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1.
Chem Commun (Camb) ; 55(90): 13542-13545, 2019 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-31647067
2.
Chem Commun (Camb) ; 55(90): 13518-13521, 2019 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-31608902

RESUMO

A distyryl boron dipyrromethene based photosensitiser substituted with 1,2,4,5-tetrazine and alkyne moieties was prepared. Through site-specific bioorthogonal reactions with the complementary functional tags anchored on the membrane of A431 human epidermoid carcinoma cells, this versatile photosensitiser exhibited enhanced cellular uptake and photocytotoxicity. The bioorthogonal ligation was also demonstrated in tumour-bearing nude mice.


Assuntos
Antineoplásicos/farmacologia , Compostos de Boro/farmacologia , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacologia , Porfobilinogênio/análogos & derivados , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Compostos de Boro/síntese química , Compostos de Boro/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Camundongos Nus , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Imagem Óptica , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/química , Porfobilinogênio/síntese química , Porfobilinogênio/química , Porfobilinogênio/farmacologia , Espécies Reativas de Oxigênio/análise , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-Atividade
3.
Chem Commun (Camb) ; 55(73): 10972-10975, 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31453611

RESUMO

Platinum-resistant cancer cells are sensitive to changes in the levels of reactive oxidative species (ROS). Herein, we design a biotin-modified Ru(ii) complex as a photosensitizer (denoted as Ru-Biotin). Ru-Biotin can selectively target cancer cells and produce vast amounts of singlet oxygen under two-photon excitation at 820 nm leading to cell apoptosis. Ru-Biotin is therefore an excellent candidate to overcome platinum resistance via two-photon photodynamic therapy.


Assuntos
Antineoplásicos/farmacologia , Biotina/análogos & derivados , Biotina/farmacologia , Complexos de Coordenação/farmacologia , Fármacos Fotossensibilizantes/farmacologia , Rutênio/química , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/efeitos da radiação , Apoptose/efeitos dos fármacos , Biotina/síntese química , Biotina/efeitos da radiação , Caspase 3/metabolismo , Caspase 7/metabolismo , Linhagem Celular Tumoral , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Complexos de Coordenação/efeitos da radiação , Humanos , Raios Infravermelhos , Fotoquimioterapia/métodos , Fótons , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/efeitos da radiação , Oxigênio Singlete/metabolismo
5.
Anticancer Res ; 39(8): 4199-4206, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366506

RESUMO

BACKGROUND/AIM: We previously synthesized a glucose-conjugated chlorin compound e6 (G-chlorin e6), and reported that it has very strong antitumor effects. The aim of the present study was to synthesize acetylated glucose-conjugated chlorin (AcN003HP) and evaluate its antitumor effect and excretion. MATERIALS AND METHODS: To evaluate the antitumor effect of AcN003HP, its IC50 was calculated as well as its accumulation in cancer cells was examined by flow cytometry. Confocal microscopy was used to observe the intracellular localization of AcN003HP. The excretion and antitumor effects of AcN003HP were also evaluated in vivo. RESULTS: AcN003HP showed stronger antitumor effects and accumulation into cancer cells compared to talaporfin sodium, a conventional photosensitizer. AcN003HP was localized in the endoplasmic reticulum. In a xenograft tumor mouse model, AcN003HP showed longer excretion time from the body than G-chlorin e6, and photodynamic therapy using AcN003HP showed very strong antitumor effects. CONCLUSION: The safety, improved controllability, and robust antitumor effects suggest AcN003HP as a good next-generation photosensitizer.


Assuntos
Neoplasias Gastrointestinais/terapia , Glucose/administração & dosagem , Fotoquimioterapia , Fármacos Fotossensibilizantes/administração & dosagem , Acetilação/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Retículo Endoplasmático/efeitos dos fármacos , Citometria de Fluxo , Neoplasias Gastrointestinais/patologia , Glucose/síntese química , Glucose/química , Humanos , Camundongos , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/química , Porfirinas/administração & dosagem , Porfirinas/síntese química , Porfirinas/química , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Inorg Chem ; 58(16): 10778-10790, 2019 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-31386351

RESUMO

A new family of cyclometalated ruthenium(II) complexes [Ru(N^N)2(C^N)]+ derived from the π-extended benzo[h]imidazo[4,5-f]quinolone ligand appended with thienyl groups (n = 1-4, compounds 1-4) was prepared and its members were characterized for their chemical, photophysical, and photobiological properties. The lipophilicities of 1-4, determined as octanol-water partition coefficients (log Po/w), were positive and increased with the number of thienyl units. The absorption and emission bands of the C^N compounds were red-shifted by up to 200 nm relative to the analogous Ru(II) diimine systems. All of the complexes exhibited dual emission with the intraligand fluorescence (1IL, C^N-based) shifting to lower energies with increasing n and the metal-to-ligand charge transfer phosphorescence (3MLCT, N^N-based) remaining unchanged. Compounds 1-3 exhibited excited state absorption (ESA) profiles consistent with lowest-lying 3MLCT states when probed by nanosecond transient absorption (TA) spectroscopy with 532 nm excitation and had contributions from 1IL(C^N) states with 355 nm excitation. These assignments were supported by the lifetimes observed (<10 ns for the 1IL states and around 20 ns for the 3MLCT states) as well as a noticeable ESA for 3 with 355 nm excitation that did not occur with 532 nm excitation. Compound 4 was the only member of the family with two 3MLCT emissive lifetimes (15, 110 ns), and the TA spectra collected with both 355 and 532 nm excitation was assigned to the 3IL state, which was corroborated by its 4-6 µs lifetime. The ESA for 4 had a rise time of approximately 10 ns and an initial decay of 110 ns, which suggests a possible 3MLCT-3IL excited state equilibrium that results in delayed emission from the 3MLCT state. Compound 4 was nontoxic toward human skin melanoma cells (SKMEL28) in the dark (EC50 = >300 µM); 1-3 were cytotoxic and yielded EC50 values between 1 and 20 µM. The photocytotoxicites with visible light ranged from 87 nM with a phototherapeutic index (PI) of 13 for 1 to approximately 1 µM (PI = >267) for 4. With red light, EC50 values varied from 270 nM (PI = 21) for 3 to 12 µM for 4 (PI = >25). The larger PIs for 4, especially with visible light, were attributed to the much lower dark cytotoxicity for this compound. Because the dark cytotoxicity contributes substantially to the observed photocytotoxicity for 1-3, it was not possible to assess whether the 3IL state of 4 led to a much more potent phototoxic mechanism in the absence of dark toxicity. There was no stark contrast in cellular uptake and accumulation by laser scanning confocal and differential interference contrast microscopy to explain the large differences in dark toxicities between 1-3 and 4. Nevertheless, the study highlights a new family of Ru(II) C^N complexes where π-conjugation beyond a certain point results in low dark cytotoxicity with high photocytotoxicity, opposing the notion that cyclometalated Ru(II) systems are too toxic to be phototherapeutic agents.


Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Fármacos Fotossensibilizantes/farmacologia , Quinolonas/farmacologia , Rutênio/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Ligantes , Luz , Estrutura Molecular , Processos Fotoquímicos , Fotoquimioterapia , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/química , Quinolonas/química , Rutênio/química
7.
J Photochem Photobiol B ; 197: 111548, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31288120

RESUMO

The visible light combined with photosensitizers (PSs) is exploited in both antitumoral and antimicrobial fields inducing a photo-oxidative stress within the target cells. Among the different PSs, porphyrins belong to the family of the most promising compounds to be used in clinical photodynamic applications. Although in the last years many porphyrins have been synthesised and tested, only a few reports concern the in vitro effects of the 5,15-diarylporphyrins. In this work, the activity of four 5,15-diarylporphyrins (compounds 7-10), bearing alkoxy-linked pyridinium appendixes, have been tested on cancer cell lines and against bacterial cultures. Among the synthetized PSs, compounds 7 and 9 are not symmetrically substituted porphyrins showing one cationic charge tethered at the end of one 4C or 8C carbon chains, respectively. On the other hand, compounds 8 and 10 are symmetrically substituted and show two chains of C4 and C8 carbons featuring a cationic charge at the end of both chains. The dicationic 8 and 10 were more hydrophilic than monocationic 7 and 9, outlining that the presence of two pyridinium salts have a higher impact on the solubility in the aqueous phase than the lipophilic effect exerted by the length of the alkyl chains. Furthermore, these four PSs showed a similar rate of photobleaching, irrespective of the length and number of chains and the number of positive charges. Among the eukaryotic cell lines, the SKOV3 cells were particularly sensitive to the photodynamic activity of all the tested diarylporphyrins, while the HCT116 cells were found more sensitive to PSs bearing C4 chain (7 and 8), regardless the number of cationic charges. The photo-induced killing effect of these porphyrins was also tested against two different bacterial cultures. As expected, the Gram positive Bacillus subtilis was more sensitive than the Gram negative Escherichia coli, and the dicationic porphyrin 8, bearing two C4 chains, was the most efficient on both microorganisms. In conclusion, the new compound 8 seems to be an optimal candidate to deepen as versatile anticancer and antibacterial photosensitizer.


Assuntos
Antibacterianos/química , Antineoplásicos/química , Fármacos Fotossensibilizantes/química , Porfirinas/química , Antibacterianos/síntese química , Antibacterianos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Cátions/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/efeitos da radiação , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Humanos , Luz , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/farmacologia , Porfirinas/síntese química , Porfirinas/farmacologia , Espécies Reativas de Oxigênio/metabolismo
8.
Photochem Photobiol Sci ; 18(8): 2003-2011, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31268087

RESUMO

Here we report the activatable photosensitizer BromoAcroB, a brominated BODIPY dye incorporating a reactive acrolein warhead. The acrolein moiety serves as an intramolecular switch, deactivating the BODIPY dye in its singlet and triplet excited states via internal conversion. Thiolate addition to this moiety disables the intramolecular quenching mechanism restoring the photosensitizing properties of the parent dye, characterized by a quantum yield of singlet oxygen photosensitization of 0.69 ± 0.02. In cell cultures, and upon thiol adduct formation, BromoAcroB induced light-dependent cell death in MRC-5 and HeLa cell lines. Using fluorescence microscopy and upon measuring the low yet non-negligible emission of the activated compound, we show that the phototoxicity of the dormant photosensitizer correlated with the quantity of BromoAcroB adducts generated. BromoAcroB thus serves as a dormant photosensitizer sensitive to intracellular electrophile response. Our results highlight the effective control of a triplet state process by modulation of an unsaturated moiety on the BODIPY scaffold and underscore the mechanistic opportunities arising for controlled singlet oxygen production in cells specifically sensitive to electrophile stress.


Assuntos
Acroleína/farmacologia , Compostos de Boro/farmacologia , Corantes/farmacologia , Cisteína/farmacologia , Fármacos Fotossensibilizantes/farmacologia , Oxigênio Singlete/farmacologia , Acroleína/química , Compostos de Boro/química , Morte Celular/efeitos dos fármacos , Corantes/síntese química , Corantes/química , Cisteína/química , Células HeLa , Humanos , Luz , Microscopia de Fluorescência , Estrutura Molecular , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/química , Teoria Quântica , Oxigênio Singlete/química
9.
Photochem Photobiol Sci ; 18(8): 2012-2022, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31282525

RESUMO

Organic-metal complexes are promising molecules for use in photodynamic therapy (PDT). The aim of this study was to investigate in vitro effects of novel Ru(ii) and Ir(iii) BODIPY complexes for PDT. These hybrid organic-metal molecules (Ru-BD and Ir-BD) have been synthesized via reactions of a BODIPY precursor (BD) with a phenanthroline unit bearing Ru(ii) (3) and novel Ir(iii) (4) compounds. The crystal structures of the new distyryl BODIPY (BD) and Ru(ii) complex (3) are also reported. The photophysical and singlet oxygen generation properties of Ru-BD and Ir-BD were investigated in comparison with unsubstituted BODIPY (BD). Moreover, Ru-BD and Ir-BD have been biologically evaluated in vitro in chronic myeloid leukemia and cervical cancer cell lines in terms of photodynamic therapy efficacy in the presence of BD control. These complexes were not toxic in the dark but red light was needed to induce cell death. These data support the fact that Ru-BD could be accepted as a valuable photosensitizer-drug for further PDT treatment.


Assuntos
Antineoplásicos/farmacologia , Compostos de Boro/farmacologia , Corantes/farmacologia , Compostos Organometálicos/farmacologia , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Compostos de Boro/síntese química , Compostos de Boro/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Corantes/síntese química , Corantes/química , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Irídio/química , Irídio/farmacologia , Modelos Moleculares , Estrutura Molecular , Compostos Organometálicos/síntese química , Compostos Organometálicos/química , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/química , Rutênio/química , Rutênio/farmacologia , Oxigênio Singlete/análise , Oxigênio Singlete/metabolismo , Células Tumorais Cultivadas
10.
Talanta ; 202: 591-599, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31171226

RESUMO

Photodynamic therapy (PDT) was considered as an effective treatment. Whereas only PDT is not enough to achieve effective therapy on account of irradiation intensity decreases as depth increases as well as tumor hypoxia. Combination with gene therapy and photodynamic therapy have emerged as an effective strategy to improve therapeutic effectiveness. In the present study, a GSH responsive MnO2 was employed to delivery TB and DNAzyme for cancer imaging and PDT-gene combination treatment. TB, a photosensiters with aggregation-induced emission characteristic, was employed for photodynamic therapy, while DNAzyme, acting as catalysts for the degradation of EGR-1 mRNA, was exploited for gene silencing. All of the results of tumor treatment in vitro have implied that MnO2-DNAzyme-TB nanocomposite (MDT) can internalize into cells. Subsequently, MDT could decrease the expression of EGR-1 by gene silencing that enabling inhibition of cell growth. In addition, the singlet oxygen which was generated by the aggregated TB were able to further suppress cell growth. Combination therapy of photodynamic as well as gene therapy greatly enhanced antitumor efficiencies. Furthermore, in vivo tumor treatment experiments demonstrated that MDT under illumination can effectively inhibit the tumor growth of MCF-7 tumor-bearing mice by photodynamic and gene silencing combination therapy.


Assuntos
Antineoplásicos/farmacologia , DNA Catalítico/metabolismo , Terapia Genética , Compostos de Manganês/farmacologia , Óxidos/farmacologia , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , DNA Catalítico/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Proteína 1 de Resposta de Crescimento Precoce/antagonistas & inibidores , Proteína 1 de Resposta de Crescimento Precoce/genética , Feminino , Humanos , Células MCF-7 , Neoplasias Mamárias Experimentais/diagnóstico por imagem , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/metabolismo , Compostos de Manganês/síntese química , Compostos de Manganês/química , Camundongos , Camundongos Nus , Nanocompostos , Imagem Óptica , Óxidos/síntese química , Óxidos/química , Tamanho da Partícula , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/química , RNA Mensageiro/antagonistas & inibidores , RNA Mensageiro/genética , Relação Estrutura-Atividade , Propriedades de Superfície
11.
Appl Spectrosc ; 73(8): 936-944, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31149836

RESUMO

Hypericin (Hyp) is a natural compound with interesting photophysical and pharmacological properties, which has been used in photodynamic therapy and photodynamic inactivation of microorganisms. Its synthesis is based on a series of chemical processes that ends with a light-drug interaction by the photoconversion of protohypericin (pHyp) to Hyp. Although this photosensitizer is used in a variety of medical applications, the photophysical and photochemical mechanisms involved in the final step related to the photo production of Hyp are not completely understood at the molecular level. Protohypericin concentration, solvents, light irradiation under different wavelengths, and a sort of variables could play an important role in predicting the yielding of this photoconversion process. Here, we used the high-sensitive and remote measurement characteristics of the time-resolved thermal lens technique to investigate the relation between the light-induced photoconversion rate of pHyp to Hyp and the initial concentration pHyp. The results show a linear dependence of the photoreaction rate with the concentration of pHyp, indicating that the overall reaction process includes steps comprising the formation of distinct intermediate species. We demonstrate the applicability of the thermal lens technique for the photochemical characterization of photosensitive drugs at low concentration levels.


Assuntos
Perileno/análogos & derivados , Fármacos Fotossensibilizantes/síntese química , Lentes , Perileno/síntese química , Perileno/química , Fotoquimioterapia
12.
Eur J Med Chem ; 179: 26-37, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31233920

RESUMO

PDT is a well-established therapeutic modality for many types of cancer. Photoluminescent cyclometalated iridium(III) complexes are one of the most commonly used classes of organometallic compounds with potential beneficial applications in bioimaging and as promising anticancer agents. In the present study, three new cyclometalated iridium(III) complexes (Ir1-Ir3) containing guanidinium ligands were found to exert excellent cytotoxic effects on different types of cancer cells upon light irradiation at 425 nm. Notably, Ir1 conferred almost no dark toxicity (IC50 > 100 µM) to HepG2 cells, but the value decreased by 387-fold to 0.36 µM following 10 min of light irradiation (425 nm). Further mechanistic investigation revealed that complex Ir1 could induce apoptosis via the activation of reactive oxygen species (ROS)-mediated mitochondrial signaling pathways in the presence or absence of light irradiation. In vivo studies demonstrated that Ir1 significantly inhibited tumor growth in HepG2 xenograft-bearing mice under light irradiation at 425 nm. Taken together, these findings indicate that designing PDT-based Ir(III) complexes may hold a great deal of promise for anticancer drug development.


Assuntos
Antineoplásicos/farmacologia , Guanidina/farmacologia , Irídio/farmacologia , Mitocôndrias/efeitos dos fármacos , Imagem Óptica , Compostos Organometálicos/farmacologia , Fármacos Fotossensibilizantes/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Guanidina/química , Células Hep G2 , Humanos , Irídio/química , Neoplasias Hepáticas Experimentais/diagnóstico por imagem , Neoplasias Hepáticas Experimentais/tratamento farmacológico , Neoplasias Hepáticas Experimentais/patologia , Camundongos , Mitocôndrias/patologia , Estrutura Molecular , Compostos Organometálicos/síntese química , Compostos Organometálicos/química , Fotoquimioterapia , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/química , Relação Estrutura-Atividade
13.
Chem Commun (Camb) ; 55(49): 7037-7040, 2019 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-31143887

RESUMO

A π-extended red absorbing Se-rhodamine (Se-NR) was synthesised and characterized. By masking the amine of Se-NR as an azide, we successfully constructed a bio-orthogonally activatable photosensitizer (Se-NR-Az). Se-NR-Az was not photocytotoxic, but when activated by the Staudinger reaction, photocytotoxicity was restored.


Assuntos
Azidas/farmacologia , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacologia , Rodaminas/farmacologia , Selênio/farmacologia , Azidas/química , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Células HeLa , Humanos , Estrutura Molecular , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/química , Rodaminas/química , Selênio/química , Relação Estrutura-Atividade
14.
J Photochem Photobiol B ; 195: 39-50, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31075653

RESUMO

Photodynamic therapy (PDT) of cancer uses photosensitizers (PS), a light source and oxygen to generate high levels of reactive oxygen species (ROS), that exert a cytotoxic action on tumor cells. Recently, it has been shown that mixed non-symmetrical diaryl porphyrins, with two different pendants, are more photodynamically active than symmetrical diaryl porphyrins. In the present study, we investigate the in vitro photodynamic effects of four novel non-symmetrical diaryl porphyrins, two of which bear one pentafluoro-phenyl and one bromo-alkyl (apolar) pendant, whereas the two others bear one pentafluoro-phenyl and one cationic pyridine pendant. The four compounds were tested in a small panel of human cancer cell lines, and their photodynamic activities were compared with that of m-THPC (Foscan), currently the most successful PS approved for clinical use in cancer PDT. The results of the cytotoxicity studies indicate that the two molecules bearing the cationic pendant are more potent in vitro than those with the apolar pendant, and that they are as potent as Foscan. To gain further insights into the mechanism of PS-induced phototoxicity, induction of apoptotic, autophagic and necrotic cell death, and generation of reactive oxygen species (ROS) were evaluated in cancer cells following exposure to the PSs and irradiation. The effect of the PSs on the migratory activity of the cells was also assessed. The data obtained from this work support a greater potency of diaryl porphyrins with a positive charge in inducing cell death, as compared to those with the bromo-alkyl pendant; most importantly, some of these novel compounds exhibit features that might make them superior to the clinically approved PS Foscan.


Assuntos
Fármacos Fotossensibilizantes/síntese química , Porfirinas/química , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Autofagia/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/efeitos da radiação , Humanos , Luz , Neoplasias/tratamento farmacológico , Fotodegradação , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Porfirinas/farmacologia , Porfirinas/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo
15.
Eur J Med Chem ; 177: 144-152, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31132530

RESUMO

Effective photosensitizers are particularly important factor in clinical photodynamic therapy (PDT). However, there is a scarcity of photosensitizers for simultaneous cancer photo-diagnosis and targeted PDT. Herein, two novel dimethyl 2-(guanidinyl)ethylamino chlorin e6 photosensitizers were synthesized and their efficacy in PDT in A549 tumor was investigated. It was shown that compounds 3 and 4 have a long absorption wavelength in the near infrared region and strong fluorescence emission with slow photo-bleaching rate and markedly strong ability of 1O2 generation. They exhibited lower cytotoxicity and higher photo-cytotoxicity in vitro compared to the known anticancer drug m-THPC in MTT assay in A549 lung cancer cell lines. Compound 4 exhibit better inhibition effect than compound 3 and the IC50 value of compound 4 was 0.197 µM/L under 2 J/cm2 laser irradiation, while compound 3 showed better anti-tumor effects compared to compound 4 in vivo. Intracellular ROS generation was found to be responsible for apoptotic cell death in DCFDA assay. Subcellular localization confirmed the damage site of compounds 3 and 4 in PDT. These findings suggest that the two novel photosensitizers might serve as potential photosensitizers for improved therapeutic efficiency of PDT.


Assuntos
Antineoplásicos/farmacologia , Guanidinas/farmacologia , Fármacos Fotossensibilizantes/farmacologia , Porfirinas/farmacologia , Células A549 , Adenocarcinoma Bronquioloalveolar/patologia , Animais , Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Retículo Endoplasmático/metabolismo , Feminino , Guanidinas/síntese química , Humanos , Neoplasias Pulmonares/patologia , Lisossomos/metabolismo , Masculino , Camundongos Endogâmicos BALB C , Mitocôndrias/metabolismo , Necrose , Fármacos Fotossensibilizantes/síntese química , Porfirinas/síntese química , Oxigênio Singlete/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Int J Mol Sci ; 20(10)2019 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-31121942

RESUMO

The post-functionalization of 5,10,15-tris(1-methylpyridinium-4-yl)-20-(pentafluorophenyl)porphyrin tri-iodide, known as a highly efficient photosensitizer (PS) for antimicrobial photodynamic therapy (aPDT), in the presence of 3- or 4-mercaptobenzoic acid, afforded two new tricationic porphyrins with adequate carboxylic pending groups to be immobilized on chitosan or titanium oxide. The structural characterization of the newly obtained materials confirmed the success of the porphyrin immobilization on the solid supports. The photophysical properties and the antimicrobial photodynamic efficacy of the non-immobilized porphyrins and of the new conjugates were evaluated. The results showed that the position of the carboxyl group in the mercapto units or the absence of these substituents in the porphyrin core could modulate the action of the photosensitizer towards the bioluminescent Gram-negative Escherichia coli bacterium. The antimicrobial activity was also influenced by the interaction between the photosensitizer and the type of support (chitosan or titanium dioxide). The new cationic porphyrins and some of the materials were shown to be very stable in PBS and effective in the photoinactivation of E. coli bacterium. The physicochemical properties of TiO2 allowed the interaction of the PS with its surface, increasing the absorption profile of TiO2, which enables the use of visible light, inactivating the bacteria more efficiently than the corresponding PS immobilized on chitosan.


Assuntos
Antibacterianos/química , Quitosana/análogos & derivados , Fármacos Fotossensibilizantes/química , Porfirinas/química , Titânio/química , Antibacterianos/síntese química , Antibacterianos/farmacologia , Cátions/síntese química , Cátions/química , Cátions/farmacologia , Quitosana/síntese química , Quitosana/farmacologia , Escherichia coli/efeitos dos fármacos , Infecções por Escherichia coli/tratamento farmacológico , Humanos , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/farmacologia , Porfirinas/síntese química , Porfirinas/farmacologia , Titânio/farmacologia
17.
Eur J Med Chem ; 174: 56-65, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31029944

RESUMO

A zinc(II) phthalocyanine substituted with three 2,4-dinitrobenzenesulfonate (DNBS) groups and a cyclic arginine-glycine-aspartic acid (cRGDfK) moiety was prepared and characterized. With three strongly electron-withdrawing DNBS groups, this compound was fully quenched in terms of fluorescence emission and singlet oxygen generation in N,N-dimethylformamide and phosphate buffered saline due to the strong photoinduced electron transfer effect. In the presence of glutathione (GSH), which is the most abundant intracellular thiol particularly in tumor cells, the DNBS moieties were cleaved, thereby restoring these photoactivities and making the conjugate as a GSH-activated photosensitizer. Being a well-known integrin antagonist, the cyclic RGD peptide sequence could enhance the localization of the conjugate in integrin-upregulated tumor cells. As shown by confocal laser scanning microscopy and flow cytometry, the intracellular fluorescence intensity of the conjugate was significantly higher in the integrin-positive A549 and MDA-MB-231 cells than in the integrin-negative MCF-7 and HEK293 cells. The photocytotoxicity of the conjugate against MDA-MB-231 cells was also higher than that toward MCF-7 cells. The results suggest that this dual-functional photosensitizer is a promising candidate for targeted photodynamic therapy.


Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Glutationa/metabolismo , Indóis/farmacologia , Peptídeos Cíclicos/farmacologia , Fármacos Fotossensibilizantes/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Antineoplásicos/efeitos da radiação , Benzenossulfonatos/síntese química , Benzenossulfonatos/metabolismo , Benzenossulfonatos/farmacologia , Benzenossulfonatos/efeitos da radiação , Linhagem Celular Tumoral , Complexos de Coordenação/síntese química , Complexos de Coordenação/metabolismo , Complexos de Coordenação/efeitos da radiação , Fluorescência , Células HEK293 , Humanos , Indóis/síntese química , Indóis/metabolismo , Indóis/efeitos da radiação , Integrinas/metabolismo , Luz , Peptídeos Cíclicos/síntese química , Peptídeos Cíclicos/metabolismo , Peptídeos Cíclicos/efeitos da radiação , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/metabolismo , Fármacos Fotossensibilizantes/efeitos da radiação , Oxigênio Singlete/metabolismo , Zinco/química
18.
Eur J Med Chem ; 174: 66-75, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31029945

RESUMO

Two Zn(II) nitro porphyrin derivatives bearing combinations of meso-4-nitrophenyl and meso-4-methylpyridinium moieties and their free-base precursors were synthesized through one-pot microwave process, purified and characterized. The biological activity of these nitroporphyrins was assessed under both photodynamic and non-photodynamic conditions to correlate their structure-activity relationship (SAR). Unlike, the free-base precursors, Zn(II) complexes of these nitroporphyrins displayed nearly complete inhibition in the entry of lentiviruses such as HIV-1 and SIVmac under non-photodynamic conditions. In addition, the Zn(II) complexes also exhibited a higher in vitro photodynamic activity towards human lung cancer cell-line A549 than their free-base precursors. Our results strongly suggest that incorporation of Zn(II) has improved the antiviral and anticancer properties of the nitroporphyrins. To the best of our knowledge, this is the first report demonstrating the dual activity of nitroporphyrin-zinc complexes as antiviral and anti-cancer, which will aid in their development as therapeutics in clinics.


Assuntos
Antineoplásicos/farmacologia , Inibidores da Fusão de HIV/farmacologia , Metaloporfirinas/farmacologia , Fármacos Fotossensibilizantes/farmacologia , Zinco/química , Animais , Antineoplásicos/síntese química , Antineoplásicos/efeitos da radiação , Antineoplásicos/toxicidade , Células CHO , Linhagem Celular Tumoral , Cricetulus , Fluorescência , Células HEK293 , Inibidores da Fusão de HIV/síntese química , Inibidores da Fusão de HIV/efeitos da radiação , Inibidores da Fusão de HIV/toxicidade , HIV-1/efeitos dos fármacos , Humanos , Luz , Metaloporfirinas/síntese química , Metaloporfirinas/efeitos da radiação , Metaloporfirinas/toxicidade , Estrutura Molecular , Nitrobenzenos/síntese química , Nitrobenzenos/farmacologia , Nitrobenzenos/efeitos da radiação , Nitrobenzenos/toxicidade , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/efeitos da radiação , Fármacos Fotossensibilizantes/toxicidade
19.
Eur J Med Chem ; 174: 142-158, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31035237

RESUMO

Recent clinical reports have highlighted the increasing occurrence of drug resistance of known therapeutics. Particularly, antibiotic resistant microorganisms and multidrug resistance have posed a serious threat to health of the people. Since ages, metals and metal complexes have played key role in the development of contemporary chemotherapy. Many organic compounds used in medicine do not have a purely organic mode of action and require traces of metal ions directly or indirectly for activation or biotransformation. For decades, the metallopharmaceuticals have attracted researchers across the globe due to their amplified therapeutic/modulatory effect by altering the pharmacokinetic and pharmacodynamic properties of the complexes towards biological receptors. Medicinally privileged natural and (semi)-synthetic chalcones have already been reported to possess a wide variety of pharmacological effects by modulating diverse molecular targets. The presence of carbonyl, hydroxyl, phenolic oxygen and/or heteroatom(s) in heterocyclic ring system makes them excellent chelating ligand for metal coordination. Particularly, the metal complexes of bidentate chalcone/Schiff base analogs and ferrocenyl chalcones have shown great potential. In this review, the chelating/coordinating property of substituted chalcones, the therapeutic, catalytic, chemosensing and photosensitizing potential of various metal-chalcone complexes, their structural features and structure activity relationships (SARs) have been highlighted. Further, the understanding of coordination mode, their stoichiometric characteristics, and mode of action(s), this review may be helpful for medicinal and bioinorganic chemists to design and develop novel, more potent, safe, selective and cost-effective chalcone-based coordination compounds for diverse biomedical applications.


Assuntos
Chalconas/farmacologia , Complexos de Coordenação/farmacologia , Anti-Infecciosos/síntese química , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Antioxidantes/síntese química , Antioxidantes/química , Antioxidantes/farmacologia , Bactérias/efeitos dos fármacos , Linhagem Celular Tumoral , Chalconas/síntese química , Chalconas/química , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Fungos/efeitos dos fármacos , Humanos , Metais Pesados/química , Estrutura Molecular , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Relação Estrutura-Atividade
20.
Chem Pharm Bull (Tokyo) ; 67(7): 690-692, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31006721

RESUMO

Photodynamic therapy (PDT) is a modern cancer therapy. But it is still difficult to obtain ideal photosensitizers. We synthesized six new peri-xanthenoxanthene derivatives rapidly and efficiently using solid-phase carbon-bath microwave irradiation technology, and investigated their in vitro photodynamic antitumor activity with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Our results showed that all compounds exhibited extremely low dark cytotoxicity and good phototoxicity against four human cancer cell lines. In particular, compound 3c showed the best in vitro PDT activity against Hela cells and Bel-7402 cells with IC50 values of 91 and 74 nmol/L, respectively. Its value of 1-octanol/water partition coefficient (log Kow) was 0.5309, suggesting that it is a promising photosensitizer for PDT due to its low dark cytotoxicity, high phototoxicity, and potential water solubility.


Assuntos
Fármacos Fotossensibilizantes/síntese química , Xantenos/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Humanos , Concentração Inibidora 50 , Micro-Ondas , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , Xantenos/farmacologia , Xantenos/uso terapêutico
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