RESUMO
Over the past decade, the attention of researchers has been drawn to materials with enzyme-like properties to substitute natural enzymes. The ability of nanomaterials to mimic enzymes makes them excellent enzyme mimics; nevertheless, there is a wide berth for improving their activity and providing a platform to heighten their potential. Herein, we report a green and facile route for Tectona grandis leaves extract-assisted synthesis of silver nanoparticles (Ag NPs) decorated on Mg-Al layered double hydroxides (Mg-Al-OH@TGLE-AgNPs) as a nanocatalyst. The Mg-Al-OH@TGLE-AgNPs nanocatalyst was well characterized, and the average crystallite size of the Ag NPs was found to be 7.92 nm. The peroxidase-like activity in the oxidation of o-phenylenediamine in the presence of H2O2 was found to be an intrinsic property of the Mg-Al-OH@TGLE-AgNPs nanocatalyst. In addition, the use of the Mg-Al-OH@TGLE-AgNPs nanocatalyst was extended towards the quantification of Hg2+ ions which showed a wide linearity in the concentration range of 80-400 µM with a limit of detection of 0.2 nM. Additionally, the synergistic medicinal property of Ag NPs and the phytochemicals present in the Tectona grandis leaves extract demonstrated notable antibacterial activity for the Mg-Al-OH@TGLE-AgNPs nanocatalyst against Gram-negative Escherichia coli and Gram-positive Bacillus cereus.
Assuntos
Nanopartículas Metálicas , Prata , Prata/química , Nanopartículas Metálicas/química , Peróxido de Hidrogênio , Antibacterianos/química , Peroxidases , Extratos Vegetais/farmacologia , Extratos Vegetais/químicaRESUMO
The devising and development of numerous enzyme mimics, particularly nanoparticles and nanomaterials (nanozymes), have been sparked by the inherent limitations imposed by natural enzymes. Peroxidase is one of the enzymes that is extensively utilized in commercial, medical, and biological applications because of its outstanding substrate selectivity. Herein, we present palladium nanoparticles grafted on Artocarpus heterophyllus (jackfruit) seed-derived biochar (BC-AHE@Pd) as a novel nanozyme to imitate peroxidase activity en route to the rapid and colorimetric detection of H2O2, exploiting o-phenylenediamine as a peroxidase substrate. The biogenically generated BC-AHE@Pd nanocatalyst was synthesized utilizing Artocarpus heterophyllus seed extract as the reducing agent for nanoparticle formation, while the residue became the source for biochar. Various analytical techniques like FT-IR, GC-MS, FE-SEM, EDS, TEM, SAED pattern, p-XRD, and ICP-OES, were used to characterize the BC-AHE@Pd nanocatalyst. The intrinsic peroxidase-like activity of the BC-AHE@Pd nanocatalyst was extended as a prospective nanosensor for the estimation of the biomolecules glucose and glutathione. Moreover, the BC-AHE@Pd nanocatalyst showed recyclability up to three recycles without any significant loss in activity.
RESUMO
For this work, two series of new piperazine derivatives (3a-o) and triazolo-pyrazine derivatives (3p-t) were synthesized in a single-step reaction. All twenty adducts were obtained in good to high yields and fully characterized by 1H NMR, 13C NMR, IR, and mass spectrometry techniques. To further confirm the chemical identity of the adducts, a crystal of N-{[(4-chlorophenyl)-3-(trifluoromethyl)]-5,6-dihydro-[1,2,4]triazolo[4,3-a]}pyrazine-7(8H)-carboxamide (3t) was prepared and analyzed using X-ray crystallography. In vitro screening of the antimicrobial activity of all compounds (3a-t) was evaluated against five bacterial and two fungal strains. This study disclosed that N-{[(3-chlorophenyl)]-4-(dibenzo[b,f][1,4]thiazepin-11-yl)}piperazine-1-carboxamide (3o) was the superior antimicrobial with good growth inhibition against A. baumannii. Furthermore, the results from the performed molecular docking studies were promising, since the observed data could be used to develop more potent antimicrobials.
Assuntos
Anti-Infecciosos , Pirazinas , Antibacterianos/química , Antibacterianos/farmacologia , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Molecular , Piperazina , Pirazinas/farmacologia , Relação Estrutura-AtividadeRESUMO
Coumarins are fused six-membered oxygen-containing benzoheterocycles that join two synthetically useful rings: α-pyrone and benzene. A survey of the literature shows that coumarins and their metal complexes have received great interest from synthetic chemists, medicinal scientists, and pharmacists due to their wide spectrum of biological applications. For instance, coumarin and its derivatives have been used as precursors to prepare a large variety of medicinal agents. Likewise, coumarin-derived imine-metal complexes have been found to display a variety of therapeutic applications, such as antibacterial, antifungal, anticancer, antioxidant, anthelmintic, pesticidal, and nematocidal activities. This review highlights the current synthetic methodologies and known bioactivities of coumarin-derived imine-metal complexes that make this molecule a more attractive scaffold for the discovery of newer drugs.
Assuntos
Complexos de Coordenação , Antioxidantes , Complexos de Coordenação/farmacologia , Cumarínicos/farmacologia , Cumarínicos/uso terapêutico , IminasRESUMO
Microbial infection is a leading cause of death worldwide, resulting in around 1.2 million deaths annually. Due to this, medicinal chemists are continuously searching for new or improved alternatives to combat microbial infections. Among many nitrogen-containing heterocycles, carbazole derivatives have shown significant biological activities, of which its antimicrobial and antifungal activities are the most studied. In this review, miscellaneous carbazole derivatives and their antimicrobial activity are discussed (articles published from 1999 to 2022).
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Anti-Infecciosos , Antifúngicos , Antibacterianos/farmacologia , Anti-Infecciosos/farmacologia , Antifúngicos/farmacologia , Carbazóis/farmacologia , Testes de Sensibilidade Microbiana , Nitrogênio , Relação Estrutura-AtividadeRESUMO
In this paper, highly stable, powerful, and recyclable magnetic nanoparticles tethered N-heterocyclic carbene-palladium(II) ((CH3)3-NHC-Pd@Fe3O4) as magnetic nanocatalyst was successfully synthesized from a simplistic multistep synthesis under aerobic conditions through easily available low-cost chemicals. Newly synthesized (CH3)3-NHC-Pd@Fe3O4 magnetic nanocatalyst was characterized from various analytical tools and catalytic potential of the (CH3)3-NHC-Pd@Fe3O4 magnetic nanocatalyst was studied for the catalytic reduction of toxic 4-nitrophenol (4-NP), hexavalent chromium (Cr(VI)), Methylene Blue (MB) and Methyl Orange (MO) at room temperature in aqueous media. UV-Visible spectroscopy was employed to monitor the reduction reactions. New (CH3)3-NHC-Pd@Fe3O4 magnetic nanocatalyst exhibited excellent catalytic activity for the reduction of toxic environmental pollutants. Moreover, (CH3)3-NHC-Pd@Fe3O4 magnetic nanocatalyst could be easily and rapidly separated from the reaction mixture with the help of an external magnet and recycled minimum five times in reduction of 4-NP, MB, MO and four times in Cr(VI) without significant loss of catalytic potential and remains stable even after reuse.
Assuntos
Poluentes Ambientais , Paládio , Catálise , Fenômenos Magnéticos , MagnetismoRESUMO
Herein, we describe the successful design and synthesis of seventeen new 1,4-diazinanes, compounds commonly known as piperazines. This group of piperazine derivatives (3a-q) were fully characterized by 1H NMR, 13C NMR, FT-IR, and LCMS spectral techniques. The molecular structure of piperazine derivative (3h) was further established by single crystal X-ray diffraction analysis. All reported compounds were evaluated for their antibacterial and antifungal potential against five bacterial (Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa) and two fungal strains (Candida albicans and Cryptococcus neoformans). The complete bacterial screening results are provided. As documented, piperazine derivative 3e performed the best against these bacteria. Additionally, data obtained during molecular docking studies are very encouraging with respect to potential utilization of these compounds to help overcome microbe resistance to pharmaceutical drugs, as explicitly noted in this manuscript.
Assuntos
Antibacterianos/farmacologia , Antifúngicos/farmacologia , Desenho de Fármacos , Simulação de Acoplamento Molecular , Piperazina/farmacologia , Acinetobacter baumannii/efeitos dos fármacos , Antibacterianos/síntese química , Antibacterianos/química , Antifúngicos/síntese química , Antifúngicos/química , Candida albicans/efeitos dos fármacos , Cryptococcus neoformans/efeitos dos fármacos , Relação Dose-Resposta a Droga , Escherichia coli/efeitos dos fármacos , Klebsiella pneumoniae/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Piperazina/síntese química , Piperazina/química , Pseudomonas aeruginosa/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
A series of new urea derivatives (3a-p) have been synthesized from readily available isocyanates and amines in good to high yields. All synthesized compounds were fully characterized using 1H NMR, 13C NMR, IR, and mass spectrometry. Additionally, the structure of the compound (3n) was confirmed by single-crystal X-ray diffraction. Furthermore, all compounds were evaluated for antimicrobial activity against five bacteria and two fungi. Last but not the least, molecular docking studies with Candida albicans dihydropteroate synthetase were performed and the results are presented herein.
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Antibacterianos/farmacologia , Antifúngicos/farmacologia , Bactérias/efeitos dos fármacos , Candida albicans/efeitos dos fármacos , Cryptococcus neoformans/efeitos dos fármacos , Ureia/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Antifúngicos/síntese química , Antifúngicos/química , Bactérias/crescimento & desenvolvimento , Candida albicans/crescimento & desenvolvimento , Relação Dose-Resposta a Droga , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade , Ureia/análogos & derivados , Ureia/químicaRESUMO
Liver fibrosis is a critical wound healing response to chronic liver injury such as hepatitis C virus (HCV) infection. If persistent, liver fibrosis can lead to cirrhosis and hepatocellular carcinoma (HCC). The development of new therapies for preventing liver fibrosis and its progression to cancer associated with HCV infection remains a critical challenge. Identification of novel anti-fibrotic compounds will provide opportunities for innovative therapeutic intervention of HCV-mediated liver fibrosis. We designed and synthesized a focused set of 5-arylthio-5H-chromenopyridines as a new class of anti-fibrotic agents. Liver fibrosis assays demonstrated that the compounds 3a and 3c show inhibitory activity towards human hepatic stellate cells (LX2) activation at 10µM. The HCV NS3 and NS5A proteins in HCV subgenome-expressing cells were also significantly reduced in cells treated with 3a and 3c, suggesting the possible inhibitory role of the compounds in HCV translation/replication activities. We have also examined the reactivity of these compounds with medicinally-relevant metal compounds such as platinum and gold. The reactivity of these complexes with metals and during Mass Spectrometry suggests that CS bond cleavage is relatively facile.
Assuntos
Hepatite C/complicações , Cirrose Hepática/prevenção & controle , Pirimidinas/farmacologia , Hepacivirus/metabolismo , Humanos , Cirrose Hepática/etiologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Proteínas não Estruturais Virais/genética , Proteínas não Estruturais Virais/metabolismoRESUMO
The vacuolar (Hâº)-ATPases (V-ATPases) are a family of ATP-driven proton pumps and they have been associated with cancer invasion, metastasis, and drug resistance. Despite the clear involvement of V-ATPases in cancer, the therapeutic use of V-ATPase-targeting small molecules has not reached human clinical trials to date. Thus, V-ATPases are emerging as important targets for the identification of potential novel therapeutic agents. We identified a bisbenzimidazole derivative (V) as an initial hit from a similarity search using four known V-ATPase inhibitors (I-IV). Based on the initial hit (V), we designed and synthesized a focused set of novel bisbenzimidazole analogs (2a-e). All newly prepared compounds have been screened for selected human breast cancer (MDA-MB-468, MDA-MB-231, and MCF7) and ovarian cancer (A2780, Cis-A2780, and PA-1) cell lines, along with the normal breast epithelial cell line, MCF10A. The bisbenzimidazole derivative (2e) is active against all cell lines tested. Remarkably, it demonstrated high cytotoxicity against the triple-negative breast cancer (TNBC) cell line, MDA-MB-468 (IC50 = 0.04 ± 0.02 µM). Additionally, it has been shown to inhibit the V-ATPase pump that is mainly responsible for acidification. To the best of our knowledge the bisbenzimidazole pharmacophore has been identified as the first V-ATPase inhibitor in its class. These results strongly suggest that the compound 2e could be further developed as a potential anticancer V-ATPase inhibitor for breast cancer treatment.
Assuntos
Antineoplásicos/química , Bisbenzimidazol/análogos & derivados , Bisbenzimidazol/química , ATPases Vacuolares Próton-Translocadoras/antagonistas & inibidores , Antineoplásicos/farmacologia , Bisbenzimidazol/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Feminino , Humanos , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/tratamento farmacológicoRESUMO
BACKGROUND & AIMS: The oncogene MDM2, which encodes an E3 ubiquitin ligase, is overexpressed in pancreatic cancers and is therefore a therapeutic target. Current inhibitors of MDM2 target the interaction between MDM2 and P53; these would have no effect on cancer cells that do not express full-length P53, including many pancreatic cancer cells. We searched for a compound that specifically inhibits MDM2 itself. METHODS: We performed a virtual screen and structure-based design to identify specific inhibitors of MDM2. We tested the activities of compounds identified on viability, proliferation, and protein levels of HPAC, Panc-1, AsPC-1, and Mia-Paca-2 pancreatic cancer cell lines. We tested whether intraperitoneal injections of one of the compounds identified affected growth of xenograft tumors from Panc-1 cells, or orthotopic tumors from Panc-1 and AsPC-1 cells (injected into pancreata), in nude mice. RESULTS: We identified a compound, called SP141, which bound directly to MDM2, promoting its auto-ubiquitination and degradation by the proteasome. The compound reduced levels of MDM2 in pancreatic cancer cell lines, as well as their proliferation, with 50% inhibitory concentrations <0.5 µM (0.38-0.50 µM). Increasing concentrations of SP141 induced increasing levels of apoptosis and G2-M-phase arrest of pancreatic cancer cell lines, whether or not they expressed functional P53. Injection of nude mice with SP141 (40 mg/kg/d) inhibited growth of xenograft tumors (by 75% compared with control mice), and led to regression of orthotopic tumors. CONCLUSIONS: In a screen for specific inhibitors of MDM2, we identified a compound called SP141 that reduces levels of MDM2 in pancreatic cancer cell lines, as well as their proliferation and ability to form tumors in nude mice. SP141 is a new class of MDM2 inhibitor that promotes MDM2 auto-ubiquitination and degradation. It might be further developed as a therapeutic agent for pancreatic cancer.
Assuntos
Adenocarcinoma/tratamento farmacológico , Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Indóis/farmacologia , Neoplasias Pancreáticas/tratamento farmacológico , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Piridinas/farmacologia , Adenocarcinoma/enzimologia , Adenocarcinoma/genética , Adenocarcinoma/patologia , Animais , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Desenho de Fármacos , Inibidores Enzimáticos/química , Feminino , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Humanos , Indóis/química , Concentração Inibidora 50 , Camundongos , Camundongos Nus , Terapia de Alvo Molecular , Neoplasias Pancreáticas/enzimologia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteólise , Proteínas Proto-Oncogênicas c-mdm2/genética , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Piridinas/química , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade , Fatores de Tempo , Transfecção , Carga Tumoral/efeitos dos fármacos , Ubiquitinação , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
There is an increasing interest in targeting the MDM2 oncogene for cancer therapy. SP-141, a novel designed small molecule MDM2 inhibitor, exerts excellent in vitro and in vivo anticancer activity. To facilitate the preclinical development of this candidate anticancer agent, we have developed an HPLC method for the quantitative analysis of SP-141. The method was validated to be precise, accurate, and specific, with a linear range of 16.2-32,400 ng/mL in plasma, 16.2-6480 ng/mL in homogenates of brain, heart, liver, kidneys, lungs, muscle and tumor, and 32.4-6480 ng/mL in spleen homogenates. The lower limit of quantification was 16.2 ng/mL in plasma and all the tissue homogenates, except for spleen homogenates, where it was 32.4 ng/mL. The intra- and inter-assay precisions (coefficient of variation) were between 0.86 and 13.39%, and accuracies (relative errors) ranged from -8.50 to 13.92%. The relative recoveries were 85.6-113.38%. SP-141 was stable in mouse plasma, modestly plasma bound and metabolized by S9 microsomal enzymes. We performed an initial pharmacokinetic study in tumor-bearing nude mice, demonstrating that SP-141 has a short half-life in plasma and wide tissue distribution. In summary, this HPLC method can be used in future preclinical and clinical investigations of SP-141.
Assuntos
Antineoplásicos/sangue , Cromatografia Líquida de Alta Pressão/métodos , Indóis/sangue , Neoplasias/tratamento farmacológico , Piridinas/sangue , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Feminino , Meia-Vida , Humanos , Indóis/administração & dosagem , Indóis/farmacocinética , Camundongos , Camundongos Nus , Neoplasias/sangue , Piridinas/administração & dosagem , Piridinas/farmacocinética , Distribuição TecidualRESUMO
A novel series of 5H-chromenopyridines was identified as anticancer agents in our continuing effort to discover and develop new small molecule anti-proliferative agents. Based on our initial lead SP-6-27 compound, we designed and synthesized novel tricyclic 5H-thiochromenopyridine and 5H-chromenopyridine analogs to evaluate the impact of an additional ring, as well as conformational flexibility on cytotoxic activity against human melanoma and glioma cell lines. All of the 5H-thiochromenopyridines have been achieved in good yields (89%-93%) using a single-step, three-component cyclization without the need for purification. The 5H-chromenopyridine analog of the potent 5H-thiochromenopyride was obtained in a good yield upon purification. All newly-prepared 5H-thiochromenopyridines showed good to moderate cytotoxicity against three melanoma and two glioma cell lines (3-15 µM). However, the 5H-chromenopyridine analogue that we prepared in our laboratory lost cytotoxic activity. The moderate cytotoxic activity of 5H-thiochromenopyridines shows the promise of developing chromenopyridines as potential anticancer agents.
Assuntos
Antineoplásicos/síntese química , Benzopiranos/farmacologia , Descoberta de Drogas , Piridinas/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Benzopiranos/síntese química , Benzopiranos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Glioma/tratamento farmacológico , Humanos , Melanoma/tratamento farmacológico , Piridinas/síntese química , Piridinas/química , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologiaRESUMO
The Ca(2+)/voltage-gated K(+) large conductance (BK) channel ß1 subunit is particularly abundant in vascular smooth muscle. By determining their phenotype, BK ß1 allows the BK channels to reduce myogenic tone, facilitating vasodilation. The endogenous steroid lithocholic acid (LCA) dilates cerebral arteries via BK channel activation, which requires recognition by a BK ß1 site that includes Thr169. Whether exogenous nonsteroidal agents can access this site to selectively activate ß1-containing BK channels and evoke vasodilation remain unknown. We performed a chemical structure database similarity search using LCA as a template, along with a two-step reaction to generate sodium 3-hydroxyolean-12-en-30-oate (HENA). HENA activated the BK (cbv1 + ß1) channels cloned from rat cerebral artery myocytes with a potency (EC50 = 53 µM) similar to and an efficacy (×2.5 potentiation) significantly greater than that of LCA. This HENA action was replicated on native channels in rat cerebral artery myocytes. HENA failed to activate the channels made of cbv1 + ß2, ß3, ß4, or ß1T169A, indicating that this drug selectively targets ß1-containing BK channels via the BK ß1 steroid-sensing site. HENA (3-45 µM) dilated the rat and C57BL/6 mouse pressurized cerebral arteries. Consistent with the electrophysiologic results, this effect was larger than that of LCA. HENA failed to dilate the arteries from the KCNMB1 knockout mouse, underscoring BK ß1's role in HENA action. Finally, carotid artery-infusion of HENA (45 µM) dilated the pial cerebral arterioles via selective BK-channel targeting. In conclusion, we have identified for the first time a nonsteroidal agent that selectively activates ß1-containing BK channels by targeting the steroid-sensing site in BK ß1, rendering vasodilation.
Assuntos
Artérias Cerebrais/efeitos dos fármacos , Colanos/farmacologia , Subunidades beta do Canal de Potássio Ativado por Cálcio de Condutância Alta/metabolismo , Esteroides/farmacologia , Vasodilatação/efeitos dos fármacos , Animais , Artérias Cerebrais/metabolismo , Colanos/química , Feminino , Subunidades beta do Canal de Potássio Ativado por Cálcio de Condutância Alta/química , Ácido Litocólico/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Ratos , Ratos Sprague-Dawley , Esteroides/química , Xenopus laevisRESUMO
MXenes, two-dimensional (2D) materials that consist of transition metal carbides, nitrides and/or carbonitrides, have recently attracted much attention in energy-related and biomedicine fields. These materials have substantial advantages over traditional carbon graphenes: they possess high conductivity, high strength, excellent chemical and mechanical stability, and superior hydrophilic properties. Furthermore, diverse functional groups such as -OH, -O, and -F located on the surface of MXenes aid the immobilization of numerous noble metal nanoparticles (NP). Therefore, 2D MXene composite materials have become an important and convenient option of being applied as support materials in many fields. In this review, the advances in the synthesis (including morphology studies, characterization, physicochemical properties) and applications of the currently known 2D MXene-metal (Pd, Ag, Au, and Cu) nanomaterials are summarized based on critical analysis of the literature in this field. Importantly, the current state of the art, challenges, and the potential for future research on broad applications of MXene-metal nanomaterials have been discussed.
RESUMO
Currently, in hospitals and community health centers, microbial infections are highly common diseases and are a leading cause of death worldwide. Antibiotics are generally used to fight microbial infections; however, because of the abuse of antibiotics, microbes have become increasingly more resistant to most of them. Therefore, medicinal chemists are constantly searching for new or improved alternatives to combat microbial infections. Coumarin triazole derivatives displayed a variety of therapeutic applications, such as antimicrobial, antioxidant, and anticancer activities. This review summarizes the advances of coumarin triazole derivatives as potential antimicrobial agents covering articles published from 2006 to 2022.
RESUMO
To investigate the effectiveness of EDL-291, a 6,7-dimethoxy-1-[4-(4-methoxypyridin-3-yl)benzyl]-1,2,3,4-tetrahydroisoquinoline dihydrochloride compound, in inhibiting the survival of glioblastoma in vitro and in vivo. Dose-response curves were generated to determine the EC50 in rat and human glioblastoma cell lines by treatment with different dilutions of EDL-291. To evaluate the architecture of the glioblastoma cells after treatment with EDL-291, the rat and human glioblastoma cells were stained with Mito Tracker Green FM. To determine whether autophagy was induced in EDL-291-treated glioblastoma cells, both rat and human glioblastoma cell lines were stained with acridine orange and light chain-3 immunoblots were performed. The efficacy of EDL-291 was monitored in vivo using a rat glioblastoma model. Rat glioblastoma cells were transplanted into an intracranial rat model, followed by infusions of saline, a low dose of EDL-291 (20 mg/kg for the first half hour, followed by 40 mg/kg EDL-291 in saline for 4 h), or a high dose of EDL-291 (60 mg/kg for the first half hour, followed by 90 mg/kg EDL-291 for 4 h). EDL-291 inhibits glioblastoma in vitro by destroying the mitochondria as shown with Mito Tracker Green FM. Acridine orange staining and light chain-3 immunoblots suggest that autophagy is induced when glioblastoma cells are treated with EDL-291. In vivo, a low dosage of EDL-291 is sufficient and effective in reducing glioblastoma tumor size. EDL-291 selectively induces cell death in rat and human glioblastoma cell lines by the induction of autophagy. EDL-291 exhibits antiglioblastoma effects both in vitro and in vivo.
Assuntos
Antineoplásicos/farmacologia , Glioblastoma/tratamento farmacológico , Isoquinolinas/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Astrócitos/efeitos dos fármacos , Astrócitos/patologia , Autofagia/efeitos dos fármacos , Western Blotting , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Glioblastoma/patologia , Humanos , Isoquinolinas/química , Isoquinolinas/uso terapêutico , Masculino , Microscopia Confocal , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/patologia , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Fatores de Tempo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
As a continuation of our efforts to discover and develop small molecules as anticancer agents, we identified GRI-394837 as an initial hit from similarity search on RGD and its analogs. Based on GRI-394837, we designed and synthesized a focused set of novel chromenes (4a-e) in a single step using microwave method. All five compounds showed activity in the nanomolar range (IC(50): 7.4-640 nM) in two melanoma, three prostate and four glioma cancer cell lines. The chromene 4e is active against all the cell lines and particularly against the A172 human glioma cell line (IC(50): 7.4 nM). Interestingly, in vitro tubulin polymerization assay shows 4e to be a weak tubulin polymerization inhibitor but it shows very strong cytotoxicity in cellular assays, therefore there must be additional unknown mechanism(s) for the anticancer activity. Additionally, the strong antiproliferative activity was verified by one of the selected chromene (4a) by the NCI 60 cell line screen. These results strongly suggest that the novel chromenes could be further developed as a potential therapeutic agent for a variety of aggressive cancers.
Assuntos
Antineoplásicos/química , Benzopiranos/química , Antineoplásicos/síntese química , Antineoplásicos/toxicidade , Astrócitos/efeitos dos fármacos , Benzopiranos/síntese química , Benzopiranos/toxicidade , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Simulação por Computador , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Oligopeptídeos/química , Estrutura Terciária de Proteína , Tubulina (Proteína)/química , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/química , Moduladores de Tubulina/toxicidadeRESUMO
The culmination of 80+ years of cancer research implicates the aberrant metabolism in tumor cells as a root cause of pathogenesis. Citrate is an essential molecule in intermediary metabolism, and its amplified availability to critical pathways in cancer cells via citrate transporters confers a high rate of cancer cell growth and proliferation. Inhibiting the plasma membrane and mitochondrial citrate transporters - whether individually, in combination, or partnered with complementary metabolic targets - in order to combat cancer may prove to be a consequential chemotherapeutic strategy. This review aims to summarize the use of different classes of citrate transporter inhibitors for anticancer activity, either individually or as part of a cocktail.
Assuntos
Antineoplásicos , Neoplasias , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Proteínas de Transporte/metabolismo , Proteínas de Transporte/uso terapêutico , Ácido Cítrico/metabolismo , Ácido Cítrico/uso terapêutico , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismoRESUMO
INTRODUCTION: Besides the well-established catalytic, synthetic and materials related applications of N-heterocyclic carbene (NHC) metal complexes, their use as therapeutics deserves a special attention. Many literature reports indicate that their bioactivity is superior to other organometallic compounds. The main focus of patent disclosures in this area is the elucidation of anticancer and antimicrobial activities of NHC transition metal complexes. Nonetheless, a variety of other biological activities have been reported in non-patent literature to date. AREA COVERED: Patent literature on NHC metal complexes with focus on their therapeutic applications and relationship structure-biological activity disclosed since the first issued patent (2010) up to now (2021). The information was collected from publicly available data sources (e.g. Chemical Abstracts, MedLine, Reaxys, and SciFinder). EXPERT OPINION: Although the first reports on biological applications of NHC metal complexes originate in 2000s, the greatest progress in this area was made only in the past decade. A growing number of patent disclosures indicates that structural design of new NHC metal complexes is crucial for their successful use in both medicine and biochemistry. In the next few years, we expect to see more stable and effective NHC metal complexes as potential therapeutic agents and perhaps in clinical trials.