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1.
Inorg Chem ; 58(9): 6507-6516, 2019 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-31013065

RESUMO

Cancer is characterized by abnormal cellular energy metabolism, which preferentially switches to aerobic glycolysis rather than oxidative phosphorylation as a means of glucose metabolism. Many key enzymes involved in the abnormal glycolysis are potential targets of anticancer drugs. Platinum(IV) complexes are potential anticancer prodrugs and kinetically more inert than the platinum(II) counterparts, which offer an opportunity to be modified by functional ligands for activation or targeted delivery. A novel platinum(IV) complex, c, c, t-[Pt(NH3)2Cl2(C10H15N2O3S)(C2HO2Cl2)] (DPB), was designed to explore the effects of axial ligands on the reactivity and bioactivity of the complex as well as on tumor energy metabolism. The complex was characterized by electrospray ionization mass spectrometry and multinuclear (1H, 13C, and 195Pt) NMR spectroscopy. The introduction of dichloroacetate (DCA) markedly increases the lipophilicity, reactivity, and cytotoxicity of the complex and blocks the growth of cancer cells having active glycolysis, and the introduction of biotin (C10H16N2O3S) enhances the tumor-targeting potential of the complex. The cytotoxicity of DPB is increased dramatically in a variety of cancer cell lines as compared with the platinum(IV) complex PB without the DCA group. DPB alters the mitochondrial membrane potential and disrupts the mitochondrial morphology. The levels of mitochondrial and cellular reactive oxygen species are also decreased. Furthermore, the mitochondrial function of tumor cells was impaired by DPB, leading to the inhibition of both glycolysis and glucose oxidation and finally to the death of cancer cells via a mitochondria-mediated apoptotic pathway. These findings demonstrate that DPB suppresses cancer cells mainly through altering metabolic pathways and highlight the importance of dual-targeting for the efficacy of anticancer drugs.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Metabolismo Energético/efeitos dos fármacos , Compostos Organoplatínicos/química , Compostos Organoplatínicos/farmacologia , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Células HCT116 , Células HeLa , Células Hep G2 , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo
2.
Inorg Chem ; 58(9): 6485-6494, 2019 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-31021622

RESUMO

Transplatin is an inactive platinum drug; however, a number of analogues, such as trans-EE and trans-PtTz, demonstrate promising antitumor activity in vitro and in vivo. Although the ultimate target is nuclear DNA, increasing evidence indicate that proteins also play important roles in the display of antitumor activity. The linker histone H1 is situated by the portal between the unwrapped DNA and the nucleosome core. Our recent study revealed that H1 can readily react with cisplatin, and the adducts tend to form ternary complexes with DNA. In this work, we have investigated the reaction of histone H1 with two antitumor-active trans-oriented complexes, trans-EE and trans-PtTz, and the effect of H1 upon the platination of DNA. The results show that trans-platinum drugs are much more reactive than cisplatin toward H1. Interestingly, in addition to the expected bidentate adducts (by displacement of the two labile chlorido ligands), also a tridentate adduct can be formed by displacement of one nonlabile carrier ligand of trans-EE or trans-PtTz. The trans-Pt/H1 adducts can then react with DNA and generate protein-Pt-DNA ternary complexes. Additionally, platinum can be transferred from trans-Pt/H1 adducts to DNA, generating binary trans-Pt/DNA complexes. Such a transfer of the platinum agent to DNA was not observed in the reaction of cisplatin. Furthermore, the detailed investigation carried out on a model peptide indicates that H1 promotes the DNA platination by trans- EE, while it reduces that of trans-PtTz and cisplatin. These results suggest that H1 can play a key role in the DNA platination and modulate the efficacy of different platinum agents.


Assuntos
Antineoplásicos/farmacologia , Cisplatino/farmacologia , DNA/metabolismo , Histonas/metabolismo , Compostos Organoplatínicos/farmacologia , Tiazóis/farmacologia , Antineoplásicos/química , Cisplatino/química , Adutos de DNA/metabolismo , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Compostos Organoplatínicos/química , Tiazóis/química
4.
Proc Natl Acad Sci U S A ; 116(14): 6618-6623, 2019 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-30894484

RESUMO

Although platinum-based anticancer drugs prevail in cancer treatment, their clinical applications are limited by the severe side effects as well as their ineffectiveness against drug resistant cancers. A precise combination of photodynamic therapy (PDT) and chemotherapy can synergistically improve the therapeutic outcome and thereby may overcome drug resistance through a multipronged assault. Herein, we employ the well-defined cavity of a discrete organoplatinum(II) metallacage (M) to encapsulate octaethylporphine (OEP), a photosensitizer, forming a dual-functionalized system M⊃OEP that is wrapped into the hydrophobic core of the nanoparticles (MNPs) self-assembled from an amphiphilic diblock copolymer. Using a copper-free click reaction, a targeting ligand is conjugated on the surface of the MNPs, aiming to specifically deliver a chemotherapeutic drug and a photosensitizer to cancer cells. Benefiting from the enhanced permeability and retention effect and active targeting capability, high tumor accumulation of MNPs is achieved, leading to an improved therapeutic outcome and reduced side effects. In vivo studies demonstrate that the combination of chemotherapy and PDT exhibits a superior antitumor performance against a drug-resistant tumor model attributed to their synergistic anticancer efficacy.


Assuntos
Antineoplásicos , Nanopartículas , Neoplasias Experimentais , Compostos Organoplatínicos , Fotoquimioterapia , Fármacos Fotossensibilizantes , Porfirinas , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Química Click , Humanos , Camundongos , Camundongos Nus , Nanopartículas/química , Nanopartículas/uso terapêutico , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Compostos Organoplatínicos/síntese química , Compostos Organoplatínicos/química , Compostos Organoplatínicos/farmacocinética , Compostos Organoplatínicos/farmacologia , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacocinética , Fármacos Fotossensibilizantes/farmacologia , Porfirinas/química , Porfirinas/farmacocinética , Porfirinas/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Biomolecules ; 9(3)2019 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-30845773

RESUMO

We have demonstrated the cytotoxic effects of [Pt(O,O'-acac)(γ-acac)(dimethyl sulfide (DMS))] on various immortalized cell lines, in primary cultures, and in murine xenograft models in vivo. Recently, we also showed that [Pt(O,O'-acac)(γ-acac)(DMS)] is able to kill Caki-1 renal cells both in vivo and in vitro. In the present paper, apoptotic and autophagic effects of [Pt(O,O'-acac)(γ-acac)(DMS)] and cisplatin were studied and compared using Caki-1 cancerous renal cells. The effects of cisplatin include activation of caspases, proteolysis of enzyme poly ADP ribose polymerase (PARP), control of apoptosis modulators B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (Bax), and BH3-interacting domain death agonist (Bid), and cell cycle arrest in G2/M phase. Conversely, [Pt(O,O'-acac)(γ-acac)(DMS)] did not induce caspase activation, nor chromatin condensation or DNA fragmentation. The effects of [Pt(O,O'-acac)(γ-acac)(DMS)] include microtubule-associated proteins 1A/1B light chain 3B (LC3)-I to LC3-II conversion, Beclin-1 and Atg-3, -4, and -5 increase, Bcl-2 decrease, and monodansylcadaverine accumulation in autophagic vacuoles. [Pt(O,O'-acac)(γ-acac)(DMS)] also modulated various kinases involved in intracellular transduction regulating cell fate. [Pt(O,O'-acac)(γ-acac)(DMS)] inhibited the phosphorylation of mammalian target of rapmycin (mTOR), p70S6K, and AKT, and increased the phosphorylation of c-Jun N-terminal kinase (JNK1/2), a kinase activity pattern consistent with autophagy induction. In conclusion, while in past reports the high cytotoxicity of [Pt(O,O'-acac)(γ-acac)(DMS)] was always attributed to its ability to trigger an apoptotic process, in this paper we show that Caki-1 cells die as a result of the induction of a strong autophagic process.


Assuntos
Antineoplásicos/farmacologia , Autofagia/efeitos dos fármacos , Carcinoma de Células Renais/tratamento farmacológico , Compostos Organoplatínicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Carcinoma de Células Renais/patologia , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Compostos Organoplatínicos/síntese química , Compostos Organoplatínicos/química , Relação Estrutura-Atividade , Células Tumorais Cultivadas
6.
Inorg Chem ; 58(6): 3851-3860, 2019 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-30843385

RESUMO

The reduction mechanism of Pt(IV) anticancer prodrugs, still today a matter of debate, assisted by one of the dominant reductants in human plasma, that is l-ascorbic acid in its monodeprotonated form, has been computationally examined in this work. In order to check what should be the influence on the reduction rate of the identity of the ligands in axial and equatorial position, both cisplatin and oxaliplatin derivatives have been studied, varying the ligands in axial position in connection with the role they should play as bridges, trans leaving species, and proton acceptors. OH, OAc, Cl, and Br ligands have been tested as bridging/leaving ligands, whereas Cl and aspirin have been used as trans labile and less labile ligands, respectively. The most recent theoretical and experimental investigations have demonstrated that the generally adopted grouping of reduction mechanisms into inner- and outer-sphere does not properly take into account all the viable alternatives. Therefore, inner-sphere mechanisms, classified as ligand-bridged, ligand-bridged-H transfer and enolate ß-carbon attack, have been explored for all the complexes under investigation. Concerning the outer-sphere mechanism, redox potentials have been calculated adopting a recently proposed procedure based on the separation between electrochemical and chemical events to evaluate their propensity to be reduced. Moreover, according to the hypothesis that the outer-sphere reduction mechanism involves the sequential addition of two electrons causing the formation of a Pt(III) intermediate, the possibility that singlet and triplet pathways can cross for the Pt(IV) cisplatin derivative having two chlorido ligands in axial position has been explored in detail. Results show that the mechanism indicated as base-assisted outer sphere can become competitive with respect to the inner one if two singlet-triplet spin inversions occur. Results presented here are helpful in addressing synthetic strategies as they show that Pt(IV) prodrugs propensity to be reduced can be properly tuned and give indications on how this aim can be accomplished.


Assuntos
Antineoplásicos/metabolismo , Ácido Ascórbico/metabolismo , Compostos Organoplatínicos/metabolismo , Pró-Fármacos/metabolismo , Substâncias Redutoras/metabolismo , Antineoplásicos/química , Cisplatino/química , Cisplatino/metabolismo , Transporte de Elétrons , Humanos , Modelos Moleculares , Compostos Organoplatínicos/química , Oxirredução , Pró-Fármacos/química , Termodinâmica
7.
Eur J Med Chem ; 169: 29-41, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30852385

RESUMO

Increasing evidences suggested that cisplatin can be involved in a tumor-specific immune response as an immunomodulator to improve antitumor immunity, but the designation and development are limited. Here, we report a series of novel Pt(IV) complexes derived from the conjugation of platinum(II) anticancer agents with an immune checkpoint TDO inhibitor. These complexes not only showed significant cytotoxic effects on the tested cancer cell lines, but also could enhance antitumor immune response. Particularly, complex T2, the mono-conjuagte of oxoplatin and (E)-4-oxo-4-(3-(2-(pyridin-3-yl)vinyl)-1H-indol-1-yl)butanoic acid, displayed 35-fold more potency than cisplatin against TDO-overexpressed HepG-2 cancer cells. Further study indicated that T2 could inhibit TDO via releasing a derivative of a TDO inhibitor and block kynurenine production, resulting in T-cell activation and proliferation in vitro. In vivo tests proved that T2 as a potent immunomodulator could highly promote the antitumor activity of cisplatin and effectively suppress the expression of TDO. This immunochemotherapeutic strategy can be promisingly applied to treat with TDO-overexpressed cancers.


Assuntos
Antineoplásicos Imunológicos/farmacologia , Inibidores Enzimáticos/farmacologia , Fatores Imunológicos/farmacologia , Compostos Organoplatínicos/farmacologia , Triptofano Oxigenase/antagonistas & inibidores , Animais , Antineoplásicos Imunológicos/síntese química , Antineoplásicos Imunológicos/química , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Fatores Imunológicos/química , Neoplasias Hepáticas Experimentais/tratamento farmacológico , Neoplasias Hepáticas Experimentais/metabolismo , Neoplasias Hepáticas Experimentais/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Estrutura Molecular , Compostos Organoplatínicos/síntese química , Compostos Organoplatínicos/química , Relação Estrutura-Atividade , Triptofano Oxigenase/metabolismo
8.
Eur J Med Chem ; 170: 195-202, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30897397

RESUMO

Herein, we report the design and synthesis of three novel binuclear platinum(II) complexes, [Pt(tpbtpy)Cl][Pt(DMSO)Cl3] (tpbtpy-Pt), [Pt(dthbtpy)Cl][Pt(DMSO)Cl3]⋅CH3OH (dthbtpy-Pt), and [Pt(qlbtpy)Cl][Pt(DMSO)Cl3]⋅CH3OH (qlbtpy-Pt) with 4'-(3-thiophenecarboxaldehyde)-2,2':6',2″-terpyridine (tpbtpy), 4'-(3,5-bis (1,1-dimethylethyl)-2-hydroxy-benzaldehyde)-2,2':6',2″-terpyridine (dthbtpy) and 4'-(2-quinolinecarboxaldehyde)-2,2':6',2″-terpyridine (qlbtpy) as ligands, respectively. All three novel binuclear platinum(II) complexes tpbtpy-Pt, dthbtpy-Pt, and qlbtpy-Pt were characterized by single-crystal X-ray diffraction analysis, spectroscopic analysis (ESI-MS, IR, 1H NMR), and elemental analysis. Additionally, the cytotoxicity of tpbtpy-Pt, dthbtpy-Pt and qlbtpy-Pt was assessed with human non-small cell lung cancer cell line (NCIH460 cells), yielding IC50 values in the range of 0.35-12.09 µM with tpbtpy-Pt as the most potent and qlbtpy-Pt as the least potent complexes. Mechanistic studies indicated that tpbtpy-Pt and dthbtpy-Pt induced apoptosis through mitochondrial dysfunction and telomerase inhibition. In a NCIH460 xenograft model, when administered at 10.0 mg kg-1 every 2 days, tpbtpy-Pt was shown to significantly reduce tumor growth (tumor growth inhibition rate (IR) = 70.1%, p < 0.05). Therefore, tpbtpy-Pt is a promising Pt(II) complex for further translational studies and clinical evaluation as an antitumor agent.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Compostos Organoplatínicos/química , Compostos Organoplatínicos/farmacologia , Piridinas/química , Piridinas/farmacologia , Animais , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Desenho de Drogas , Humanos , Camundongos Nus , Modelos Moleculares , Neoplasias/tratamento farmacológico , Compostos Organoplatínicos/uso terapêutico , Piridinas/uso terapêutico
9.
Int J Mol Sci ; 20(3)2019 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-30736413

RESUMO

The development of UV⁻vis spectrophotometric methods based on metalloporphyrins for fast, highly sensitive and selective anion detection, which avoids several of the practical challenges associated with other detection methods, is of tremendous importance in analytical chemistry. In this study, we focused on achieving a selective optical sensor for triiodide ion detection in traces based on a novel hybrid material comprised of Pt(II) 5,10,15,20-tetra(4-methoxy-phenyl)-porphyrin (PtTMeOPP) and gold nanoparticles (AuNPs). This sensor has high relevance in medical physiological tests. The structure of PtTMeOPP was investigated by single crystal X-ray diffraction in order to understand the metal surroundings and the molecule conformation and to assess if it qualifies as a potential sensitive material. It was proven that the Pt-porphyrin generated 1D H-bond supramolecular chains due to the weak C-H···O intermolecular hydrogen bonding. The presence of ordered voids in the crystal encouraged us to use PtTMeOPP as the sensing material for triiodide ion and to enhance its potential in a novel AuNPs/PtTMeOPP hybrid by the synergistic effects provided by the plasmonic gold nanoparticles. The spectrophotometric sensor is characterized by a detection limit of 1.5 × 10-9 M triiodide ion concentration and a remarkable confidence coefficient of 99.98%.


Assuntos
Ânions/análise , Ouro , Iodetos/análise , Nanopartículas Metálicas , Metaloporfirinas/química , Modelos Moleculares , Compostos Organoplatínicos/química , Ouro/química , Nanopartículas Metálicas/química , Nanopartículas Metálicas/ultraestrutura , Microscopia de Força Atômica , Conformação Molecular , Termogravimetria
11.
Inorg Chem ; 58(3): 2191-2200, 2019 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-30657321

RESUMO

Quinone oxidoreductase isozyme I (NQO1) is a cytoprotective two-electron-specific reductase that highly expresses in various cancer cells. Taking NQO1 as the target, we herein report three hybrid compounds from Pt(IV) complexes and a quinone propionic acid unit. The mechanism studies showed that the hybrids could be activated by both NQO1 and ascorbic acid to release the cytotoxic Pt(II) unit, exhibiting a dual stimuli-responsive character. In the pharmacological studies, complexes 2 and 3 presented higher antitumor activity than cisplatin. More importantly, the hybrid could also overcome cisplatin resistance due to the NQO1 targeting ability, improved cellular uptake, and/or different action mechanism. Significantly, complex 3 containing a coumarin moiety could be effectively activated in NQO1-overexpressed cancer cells to "turn on" fluorescence, showing a promising visual effect in cancer cells. In vivo study revealed that both 2 and 3 exhibited higher antitumor efficacy than cisplatin in the A549 xenograft mouse model at an equimolar dose to cisplatin. In all, the hybrids may serve as promising NQO1-targeting anticancer agents.


Assuntos
Antineoplásicos/farmacologia , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , NAD(P)H Desidrogenase (Quinona)/antagonistas & inibidores , Compostos Organoplatínicos/farmacologia , Platina/farmacologia , Células A549 , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Cisplatino/química , Ensaios de Seleção de Medicamentos Antitumorais , Células Hep G2 , Humanos , Camundongos , NAD(P)H Desidrogenase (Quinona)/metabolismo , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Compostos Organoplatínicos/síntese química , Compostos Organoplatínicos/química , Platina/química
12.
Eur J Med Chem ; 164: 546-561, 2019 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-30622026

RESUMO

The current study unveils ONS-donor ligand based Pt(II) complexes with unusual anticancer potency showing higher anticancer effect as compared to cisplatin. This series of Pt(II)(R-salicylaldimine)Cl (C1a-C4a) (R = 5-H, 5-CH3, F, 3-CH3O) complexes were prepared in single step in good isolated yields from commercially available materials. The chloride ancillary ligand of "a" series (C1a-C4a) was replaced with 4-picoline and "b" series of four complexes Pt(II)(R-salicylaldimine)(4-picoline)BF4 (C1b-C4b) (R = 5-H, 5-CH3, F, 3-CH3O) was obtained. All these complexes were characterized by different structure elucidation techniques. Among these, the structures of C1a, C2a, C2b and C3b were determined in solid state by single crystal X-ray analysis. We found quick aquation of "a" series of complexes in DMSO/water mixture that was well investigated by 1H NMNR, LCMS and ESI-MS, while "b" series of these complexes was quite stable over a month as described by the 1H NMNR in DMSO/D2O mixture. This ONS-donor ligand based class of Pt(II) complexes showed unusual anticancer potency in non-small cell lung cancer A549, colorectal cancer HT-29 and triple negative breast cancer MDA-MB-231 cells. These Pt(II) complexes induced PARP cleavage and significantly inhibited colony formation ability of cancer cells. Mechanistically, we found reduced aggressive growth of cancer cells by the induction of autophagic cell death via LC3-I/LC3-II expression and recruitment of LC3B to autophagosomal membrane. These complexes induced p21 expression, that suggested their potentials to suppress cell cycle progression. Significant activation of Caspase3/7-dependent apoptotic signaling was observed in cancer cells treated with these Pt(II) complexes. Morphological changes of cancer cells suggested their potentials to modulate epithelial-mesenchymal-transition (EMT) like features of cancer cells. Gel electrophoresis study revealed their interaction with plasmid DNA. Similarly, strong growth retardation effect and filamentous morphology was observed in Escherichia coli (E. coli). These ONS-donor Pt(II) complexes possessed strong anticancer effect in multiple human cancer cells via activation of multiple pathways for apoptotic and autophagic cell death.


Assuntos
Antineoplásicos/química , Autofagia/efeitos dos fármacos , Compostos Organoplatínicos/uso terapêutico , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Linhagem Celular Tumoral , Neoplasias Colorretais/tratamento farmacológico , Cristalografia por Raios X , Humanos , Ligantes , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Compostos Organoplatínicos/síntese química , Compostos Organoplatínicos/química , Relação Estrutura-Atividade , Neoplasias de Mama Triplo Negativas/tratamento farmacológico
13.
Inorg Chem ; 58(2): 1657-1673, 2019 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-30601653

RESUMO

Two series of neutral luminescent pentafluorophenyl cycloplatinated(II) complexes [Pt(C^N)(C6F5)L] [C^N = C-deprotonated 2-phenylpyridine (ppy; a), 2-(2,4-difluorophenylpyridine (dfppy; b)] incorporating dimethyl sulfoxide [L = DMSO for 1 (1a reported by us in ref (14) )] or biocompatible phosphine [L = PPh2C6H4COOH (dpbH; 2), PPh2C6H4CONHCH2COOMe (dpbGlyOMe; 3), P(C6H4SO3Na)3 (TPPTS; 4)] ligands have been prepared and characterized and their optical properties studied. Their cytotoxic activities against tumor A549 (lung carcinoma), HeLa (cervix carcinoma), and nontumor NL-20 (lung epithelium) cell lines, as well as the ability to interact with DNA (plasmid pBR322), were evaluated. Complexes 2 exhibit higher cytotoxicity (IC50 3.89-20.29 µM) than compounds 1 (9.03-20.50 µM), whereas the activities of complexes 3 and 4 are negligible. All cytotoxic complexes show low selective toxicities toward cancer cells. Interestingly, except 1a, these complexes do not show evidence of DNA intercalation. Along the same lines, fluorescence costaining with Hoechst (2,5'-bi-1 H-benzimidazole, 2'-(4-ethoxyphenyl)-5-(4-methyl-1-piperazinyl), a nuclear DNA stain) reveals that all complexes easily internalize, being mainly localized in the cytoplasm. In order to deepen the mechanism of biological action, the effect of the most cytotoxic complex 2b toward the dynamics of tubulin was explored. This complex displays tubulin depolymerization activity, exhibiting more potent inhibition of microtubule formation in A549 than in HeLa cells, in accordance with its higher antiproliferative activity (IC50 6.98 vs 12.45 µM), placing this complex as a potential antitubulin agent.


Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Luminescência , Compostos Organoplatínicos/farmacologia , Fosfinas/farmacologia , Células A549 , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Células HeLa , Humanos , Ligantes , Modelos Moleculares , Estrutura Molecular , Imagem Óptica , Compostos Organoplatínicos/síntese química , Compostos Organoplatínicos/química , Fosfinas/química , Relação Estrutura-Atividade
14.
ACS Appl Mater Interfaces ; 11(5): 4799-4808, 2019 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-30694047

RESUMO

A new approach toward acetylcholinesterase (AChE) detection has been demonstrated based on the electrostatic interactions between anionic alkynylplatinum(II) complex molecules and cationic coordination polymer, together with the spectroscopic and emission characteristics of alkynylplatinum(II) complexes upon supramolecular self-assembly. This process involves strengthening of distinct noncovalent Pt(II)···Pt(II) and π-π stacking interactions, which is evidenced by UV-vis absorption, emission, and resonance light scattering results. Such a method has been applied to AChE inhibitor screening, which is important as the demand for AChE inhibitor assays arises along with the drug development for Alzheimer's disease. It affords an emission turn-on response and operates in a continuous and label-free fashion. The low-energy red emission and large Stokes shift of alkynylplatinum(II) complexes are advantageous to biological applications.


Assuntos
Acetilcolinesterase , Descoberta de Drogas/métodos , Medições Luminescentes/métodos , Compostos Organoplatínicos/química , Acetilcolinesterase/análise , Acetilcolinesterase/metabolismo , Animais , Técnicas Biossensoriais/métodos , Inibidores da Colinesterase/análise , Inibidores da Colinesterase/metabolismo , Humanos , Polímeros/química
15.
Molecules ; 24(3)2019 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-30696004

RESUMO

Highly efficient, operationally stable, and pure-color organic light-emitting diodes (OLEDs) are of considerable significance for developing practical wide-color-gamut displays. Further, we have demonstrated the feasibility of an efficient pure green phosphorescent OLED (PHOLED) by employing a narrow-band platinum complex and a top-emitting structure. The utilization of the thermally activated delayed fluorescence (TADF) material as the phosphorescent host is expected to serve as a promising solution for obtaining operationally stable PHOLEDs with high color purity. However, the emission spectrum of the platinum complex in the TADF host exhibits a considerably broad emission spectrum. This study investigates the cause of the spectral change by evaluating the photoluminescence spectra of the platinum complex in various hosts exhibiting different molecular structures. The triazine unit in the host material was observed to result in exciplex formation between the lowest unoccupied molecular orbital (LUMO) of the host and the highest occupied molecular orbital (HOMO) of the platinum complex. Therefore, the TADF material that sterically hinders the triazine unit is considered to be suitable to prevent both exciplex formation and spectral broadening.


Assuntos
Medições Luminescentes , Compostos Organoplatínicos/química , Platina/química , Análise Espectral , Carbazóis/química , Medições Luminescentes/métodos , Modelos Moleculares , Conformação Molecular , Estrutura Molecular , Compostos Organoplatínicos/análise , Platina/análise , Análise Espectral/métodos
16.
Dalton Trans ; 48(2): 435-445, 2019 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-30539948

RESUMO

Three pairs of asymmetric dicarboxylato derivatives based on the cisplatin and oxaliplatin-like skeletons have been synthesized de novo or re-synthesized. The axial ligands consist of one medium-chain fatty acid (MCFA), namely clofibrate (i.e. 2-(p-chlorophenoxy)-2-methylpropionic acid, CA), heptanoate (HA) or octanoate (OA), respectively, and an inactive acetato ligand that imparts acceptable water solubility to such conjugates. Stability tests provided evidence for the partial formation of two hydrolyzed products, corresponding to two monoaqua diastereomers derived from the substitution of an equatorial chlorido ligand with a water molecule. The complexes have been tested on three different colon cancer cell lines having different histological history, and also on the cisplatin-sensitive A2780 ovarian cancer cell line for comparison. This allowed the evaluation not only of the increase in activity on passing from Pt(ii) to Pt(iv) derivatives, but also the selectivity towards colon cancer cells brought about by the cyclohexane-1R,2R-diamine carrier ligand.


Assuntos
Antineoplásicos/síntese química , Proliferação de Células/efeitos dos fármacos , Compostos Organoplatínicos/síntese química , Pró-Fármacos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Neoplasias do Colo/patologia , Estabilidade de Medicamentos , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Compostos Organoplatínicos/química , Compostos Organoplatínicos/farmacologia , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Solubilidade
17.
Chemistry ; 25(12): 2995-2999, 2019 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-30565774

RESUMO

Compounds condensing DNA and RNA molecules can essentially affect important biological processes including DNA replication and transcription. Here, this work shows with the aid of total intensity light scattering, gel electrophoresis, and atomic force microscopy (AFM) that the substitution-inert polynuclear platinum complexes (SI-PPCs), particularly [{trans-Pt(NH3 )2 (NH2 (CH2 )6 - NH3 + )}2 -µ-{trans-Pt(NH3 )2 (NH2 (CH2 )6 NH2 )2 }]8+ (Triplatin NC), exhibit an unprecedented high potency to condense/aggregate fragments of DNA and RNA as short as 20 base pairs. SI-PPCs condensates are distinctive from those generated by the naturally occurring polyamines (commonly used DNA compacting/condensing agents). Collectively, the results further confirm that SI-PPCs are very efficient inducers of condensation of DNA and RNA, including their short fragments that might have potential in gene therapy, biotechnology, and bionanotechnology. Moreover, the data confirm the structural advantages of the phosphate clamp, with a well-defined rigid DNA recognition motif in initiating condensation and aggregation phenomena on oligonucleotides.


Assuntos
DNA de Cadeia Simples/química , DNA/química , Oligonucleotídeos/química , Compostos Organoplatínicos/química , RNA/química , Sequência de Bases , Catálise , Dimerização , Microscopia de Força Atômica , Platina/química
18.
Dalton Trans ; 48(3): 936-944, 2019 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-30565617

RESUMO

After more than 50 years of platinum-based anticancer research only three compounds are in clinical use worldwide. The use of the well-known lead compound of this class of anticancer agents, cisplatin, is limited by its side effects and varying resistance mechanisms. Therefore, we report on platinum(ii) compounds with asparagusic acid derivatives as ligands which show interesting anticancer results on cisplatin resistant cell lines.


Assuntos
Antineoplásicos/farmacologia , Compostos Organoplatínicos/farmacologia , Tiofenos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cisplatino/química , Cisplatino/farmacologia , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Ligantes , Estrutura Molecular , Compostos Organoplatínicos/síntese química , Compostos Organoplatínicos/química , Relação Estrutura-Atividade , Tiofenos/química
19.
J Colloid Interface Sci ; 535: 505-515, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30340170

RESUMO

HYPOTHESIS: The presence of pendant thioether groups on poly(ethylene glycol)-poly(N(2-hydroxypropyl) methacrylamide) (PEG-P(HPMA)) block copolymers allows for platinum-mediated coordinative micellar core-crosslinking, resulting in enhanced micellar stability and stimulus-responsive drug delivery. EXPERIMENTS: A new PEG-P(HPMA) based block copolymer with pendant 4-(methylthio)benzoyl (MTB) groups along the P(HPMA) block was synthesized by free radical polymerization of a novel HPMA-MTB monomer using a PEG based macro-initiator. As crosslinker the metal-organic linker [ethylenediamineplatinum(II)]2+ was used, herein called Lx, which is a coordinative linker molecule that has been used for the conjugation of drug molecules to a number of synthetic or natural carrier systems such as hyperbranched polymers and antibodies. FINDINGS: The introduction of Lx in the micellar core results in a smaller size, a lower critical micelle concentration and a better retention of the hydrophobic drug curcumin thanks to coordination bonds between the central platinum atom of Lx and thioether groups on different polymer chains. The drug release from Lx crosslinked micelles is significantly accelerated under conditions mimicking the intracellular environment due to competitive coordination and subsequent micellar de-crosslinking. Because of their straightforward preparation and favorable drug release characteristics, core-crosslinked Lx PEG-P(HPMA) micelles hold promise as a versatile nanomedicine platform.


Assuntos
Reagentes para Ligações Cruzadas/química , Sistemas de Liberação de Medicamentos , Metacrilatos/química , Compostos Organoplatínicos/química , Polietilenoglicóis/química , Reagentes para Ligações Cruzadas/síntese química , Ligantes , Micelas , Estrutura Molecular , Tamanho da Partícula , Propriedades de Superfície
20.
Eur J Med Chem ; 161: 334-342, 2019 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-30384040

RESUMO

Two platinum(II) complexes, [Pt(ClQ)(DMSO)Cl] (ClQ-Pt) and [Pt(BrQ)(DMSO)Cl] (BrQ-Pt), with 5,7-dichloro-2-methyl-8-quinolinol (H-ClQ) and 5,7-dibromo-2-methyl-8-quinolinol (H-BrQ) as ligands, respectively, have been synthesized and characterized. The single-crystal X-ray diffraction characterization as well as other spectroscopic and analytical studies of ClQ-Pt and BrQ-Pt revealed that the coordination geometry of Pt(II) can be described as a four-coordinated square planar geometry. By MTT assay, ClQ-Pt displayed the most potent activity, with IC50 values of 5.02-34.38 µM against MGC80-3, T-24, Hep-G2 and BEL-7402 tumor cells. Among them, the T-24 cells the highest sensitivity to ClQ-Pt and BrQ-Pt with IC50 value of 5.02 ±â€¯0.62 µM and 18.02 ±â€¯1.05 µM, respectively. In addition, ClQ-Pt caused a higher percentage of apoptotic T-24 cells (ca. 33.75%) than that of BrQ-Pt (ca. 23.85%) and cisplatin (ca. 12.82%). Mechanistic studies revealed that ClQ-Pt and BrQ-Pt caused T-24 cell cycle arrest at the S phase, as shown by the down-regulation of cyclin A and CDK2 expression levels. In addition, ClQ-Pt and BrQ-Pt also caused mitochondrial dysfunction. Interestingly, the in vitro anticancer activity of ClQ-Pt was higher than those of BrQ-Pt and cisplatin, more selective for T-24 tumor cells than for normal HL-7702 cells. Taken together, we concluded that the 5- and 7-substitution groups of the ClQ ligands play an important role in determining the anti-proliferation activity of the corresponding Pt(II) complexes.


Assuntos
Antineoplásicos/farmacologia , Hidroxiquinolinas/farmacologia , Compostos Organoplatínicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Hidroxiquinolinas/química , Ligantes , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Modelos Moleculares , Estrutura Molecular , Compostos Organoplatínicos/síntese química , Compostos Organoplatínicos/química , Relação Estrutura-Atividade
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