes and cavity sizes show different degrees of flexibility to accommodate the C60 guest in response to mechanical stretching. DFT calculations provide further insights into the electronic structures and charge transport properties of the molecular junctions based on metallocycles and the metallocycle-C60 complexes.


Assuntos
Fulerenos/química , Compostos Organoplatínicos/química , Teoria da Densidade Funcional , Eletrodos , Ouro , Espectroscopia de Ressonância Magnética , Microscopia de Força Atômica , Microscopia de Tunelamento , Espectrofotometria Ultravioleta
16.
Chem Commun (Camb) ; 55(87): 13066-13069, 2019 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-31570904

RESUMO

A platinum(ii) complex containing an aminophosphonate ligand preferentially accumulates in the endoplamic reticulum (ER) in association with potent ER stress and reactive oxygen species generation, followed by the activation of damage-associated molecular pattern signals and immune responses. Importantly, the Pt complex exhibits potent anti-tumour activities in two independent mouse models via an immunogenic cell death pathway.


Assuntos
Antineoplásicos Imunológicos/farmacologia , Ésteres/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Organofosfonatos/farmacologia , Compostos Organoplatínicos/farmacologia , Animais , Antineoplásicos Imunológicos/química , Morte Celular/efeitos dos fármacos , Ésteres/química , Humanos , Ligantes , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/imunologia , Neoplasias Experimentais/patologia , Organofosfonatos/química , Compostos Organoplatínicos/química
17.
Dalton Trans ; 48(40): 15247-15254, 2019 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-31577283

RESUMO

Two novel Pt(ii) complexes, [Pt(B-TFA)Cl]Cl (Pt1) and [Pt(J-TFA)Cl]Cl (Pt2) with jatrorrhizine and berberine derivatives (B-TFA and J-TFA) were first prepared as desirable luminescent agents for cellular applications and potent telomerase inhibitors, which can induce bladder T-24 tumor cell apoptosis by targeting telomerase, together with induction of mitochondrial dysfunction, telomere DNA damage and cell-cycle arrest. Importantly, T-24 tumor inhibition rate (TIR) was 50.4% for Pt2, which was higher than that of Pt1 (26.4%) and cisplatin (37.1%). Taken together, all the results indicated that jatrorrhizine and berberine derivatives Pt1 and Pt2 show low toxicity and could be novel Pt-based anti-cancer drug candidates.


Assuntos
Antineoplásicos/farmacologia , Berberina/análogos & derivados , Berberina/farmacologia , Compostos Organoplatínicos/farmacologia , Telomerase/antagonistas & inibidores , Neoplasias da Bexiga Urinária/tratamento farmacológico , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Berberina/química , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Dano ao DNA , Humanos , Mitocôndrias/efeitos dos fármacos , Compostos Organoplatínicos/química , Telomerase/metabolismo
18.
Inorg Chem ; 58(19): 13150-13160, 2019 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-31539237

RESUMO

Mitochondrial DNA (mtDNA) is an attractive cellular target for anticancer agents in addition to nuclear DNA (nDNA). The cationic platinum(II) complex cis-[Pt(NP)(NH3)2Cl]NO3 (PtNP, NP = N-(2-ethylpyridine)-1,8-naphthalimide) bearing the DNA-intercalating moiety NP was designed. The structure of PtNP was fully characterized by single-crystal X-ray crystallography, NMR, and HRMS. PtNP is superior to cisplatin in both in vitro and in vivo anticancer activities with low systemic toxicity. The interaction of PtNP with CT-DNA demonstrated that PtNP could effectively bind to DNA through both covalent and noncovalent double binding modes. In addition to causing significant damage to nDNA and remarkable inhibition to DNA damage repair, PtNP also distributed in mitochondria, inducing mtDNA damage and affecting the downstream transcriptional level of mitochondrion-encoded genes. In addition, PtNP disturbed the physiological processes of mitochondria by reducing the mitochondrial membrane potential and promoting the generation of reactive oxygen species. Mechanistic studies demonstrate that PtNP induced apoptosis via mitochondrial pathways by upregulating Bax and Puma and downregulating Bcl-2 proteins, leading to the release of cytochrome c and activation of caspase-3 and caspase-9. As a dual-DNA-damage agent, PtNP is able to improve the anticancer activity by damaging both nuclear and mitochondrial DNA, thus providing a new anticancer mechanism of action for the naphthalimide monofunctional platinum(II) complexes.


Assuntos
Antineoplásicos/farmacologia , Dano ao DNA/efeitos dos fármacos , Substâncias Intercalantes/farmacologia , Compostos Organoplatínicos/farmacologia , Animais , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Cristalografia por Raios X , Humanos , Substâncias Intercalantes/química , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos Endogâmicos ICR , Modelos Moleculares , Naftalimidas/química , Naftalimidas/farmacologia , Neoplasias/tratamento farmacológico , Neoplasias/genética , Compostos Organoplatínicos/química , Piridinas/química , Piridinas/farmacologia
19.
Eur J Med Chem ; 183: 111727, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31563806

RESUMO

Two highly active anticancer Pt(II) complexes, [Pt(Jat1)Cl]Cl (Pt1) and [Pt(Jat2)Cl]Cl (Pt2), containing jatrorrhizine derivative ligands (Jat1 and Jat2) are described. Cell intake study showed high accumulation in cell nuclear fraction. Pt1 and Pt2 exhibited high selectivity for HeLa cancer cells (IC50 = 15.01 ±â€¯1.05 nM and 1.00 ±â€¯0.17 nM) comparing with HL-7702 normal cells (IC50 > 150 µM), by targeting p53 and telomerase. Pt2 containing Jat2 ligand was more potent and showed high selectivity for telomerase. It also caused mitochondria and DNA damage, sub-G1 phase arrest, and a high rate of cell apoptosis at the low dose of 1.00 nM. The HeLa tumor inhibition rate (TIR) of Pt2 was 48.8%, which was even higher than cisplatin (35.2%). In addition, Pt2 displayed green luminescent property and potent telomerase inhibition. Our findings demonstrated the promising development of platinum(II) complexes containing jatrorrhizine derivatives as novel Pt-based anti-cancer agents.


Assuntos
Antineoplásicos , Berberina/análogos & derivados , Compostos Organoplatínicos , Platina/química , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Berberina/química , Sobrevivência Celular/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/química , Células HeLa , Humanos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Mitocôndrias/efeitos dos fármacos , Imagem Óptica , Compostos Organoplatínicos/síntese química , Compostos Organoplatínicos/química , Compostos Organoplatínicos/farmacologia , Telomerase/antagonistas & inibidores
20.
ACS Appl Mater Interfaces ; 11(35): 31585-31593, 2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31436404

RESUMO

A label-free detection assay is developed based on the design and synthesis of a new anionic alkynylplatinum(II) 2,6-bis(benzimidazol-2'-yl)pyridine complex with water-soluble pendants. With the aid of electrostatic interaction and noncovalent metal-metal and π-π stacking interactions, protamine is shown to induce supramolecular self-assembly of platinum(II) complexes with drastic UV-vis absorption and red emission changes. On the basis of the strong binding affinity of protamine and heparin, the ensemble has been further employed to probe heparin by monitoring the spectroscopic changes. Other than heparin, this ensemble can also detect the activity of trypsin, which can hydrolyze protamine into fragments, leading to the deaggregation of platinum(II) complexes. By modulation of the self-assembly properties of platinum(II) complexes via real-time UV-vis absorption and emission studies, the reported assay has been demonstrated to be a sensitive and selective detection method for trypsin, as well as trypsin inhibitor screening, which is essential for drug discovery.


Assuntos
Corantes Fluorescentes/química , Heparina/análise , Compostos Organoplatínicos/química , Protaminas/química , Tripsina/análise , Espectrometria de Fluorescência
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA