RESUMO
Photodynamic therapy (PDT) is a well-established treatment modality, typically conducted with single-wavelength irradiation, which may not always be optimal for varying tumor locations and sizes. To address this, photosensitizers with absorption wavelengths ranging from 550 to 760 nm are being explored. Herein, a series of 5,15-diaryltetrabenzoporphyrins (Ar2TBPs) were synthesized. All compounds displayed obvious absorption at 550-700 nm (especially at â¼668 nm), intense fluorescence, efficient generation of singlet oxygen and good photodynamic antitumor effects. Notably, compound I3 (5,15-bis[(4-carboxymethoxy)phenyl]tetrabenzoporphyrin) showed excellent cytotoxicity against Eca-109 cell line upon red light irradiation, with an IC50 value of 0.45 µM, and phototherapeutic index of 25.8. Flow cytometry revealed that I3 could induce distinct cell apoptosis. In vivo studies revealed that compound I3 selectively accumulated at tumor site and exhibited outstanding PDT effect with antitumor activity under single-time administration and light irradiation, and revealed more efficiency than the clinical photosensitizer Verteporfin. These findings underscore the considerable promise of I3 as a robust theranostic agent, offering capabilities in real-time fluorescence imaging and serving as a potent photosensitizer for personalized and precise photodynamic therapy of tumors.
RESUMO
Aim: A study of the enhancement of photodynamic activities of pyropheophorbide-a using PG-Ag-PPa nanoconjugates. Materials & methods: The nanoconjugates were formulated from silver nanoparticles and PPa via amide linkage, then characterized, and their photodynamic activities were examined. Results: The nanoconjugates displayed a higher rate of reactive oxygen species generation, commendable cellular uptake by Eca-109 cancer cells, higher photocytotoxicity toward the cancer cells and better bio-safety. They revealed strong antibacterial activity against Escherichia coli following internal reactive oxygen species generation and membrane disintegration. The in vivo anticancer studies confirmed higher cytotoxicity of the nanoconjugates toward cancer cells and better safety than PPa. Conclusion: Therefore, PG-Ag-PPa nanoconjugates could be considered potential nano photosensitizers for photodynamic therapy of tumors and bacterial infection with good bio-safety.
[Box: see text].
RESUMO
To discover effective photosensitizers for photodynamic therapy (PDT), a series of new meso-tetraphenyltetrabenzoporphyrin (m-Ph4TBP) derivatives were designed, prepared, and characterized. All m-Ph4TBPs own two characteristic absorption bands in the range of 450-500 and 600-700 nm and have the ability to generate singlet oxygen upon photoexcitation. Most of the m-Ph4TBPs demonstrated high photoactivity, among which compounds I4, I6, I12, and I13 induced apoptosis and also exhibited excellent photodynamic activities in vivo. Nonetheless, the liver organs of the I4 and I6-PDT groups showed clear calcifications, whereas the liver tissues of the other PDT groups showed no calcification. It was indicated that compared to phenolic m-Ph4TBPs, glycol m-Ph4TBPs exhibited superior biological safety in mice. According to comprehensive evaluations, m-Ph4TBP I12 displayed excellent photodynamic antitumor efficacy and biological safety and can be regarded as a promising antitumor drug candidate.
RESUMO
In quest for new photosensitizers (PSs) with remarkable antitumor photodynamic efficacy, a series of fifteen quaternary ammonium (QA) cations conjugated 5,15-diaryltetranaphtho[2,3]porphyrins (Ar2TNPs) was synthesized and evaluated in vitro and in vivo to understand how variations in the length of the alkoxy group and the kind of QA cations on meso-phenyl influence the photodynamic antitumor activity. All final compounds (I1-5, II1-5, and III1-5) exhibited robust absorption at 729 nm with significant bathochromic shift and high molar extinction coefficients (1.16 × 105-1.41 × 105 M-1 cm-1), as well as other absorptions at 445, 475, 651, and 714 nm for tumors and other diseases of diverse sizes and depths. Upon exposure to 474 nm light, they displayed intense fluorescence emission with fluorescence quantum yields ranging from 0.32 to 0.43. The ability to generate reactive oxygen species (ROS) was also quantified, attaining a maximum rate of up to 0.0961 s-1. The IC50 values of all the compounds regarding phototoxicity and dark toxicity were determined using KYSE-150 cells, and the phototoxicity indices were calculated. Among these compounds, III1 demonstrated the highest phototoxic index with minimal dark toxicity, and suppressed successfully the growth of esophageal carcinoma xenograft with favorable tolerance in vivo. Furthermore, the histological results showed III1-mediated PDT had a significant cytotoxic effect on the tumor. These outcomes underscore the potential of III1 as a highly effective antitumor photosensitizer drug in photodynamic therapy (PDT).
Assuntos
Compostos de Amônio , Fotoquimioterapia , Porfirinas , Humanos , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Fotoquimioterapia/métodos , Porfirinas/farmacologia , CátionsRESUMO
To discover new photosensitizers with long wavelength UV-visible absorption, high efficiency, and low side effects for photodynamic therapy, here, a series of novel thieno[3,2-b]thiophene-fused BODIPY derivatives were designed, synthesized and characterized. These compounds had a distinct absorption band at 640-680 nm, fluorescence emission at 650-760 nm, and good solubility with anti-aggregation effects. These new compounds possessed obvious singlet oxygen generation ability and photodynamic anti-Eca-109 cancer cells activities in vitro. Among them, compound II4 could be well uptaked by Eca-109 cells, and result in the apoptosis after laser irradiation, and have outstanding photodynamic efficiency both in vitro and in vivo. Therefore, II4 could be considered as a potential photosensitizer drug candidate for PDT and photo-imaging.
Assuntos
Compostos de Boro , Fotoquimioterapia , Fotoquimioterapia/métodos , Solubilidade , Tiofenos/farmacologia , Fármacos Fotossensibilizantes/farmacologiaRESUMO
The discovery of new photosensitizer drugs with long wavelength Uv-vis absorption, high efficiency and low side-effects is still a challenge in photodynamic therapy. Here a series of novel meso-substitutedphenyl thieno[3,2-b]thiophene-fused BODIPY derivatives were designed, synthesized and characterized. All these compounds have strong absorption at 640-680 nm and obvious fluorescence emission at 650-760 nm. They exhibited high singlet oxygen generation ability and significant photodynamic efficiency against Eca-109 cancer cells. Compounds II4, II6, II9, II10 and II13 could generate intracellular ROS and induce cell apoptosis after laser irradiation, which displayed superior photodynamic efficiency against Eca-109 cells than Temoporfin in vitro and in vivo. Among them, compound II4 specifically exhibited excellent anti-tumor efficacy, and could be selected as a new drug candidate for PDT.
Assuntos
Fotoquimioterapia , Fármacos Fotossensibilizantes , Fármacos Fotossensibilizantes/farmacologia , Tiofenos/farmacologia , Compostos de Boro/farmacologia , Oxigênio SingleteRESUMO
In the pursuit of new potent photosensitizers (PSs) for photodynamic therapy (PDT) with better efficacy, a series of 5,15-diaryltetranaphtho [2,3]porphyrins (Ar2TNPs) with two or four carboxyalkoxy groups were designed, synthesized, and evaluated. These new compounds exhibited strong, broad and red-shifted UV-vis absorptions at 729 nm and other strong absorptions at 446, 475, 650, 659, 714 nm for tumors and other diseases of varying sizes and depths. They possess high molar extinction coefficients (0.95 × 105-1.48 × 105 M-1 cm-1), good singlet oxygen quantum yields and photodynamic antitumor effects towards Eca-109 cells in vitro. It is suggested that the extension of porphyrin with naphthalene into Ar2TNP results into remarkable improvement of photophysical characteristics, while the introduction of carboxyalkoxy groups on meso-phenyl can significantly improve the solubility and photodynamic effects in vitro and in vivo. Notably, compound II3 can localize primarily in lysosomes of Eca-109 cells and induce substantial cell apoptosis after PDT. It can also selectively accumulate in tumor tissues and be traced real-timely through in vivo fluorescence imaging with distinctive inhibition of tumor growth. Therefore, compound II3 deserves to be considered as a promising PDT drug candidate for individualized tumor real-time tracing and treatment.
Assuntos
Neoplasias , Fotoquimioterapia , Porfirinas , Humanos , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Fotoquimioterapia/métodos , Porfirinas/farmacologia , ApoptoseRESUMO
Background: Photodynamic therapy (PDT) of cancer has been limited by the poor solubility of most photosensitizers, use of high drug dosages, and the pH difference between the tumor tissue microenvironment (slightly acidic) and the bloodstream. These affect cellular uptake, selectivity and singlet oxygen generation. Materials & methods: We formulated Photinia glabra-green synthesized zinc oxide-protoporphyrin IX (PG-ZnO-PP) nanoconjugates by conjugating the ZnO nanoparticles enriched with amino groups and PP. Results: PG-ZnO-PP nanoconjugates showed higher rate of reactive oxygen species generation, improved cellular uptake in the acidic pH and lower IC50 toward Eca-109 cells for PDT. Conclusion: PG-ZnO-PP nanoconjugates are a potential solution to reducing drug dosage of PP through improved drug uptake, for enhanced targetability and reduced skin photosensitivity with improved PDT efficacy.
The progress of treating cancer using light-sensitive drugs and laser light of known wavelength has been limited by the poor solubility of most light-sensitive drugs, the use of high drug dosages and the slightly acidic environment within the cancerous tissues compared with normal blood in the body. These affect the ability of drugs to accumulate in cancerous cells, and not the normal cells, and the ability to produce the oxygen species that are toxic to the cancerous cells. In this paper, we prepared nanoparticles from zinc acetate using Photinia glabra (PG) fruit extract which were then used to chemically react with a light-sensitive drug called protoporphyrin IX (PP) to formulate small particles known as PGzinc oxide (ZnO)PP nanoconjugates. Our results showed that PGZnOPP nanoconjugates had the ability to produce the toxic oxygen particles at a high rate and in good quantity. They also had a higher capability to accumulate in the cancerous cells at a pH below 7 with lower values of the drug needed to cause 50% of cell death toward the cancerous cells which affect the tube that connects from the throat to the stomach when projected with laser light. We could consider PGZnOPP nanoconjugates to serve as a potential solution for reducing the dosage of PP needed to treat cancer in the presence of laser light, and at the same time they can help to reduce the skin-related side effects for patients after treatment when exposed to light.
Assuntos
Neoplasias , Photinia , Fotoquimioterapia , Protoporfirinas , Óxido de Zinco , Nanoconjugados , Óxidos , Fármacos Fotossensibilizantes/farmacologia , Linhagem Celular Tumoral , Concentração de Íons de Hidrogênio , Neoplasias/tratamento farmacológicoRESUMO
Aims: We prepared Photinia glabra (PG) aqueous fruit extract, utilized it to synthesize silver nanoparticles (PG-Ag NPs) and evaluated the antibacterial and anticancer activities of the nanoparticles (NPs). Materials & methods: Silver nitrate aqueous solution was reduced to PG-Ag NPs using aqueous PG fruit extract. NP shape, size, composition and functionalization were determined using transmission electron microscopy, x-ray photoelectron spectroscopy, Fourier transform infrared and x-ray diffraction. Results & conclusions: PG-Ag NPs were spherical, approximately 39-77 nm-sized, functionalized surfaces with notable antibacterial activity against both Escherichia coli and Staphylococcus aureus, with an MIC <30 ug/ml and cytotoxicity toward esophageal cancer cells, with IC50 values less than 20 ug/ml. PG-Ag@rt NPs have been shown to be a potent antibacterial and anticancer agent, and their enriched particle surfaces can be conjugated with other compounds for multibiomedical applications.
The present study reports for the first time the preparation of Photinia glabra (PG) aqueous fruit extract and its use for the synthesis of smaller silver particles (PG-Ag NPs) from bulk aqueous silver nitrate solution (AgNO3). The preparation followed the reduction ability of PG fruit extract phytochemical under different preparation conditions: at room temperature (PG-Ag@rt), at 70°C (PG-Ag@70) and in the presence of cerium oxide at 70°C (PG-Ag+CeO2@70). The prepared smaller particles were found using transmission electron microscopy to be spherical in shape with sizes 39, 77 and 44 nm for PG-Ag@rt, PG-Ag@70 and PG-Ag+CeO2@70, respectively. The NPs contained different functional groups on their surfaces due to the capping ability of PG fruit extract components. Among all, PG-Ag@rt NPs showed strongest antibacterial activity against Escherichia coli and Staphylococcus aureus with MIC 7.0 µg/ml and 28.0 µg/ml, respectively, and commendable anticancer activity toward Eca-109 cancer cells with IC50 less than 20 ug/ml.
Assuntos
Antibacterianos , Antineoplásicos , Nanopartículas Metálicas , Prata , Antibacterianos/farmacologia , Frutas/química , Nanopartículas Metálicas/química , Photinia/química , Extratos Vegetais/química , Prata/farmacologia , Antineoplásicos/farmacologiaRESUMO
The synthesis of ideal photosensitizers (PSs) is considered to be the most significant bottleneck in photodynamic therapy (PDT). To discover novel PSs with excellent photodynamic anti-tumor activities, a series of novel photosensitizers 5,15-diaryl-10,20-dibromoporphyrins (I1-6) were synthesized by a facile method. Compared with hematoporphyrin monomethyl ether (HMME) as the representative porphyrin-based photosensitizers, it is found that not only the longest absorption wavelength of all compounds was red-shifted to therapeutic window (660 nm) of photodynamic therapy, but also the singlet oxygen quantum yields were significantly increased. Furthermore, all compounds exhibited lower dark toxicity (except I2) and stronger phototoxicity (except I4) against Eca-109 tumor cells than HMME. Among them, I3 possessed the highest singlet oxygen quantum yield (ΦΔ = 0.205), the lower dark toxicity and the strongest phototoxicity (IC50 = 3.5 µM) in vitro. The findings indicated the compounds I3 had the potential to become anti-tumor agents for PDT.
Assuntos
Neoplasias , Fotoquimioterapia , Porfirinas , Humanos , Fármacos Fotossensibilizantes/química , Oxigênio Singlete/química , Porfirinas/química , Neoplasias/tratamento farmacológicoRESUMO
PURPOSE: Esophageal cancer is the most common gastrointestinal tumor and is difficult to be eradicated with conventional treatment. Porphyrin-based photosensitizers (PSs) mediated photodynamic therapy (PDT) could kill tumor cells with less damage to normal cells. As the most widely used porphyrin-based photosensitizer in clinics, Photofrin II has excellent anti-tumor effect. However, it has some disadvantages such as weak absorption at near infrared region, the complexity of components and prolonged skin photosensitivity. Here series novel 5,15-diaryl-10,20-dihalogeno porphyrin derivatives were afforded and evaluated to develop more effective and safer photosensitizers for tumor therapy. METHODS: The photophysical properties and singlet oxygen generation rates of 5,15-diaryl-10,20-dihalogeno porphyrins (I1-6, II1-4) were tested. The cytotoxicity of I1-6 and II1-4 were measured by MTT assay. The pathway of cell death was studied by flow cytometry. In vivo photodynamic efficacy of I3 and II2-4 in Eca-109 tumor-bearing BABL/c nude mice were measured and histopathological analysis were examined. RESULTS: 5,15-Diaryl-10,20-dihalogeno porphyrins I1-6 and II1-4 were synthesized. The longest absorption wavelength of these halogenated porphyrins (λmax = 660 nm) displayed a red shift around 30 nm compared to the unhalogenated porphyrins PS1 (λmax = 630 nm). The singlet oxygen generation rates of I1-6 and II1-4 were significantly higher than PS1 and HMME. All PSs mediated PDT showed obvious cytotoxic effect against Eca-109 cells compared to HMME in vitro and in vivo. Among these PSs, II4 exhibited appropriate absorption in the phototherapeutic window, higher 1O2 generation rate (k = 0.0061 s-1), the strongest phototoxicity (IC50 = 0.4 µM), lower dark toxicity, high generation of intracellular ROS in Eca-109 cells and excellent photodynamic anti-tumor efficacy in vivo. Besides, cell necrosis was induced by compound II4 mediated PDT. CONCLUSION: All new compounds have obvious photodynamic anti-esophageal cancer effects. Among them, the photosensitizer II4 showed excellent efficacy in vitro and in vivo, which has the potential to become a photodynamic anti-tumor drug.
Assuntos
Antineoplásicos , Neoplasias Esofágicas , Fotoquimioterapia , Porfirinas , Animais , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Neoplasias Esofágicas/patologia , Camundongos , Camundongos Nus , Fármacos Fotossensibilizantes/farmacologia , Porfirinas/farmacologia , Porfirinas/uso terapêutico , Oxigênio Singlete/uso terapêuticoRESUMO
BACKGROUND: Photodynamic therapy has been increasingly used to cope with the alarming problem of cancer. Porphyrins and their derivatives are widely used as Potent Photosensitizers (PS) for PDT. However, the hydrophobicity of porphyrins poses a challenge for their use in clinics, while most of the carbon dots (CDs) are known for good biocompatibility, solubility, and pH sensitivity. OBJECTIVE: This study aimed to improve the properties/biocompatibility of the pyropheophorbide-α for PDT. METHODS: The PPa-CD conjugate was synthesized through covalent interaction using amide condensation. The structure of synthesized conjugate was confirmed by TEM, 1HNMR, and FTIR. The absorption and emission spectra were studied. In vitro, cytotoxicity of the conjugate was examined in human esophageal cancer cell line (Eca-109). RESULTS: The results showed that the fluorescence of the drug was increased compared to its precursor. CDbased conjugate could generate ROS as well as enhanced biocompatibility by decreasing cytotoxicity. The conjugated drug also showed pH sensitivity in different solutions. CONCLUSION: The dark toxicity, as well as hemocompatibility, was improved.
Assuntos
Neoplasias , Fotoquimioterapia , Porfirinas , Carbono/química , Linhagem Celular Tumoral , Humanos , Concentração de Íons de Hidrogênio , Neoplasias/tratamento farmacológico , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/uso terapêutico , Porfirinas/farmacologiaRESUMO
Carbon based polymer dots have piqued attention of researchers because of excellent biocompatibility, and good solubility. Most of the p-dots are able to generate ROS which is effective for photodynamic therapy for the treatment of cancer while some photosensitizers such as porphyrins possess some drawbacks such as hydrophobicity, and dark toxicity. Therefore in this study we conjugated red emission carbon based polymer with pyropheophorbide-α through amide condensation and π-π stacking. One pot synthesis of the conjugate was successfully achieved. Their photophysiological properties were studied and structures were characterized by FT-IR, TEM and 1HNMR. pH- sensitivity of the conjugates was confirmed using fluorescence and UV-vis spectroscopy. Photo toxicity and dark toxicity of the prepared conjugates were evaluated in human esophageal cancer cell line (Eca-109). Hemocompatibility of the synthesized conjugates was evaluated and proved that the conjugates are safe to use for the treatment of tumor. Our results showed the PS doped p-dots had less dark toxicity and increased light toxicity as well as ROS generation was high as compared to precursor drug. Therefore, incorporation of p-dots to porphyrin improved biocompatibility and enhanced the photodynamic effect.
RESUMO
BACKGROUND: Antibiotic resistance is increasing day by day, thereby increase the chances of more infections by resistant bacteria. In this situation, antimicrobial photodynamic therapy (aPDT) is gaining more attraction. OBJECTIVE: To evaluate the antimicrobial effect of ALA derivatives using photodynamic therapy. MATERIALS AND METHODS: In this study, we evaluated the aPDT effect of different derivatives of 5-ALA. In vivo and in vitro studies were performed to measure the antimicrobial activity. Different light doses and different concentrations of drugs were used to test anti-bacterial effect of drugs as well as to detect any physiological changes in animal model after the treatment. RESULTS: In vivo studies revealed that ALA-methyl ester, ALA-hexyl ester, and ALA-13A are potent photosensitizers. In vitro studies involved wound healing rate, body weight, and dietary intake were evaluated, and results showed that ALA, ALA-methyl ester, ALA-hexyl ester, and ALA-13A had good anti-bacterial effects, fast healing rate, and no effect on other physical parameters. CONCLUSION: Photodynamic therapy is increasingly used to treat different types of skin infections caused by bacterial strains. Our studies revealed that ALA-methyl ester, ALA-hexyl ester, and ALA-13A are promising photosensitizers for photodynamic therapy to inhibit the growth of resistant bacterial strains.
Assuntos
Anti-Infecciosos , Fotoquimioterapia , Ácido Aminolevulínico/farmacologia , Animais , Anti-Infecciosos/farmacologia , Ésteres , Preparações Farmacêuticas , Fármacos Fotossensibilizantes/farmacologiaRESUMO
A photosensitizer with high phototoxicity, suitable amphipathy and low dark toxicity could play a pivotal role in photodynamic therapy (PDT). In this study, a facile and versatile approach was adopted to synthesize a series of novel fluorinated hematoporphyrin ether derivatives (I1-I5 and II1-II4), and the photodynamic activities of these compounds were studied. Compared to hematoporphyrin monomethyl ether (HMME), all PSs showed preferable photodynamic activity against A549 lung tumor cells. The longest visible absorption wavelength of these compounds was approximately 622 nm. Among them, II3 revealed the highest singlet oxygen yield (0.0957 min-1), the strongest phototoxicity (IC50 = 1.24 µM), the lowest dark toxicity in vitro, and exhibited excellent anti-tumor effects in vivo. So compound II3 could act as new drug candidate for photodynamic therapy.
Assuntos
Antineoplásicos/uso terapêutico , Éteres/uso terapêutico , Hematoporfirinas/uso terapêutico , Hidrocarbonetos Fluorados/uso terapêutico , Neoplasias/tratamento farmacológico , Fármacos Fotossensibilizantes/uso terapêutico , Células A549 , Animais , Antineoplásicos/síntese química , Antineoplásicos/efeitos da radiação , Teoria da Densidade Funcional , Éteres/síntese química , Éteres/efeitos da radiação , Feminino , Hematoporfirinas/síntese química , Hematoporfirinas/efeitos da radiação , Humanos , Hidrocarbonetos Fluorados/síntese química , Hidrocarbonetos Fluorados/efeitos da radiação , Luz , Camundongos Endogâmicos BALB C , Camundongos Nus , Modelos Químicos , Neoplasias/patologia , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/efeitos da radiação , Oxigênio Singlete/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
A series of new fluoro-substituted benzimidazole derivatives were designed, synthesized and pharmacologically evaluated. All the target compounds were characterized by 1HNMR, 13CNMR, mass spectra and elemental analysis. The biological evaluation showed that most of the synthesized compounds displayed nanomolar affinity to the angiotensin II type 1 (AT1) receptor and could decrease blood pressure efficiently in spontaneously hypertensive rats. The maximal response of mean blood pressure (MBP) lowered 74.5 ± 3.5 mmHg (1g) and 69.2 ± 0.9 mmHg (2a) at 10 g/kg after oral administration, and the antihypertensive effect lasted beyond 24 h, which performed better than both losartan and telmisartan. So, compounds 1g and 2a may be considered as potential antihypertension drug candidates.
Assuntos
Anti-Hipertensivos/uso terapêutico , Benzimidazóis/síntese química , Benzimidazóis/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Animais , Anti-Hipertensivos/farmacologia , Desenho de Fármacos , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Photodynamic therapy (PDT) has been developed as a promising therapeutic method in cancer treatment. The discovery of effective photosensitizer, which is the key factor of PDT, is highly desired. This paper reports the synthesis of novel chlorin derivatives, 5,10,15,20-tetraphenyl-[2:3]-[(methoxycarbonyl, carboxy)methano] chlorin I and 5,10,15,20-tetraphenyl-[2:3]- {[methoxycarbonyl, (2-hydroxyethyl)amide]methano}chlorin II. Their structures were characterized with UV-vis, 1HNMR, 13CNMR and HRMS spectroscopies. Photophysical and photochemical experiments results showed that compound I and II had an absorption maximum around 650 nm, with molar extinction coefficients of 1 × 104 M-1 cm-1. They had strong fluorescence emission in 650-660 nm upon excitation with 419-422 nm light. ESR showed that singlet oxygen was produced upon irradiation of compounds with 650 nm light in the presence of molecular oxygen. The photo-bleaching test indicated that the structure of compounds was stable. These new compounds exhibit excellent anti-tumor effects and lower toxicity compared to m-THPC in vitro and in vivo. Compound I and II had high tumor selectivity, which could induced tumor cells shrinkage and necrosis under 650 nm laser irradiation. Flow cytometry revealed that the compounds might mediate PDT effect at late apoptotic phase. These results make these compound I and II promising candidates for future study in photo-diagnosis and photodynamic therapy of cholangiocarcinoma.
Assuntos
Antineoplásicos/farmacologia , Neoplasias dos Ductos Biliares/tratamento farmacológico , Colangiocarcinoma/tratamento farmacológico , Fármacos Fotossensibilizantes/farmacologia , Porfirinas/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/efeitos da radiação , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Feminino , Humanos , Luz , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos ICR , Camundongos Nus , Necrose/induzido quimicamente , Fotoquimioterapia , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/efeitos da radiação , Porfirinas/síntese química , Porfirinas/efeitos da radiação , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Chlorophyll a exhibits excellent photosensitive activity in photosynthesis. The unstability limited its application as photoensitizer drug in photodynamic therapy. Here a series of novel chlorophyll a degradation products pyropheophorbide-a derivatives were synthesized and evaluated for lung cancer in PDT. These compounds have strong absorption in 660-670 nm with high molar extinction coefficient, and fluorescence emission in 660-675 nm upon excitation with 410-415 nm light. They all have much higher ROS yields than pyropheophorbide-a, and compound 10 was even higher than [3-(1-hexyloxyethyl)]-pyrophoeophorbide a (HPPH). Distinctive phototoxicity was observed in vitro and the inhibition effect was in light dose-dependent and drug dose-dependent style. They can effectively inhibit the growth of lung tumor in vivo. Among them, compound 8 and 11 have outstanding photodynamic anti-tumor effects without obvious skin photo-toxicity, so they can act as new drug candidates for photodynamic therapy.
Assuntos
Antineoplásicos/farmacologia , Clorofila A/farmacologia , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacologia , Células A549 , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Clorofila A/síntese química , Clorofila A/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Imagem Óptica , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/química , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
A series of new 6-substituted aminocarbonyl benzimidazole derivatives with 1, 4-disubsituted or 1, 5-disubsituted indole moiety and benzoic acid moiety were designed, synthesized and pharmacologically evaluated. Most of the synthesized compounds could bind to the AT1 receptor and decrease blood pressure significantly. Notably, 2e and 1h could obviously decrease MBP in a dose dependent manner. The maximal response lowered 57.9⯱â¯2.3â¯mmHg (2e) and 57.6⯱â¯1.9â¯mmHg (1h) of MBP at 10â¯mg/kg after oral administration, and the antihypertensive effect lasted beyond 24â¯h, which performed better than Losartan (Fig. 1). These results indicate that 2e and 1h are effective and long-lasting anti-hypertension drug candidates and deserve further investigation for therapeutic application.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Benzimidazóis/farmacologia , Desenho de Fármacos , Receptor Tipo 1 de Angiotensina/metabolismo , Bloqueadores do Receptor Tipo 1 de Angiotensina II/síntese química , Bloqueadores do Receptor Tipo 1 de Angiotensina II/química , Animais , Benzimidazóis/síntese química , Benzimidazóis/química , Relação Dose-Resposta a Droga , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
A series of new angiotensin II receptor 1 antagonists were prepared. They displayed nanomolar affinity to AT1 receptor and could decrease blood pressure efficiently in spontaneously hypertensive rats. Among them, compounds 1b and 2b could reduce the blood pressure with more or equal potency compared to Losartan. So, compounds 1b and 2b could be considered as potential antihypertension drug candidates.