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1.
J Enzyme Inhib Med Chem ; 36(1): 605-617, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33557644

RESUMO

The aim of this study was to prepare and characterise inclusion complexes of a low water-soluble drug, mefenamic acid (MA), with ß-cyclodextrin (ß-CD). First, the phase solubility diagram of MA in ß-CD was drawn from 0 to 21 × 10-3 M of ß-CD concentration. A job's plot experiment was used to determine the stoichiometry of the MA:ß-CD complex (2:1). The stability of this complex was confirmed by molecular modelling simulation. Three methods, namely solvent co-evaporation (CE), kneading (KN), and physical mixture (PM), were used to prepare the (2:1) MA:ß-CD complexes. All complexes were fully characterised. The drug dissolution tests were established in simulated liquid gastric and the MA water solubility at pH 1.2 from complexes was significantly improved. The mechanism of MA released from the ß-CD complexes was illustrated through a mathematical treatment. Finally, two in vitro experiments confirmed the interest to use a (2:1) MA:ß-CD complex.


Assuntos
Ácido Mefenâmico/química , beta-Ciclodextrinas/química , Animais , Bovinos , Eritrócitos/efeitos dos fármacos , Humanos , Ácido Mefenâmico/farmacologia , Modelos Moleculares , Estrutura Molecular , Desnaturação Proteica/efeitos dos fármacos , Soroalbumina Bovina/química , Solubilidade , beta-Ciclodextrinas/farmacologia
2.
J Enzyme Inhib Med Chem ; 35(1): 398-403, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31899979

RESUMO

(2-(2,4-Dichlorophenyl)-3-(1H-indol-1-yl)-1-(1,2,4-1H-triazol-1-yl)propan-2-ol (8 g), a new 1,2,4-triazole-indole hybrid molecule, showed a broad-spectrum activity against Candida, particularly against low fluconazole-susceptible species. Its activity was higher than fluconazole and similar to voriconazole on C. glabrata (MIC90 = 0.25, 64 and 1 µg/mL, respectively), C. krusei (MIC90 = 0.125, 64 and 0.125 µg/mL, respectively) and C. albicans (MIC90 = 0.5, 8 and 0.25 µg/mL, respectively). The action mechanisms of 8 g were also identified as inhibition of ergosterol biosynthesis and phospholipase A2-like activity. At concentration as low as 4 ng/mL, 8g inhibited ergosterol production by 82% and induced production of 14a-methyl sterols, that is comparable to the results obtained with fluconazole at higher concentration. 8 g demonstrated moderate inhibitory effect on phospholipase A2-like activity being a putative virulence factor. Due to a low MRC5 cytotoxicity, this compound presents a high therapeutic index. These results pointed out that 8 g is a new lead antifungal candidate with potent ergosterol biosynthesis inhibition.


Assuntos
Antifúngicos/farmacologia , Candida/efeitos dos fármacos , Indóis/farmacologia , Triazóis/farmacologia , Animais , Antifúngicos/química , Candida/enzimologia , Candida/metabolismo , Linhagem Celular , Ergosterol/antagonistas & inibidores , Ergosterol/biossíntese , Feminino , Humanos , Indóis/química , Camundongos , Testes de Sensibilidade Microbiana , Especificidade da Espécie , Triazóis/química
3.
J Enzyme Inhib Med Chem ; 34(1): 1321-1346, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31328585

RESUMO

For over half a century, the carbazole skeleton has been the key structural motif of many biologically active compounds including natural and synthetic products. Carbazoles have taken an important part in all the existing anti-cancer drugs because of their discovery from a large variety of organisms, including bacteria, fungi, plants, and animals. In this article, we specifically explored the literature from 2012 to 2018 on the anti-tumour activities reported to carbazole derivatives and we have critically collected the most significant data. The most described carbazole anti-tumour agents were classified according to their structure, starting from the tricyclic-carbazole motif to fused tetra-, penta-, hexa- and heptacyclic carbazoles. To date, three derivatives are available on the market and approved in cancer therapy.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Carbazóis/química , Carbazóis/farmacologia , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Humanos , Estrutura Molecular , Neoplasias/patologia
4.
J Enzyme Inhib Med Chem ; 34(1): 1218-1225, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31286785

RESUMO

WaterLOGSY is a sensitive ligand-observed NMR experiment for detection of interaction between a ligand and a protein and is now well-established as a screening technique for fragment-based lead discovery. Here we develop and assess a protocol to derive ligand epitope mapping from WaterLOGSY data and demonstrate its general applicability in studies of fragment-sized ligands binding to six different proteins (glycogen phosphorylase, protein peroxiredoxin 5, Bcl-xL, Mcl-1, HSP90, and human serum albumin). We compare the WaterLOGSY results to those obtained from the more widely used saturation transfer difference experiments and to the 3D structures of the complexes when available. In addition, we evaluate the impact of ligand labile protons on the WaterLOGSY data. Our results demonstrate that the WaterLOGSY experiment can be used as an additional confirmation of the binding mode of a ligand to a protein.


Assuntos
Descoberta de Drogas/métodos , Espectroscopia de Ressonância Magnética/métodos , Sítios de Ligação , Proteínas/química
5.
J Enzyme Inhib Med Chem ; 34(1): 684-691, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30777494

RESUMO

Synthetic progesterone and 5α/ß-pregnane-3,20-dione derivatives were evaluated as in vitro and in vivo modulators of multidrug-resistance (MDR) using two P-gp-expressing human cell lines, the non-steroidogenic K562/R7 erythroleukaemia cells and the steroidogenic NCI-H295R adrenocortical carcinoma cells, both resistant to doxorubicin. The maximal effect in both cell lines was observed for 7α-O-benzoyloxy,11α(R)-O-tetrahydropyranyloxy-5ß-pregnane-3,20-dione 4. This modulator co-injected with doxorubicin significantly decreased the tumour size and increased the survival time of immunodeficient mice xenografted with NCI-H295R or K562/R7 cells.


Assuntos
Antineoplásicos/farmacologia , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Pregnanos/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Camundongos , Camundongos SCID , Conformação Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Pregnanos/síntese química , Pregnanos/química , Relação Estrutura-Atividade , Células Tumorais Cultivadas
6.
Molecules ; 25(1)2019 Dec 26.
Artigo em Inglês | MEDLINE | ID: mdl-31888043

RESUMO

Casein kinase II (CK2) is an intensively studied enzyme, involved in different diseases, cancer in particular. Different scaffolds were used to develop inhibitors of this enzyme. Here, we report on the synthesis and biological evaluation of twenty phenolic, ketonic, and para-quinonic indeno[1,2-b]indole derivatives as CK2 inhibitors. The most active compounds were 5-isopropyl-1-methyl-5,6,7,8-tetrahydroindeno[1,2-b]indole-9,10-dione 4h and 1,3-dibromo-5-isopropyl-5,6,7,8-tetrahydroindeno[1,2-b]indole-9,10-dione 4w with identical IC50 values of 0.11 µM. Furthermore, the development of a QSAR model based on the structure of indeno[1,2-b]indoles was performed. This model was used to predict the activity of 25 compounds with naphtho[2,3-b]furan-4,9-dione derivatives, which were previously predicted as CK2 inhibitors via a molecular modeling approach. The activities of four naphtho[2,3-b]furan-4,9-dione derivatives were determined in vitro and one of them (N-isopentyl-2-methyl-4,9-dioxo-4,9-dihydronaphtho[2,3-b]furan-3-carboxamide) turned out to inhibit CK2 with an IC50 value of 2.33 µM. All four candidates were able to reduce the cell viability by more than 60% after 24 h of incubation using 10 µM.


Assuntos
Caseína Quinase II/antagonistas & inibidores , Furanos/síntese química , Inibidores de Proteínas Quinases/síntese química , Caseína Quinase II/química , Sobrevivência Celular/efeitos dos fármacos , Furanos/química , Furanos/farmacologia , Humanos , Indóis/síntese química , Indóis/química , Concentração Inibidora 50 , Células MCF-7 , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Relação Quantitativa Estrutura-Atividade
7.
J Enzyme Inhib Med Chem ; 33(1): 1150-1159, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30001665

RESUMO

Three coordination compounds of formula {M(bmim)2Cl2} were synthetised (M = Co, Zn, and Hg) and fully characterised. Each complex incorporates 1-benzyl-2-methylimidazole (bmim) as ligand. The coordination polyhedron around the metal center for all complexes has a quasi-regular tetragonal geometry. Density functional theory calculations were carried out on the title compounds and as well on hypothetical complexes (Cu, Ni), in order to elucidate their electronic and molecular structure. The calculations reproduced the Co, Zn, and Hg experimental structures and could predict stable complexes in the case of Ni(II) and Cu(II) ions. The carbonic anhydrase (CA, EC 4.2.1.1) inhibitory effects of the three complexes were investigated. Only compound {Hg(bmim)2Cl2} (3) exhibited a modest inhibitory effect against hCA I, probably due to the affinity of Hg(II) for His residues at the entrance of the active site cavity.


Assuntos
Anidrase Carbônica II/antagonistas & inibidores , Anidrase Carbônica I/antagonistas & inibidores , Inibidores da Anidrase Carbônica/farmacologia , Imidazóis/farmacologia , Compostos Organometálicos/farmacologia , Teoria Quântica , Anidrase Carbônica I/metabolismo , Anidrase Carbônica II/metabolismo , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Simulação por Computador , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Humanos , Imidazóis/química , Modelos Moleculares , Estrutura Molecular , Compostos Organometálicos/síntese química , Compostos Organometálicos/química , Relação Estrutura-Atividade
8.
J Enzyme Inhib Med Chem ; 33(1): 370-375, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29336193

RESUMO

Phenazine is known to regroup planar nitrogen-containing heterocyclic compounds. It was used here to enhance the bioavailability of the biologically important compound iodinin, which is near insoluble in aqueous solutions. Its water solubility has led to the development of new formulations using diverse amphiphilic α-cyclodextrins (CDs). With the per-[6-desoxy-6-(3-perfluorohexylpropanethio)-2,3-di-O-methyl]-α-CD, we succeeded to get iodinin-loaded nanoformulations with good parameters such as a size of 97.9 nm, 62% encapsulation efficiency and efficient control release. The study presents an interesting alternative to optimizing the water solubility of iodinin by chemical modifications of iodinin.


Assuntos
Nanopartículas/química , Fenazinas/química , alfa-Ciclodextrinas/química , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Estrutura Molecular , Tamanho da Partícula , Fenazinas/farmacologia , Ratos , Solubilidade , Relação Estrutura-Atividade , Propriedades de Superfície , alfa-Ciclodextrinas/farmacologia
9.
J Enzyme Inhib Med Chem ; 33(1): 639-650, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29536772

RESUMO

Oxidative stress may be the major cause of induction of Shiga toxin-converting (Stx) prophages from chromosomes of Shiga toxin-producing Escherichia coli (STEC) in human intestine. Thus, we aimed to test a series of novel antioxidant compounds for their activities against prophage induction, thus, preventing pathogenicity of STEC. Forty-six compounds (derivatives of carbazole, indazole, triazole, quinolone, ninhydrine, and indenoindole) were tested. Fifteen of them gave promising results and were further characterized. Eleven compounds had acceptable profiles in cytotoxicity tests with human HEK-293 and HDFa cell lines. Three of them (selected for molecular studies) prevent the prophage induction at the level of expression of specific phage genes. In bacterial cells treated with hydrogen peroxide, expression of genes involved in the oxidative stress response was significantly less efficient in the presence of the tested compounds. Therefore, they apparently reduce the oxidative stress, which prevents induction of Stx prophage in E. coli.


Assuntos
Antibacterianos/farmacologia , Antioxidantes/farmacologia , Toxina Shiga/antagonistas & inibidores , Escherichia coli Shiga Toxigênica/efeitos dos fármacos , Antibacterianos/síntese química , Antibacterianos/química , Antioxidantes/síntese química , Antioxidantes/química , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Estrutura Molecular , Estresse Oxidativo/efeitos dos fármacos , Toxina Shiga/genética , Toxina Shiga/metabolismo , Escherichia coli Shiga Toxigênica/citologia , Escherichia coli Shiga Toxigênica/metabolismo , Relação Estrutura-Atividade
10.
Molecules ; 23(7)2018 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-29996552

RESUMO

Several new sulfamidocarbonyloxyphosphonates were prepared in two steps, namely carbamoylation and sulfamoylation, by using chlorosulfonyl isocyanate (CSI), α-hydroxyphosphonates, and various amino derivatives and related (primary or secondary amines, ß-amino esters, and oxazolidin-2-ones). All structures were confirmed by ¹H, 13C, and 31P NMR spectroscopy, IR spectroscopy, and mass spectroscopy, as well as elemental analysis. Eight compounds were evaluated for their in vitro antibacterial activity against four reference bacteria including Gram-positive Staphylococcus aureus (ATCC 25923), and Gram-negative Escherichia coli (ATCC 25922), Klebsiella pneumonia (ATCC 700603), Pseudomonas aeruginosa (ATCC 27853), in addition to three clinical strains of each studied bacterial species. Compounds 1a⁻7a and 1b showed significant antibacterial activity compared to sulfamethoxazole/trimethoprim, the reference drug used in this study.


Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Organofosfonatos/síntese química , Organofosfonatos/farmacologia , Antibacterianos/química , Bactérias/efeitos dos fármacos , Humanos , Testes de Sensibilidade Microbiana , Organofosfonatos/química , Oxazóis/síntese química , Oxazóis/química , Oxazóis/farmacologia , Preparações Farmacêuticas/química
11.
J Enzyme Inhib Med Chem ; 31(sup3): 25-32, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27362889

RESUMO

Quinones and quinones-like compounds are potential candidates for the inhibition of CDC25 phosphatases. The combination of MALDI-MS analyses and biological studies was used to develop a rapid screening of a targeted library of indeno[1,2-b]indoloquinone derivatives. The screening protocol using MALDI-TOFMS and MALDI-FTICRMS highlighted four new promising candidates. Biological investigations showed that only compounds 5c-f inhibited CDC25A and -C phosphatases, with IC50 values around the micromolar range. The direct use of a screening method based on MALDI-MS technology allowed achieving fast scaffold identification of a new class of potent inhibitors of CDC25 phosphatases. These four molecules appeared as novel molecules of a new class of CDC25 inhibitors. Assessment of 5c-e in an MRC5 proliferation assay provided an early indicator of toxicity to mammalian cells. Compound 5d seems the most promising hit for developing new CDC25 inhibitors.


Assuntos
Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/farmacologia , Indenos/farmacologia , Quinonas/farmacologia , Fosfatases cdc25/antagonistas & inibidores , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Indenos/síntese química , Indenos/química , Estrutura Molecular , Quinonas/síntese química , Quinonas/química , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Relação Estrutura-Atividade , Fosfatases cdc25/metabolismo
12.
Microb Cell Fact ; 14: 74, 2015 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-26036951

RESUMO

BACKGROUND: Human protein kinase CK2 represents a novel therapeutic target for neoplastic diseases. Inhibitors are in need to explore the druggability and the therapeutic options of this enzyme. A bottleneck in the search for new inhibitors is the availability of the target for testing. Therefore an assay was developed to provide easy access to CK2 for discovery of novel inhibitors. RESULTS: Autodisplay was used to present human CK2 on the surface of Escherichia coli. Heterotetrameric CK2 consists of two subunits, α and ß, which were displayed individually on the surface. Co-display of CK2α and CK2ß on the cell surface led to the formation of functional holoenzyme, as demonstrated by NaCl dependency of enzymatic activity, which differs from that of the catalytic subunit CK2α without ß. In addition interaction of CK2α and CK2ß at the cell surface was confirmed by co-immunoprecipitation assays. Surface displayed CK2 holoenzyme enabled an easy IC50 value determination. The IC50 values for the known CK2 inhibitors TBB and Silmitasertib were determined to be 50 and 3.3 nM, respectively. CONCLUSION: Surface-displayed CK2α and CK2ß assembled on the cell surface of E. coli to an active tetrameric holoenzyme. The whole-cell CK2 autodisplay assay as developed is suitable for inhibition studies. Furthermore, it can be used to determine quantitative CK2 inhibition data such as IC50 values. In summary, this is the first report on the functional surface display of a heterotetrameric enzyme on E. coli.


Assuntos
Escherichia coli/metabolismo , Sequência de Aminoácidos , Caseína Quinase II/metabolismo , Descoberta de Drogas , Humanos , Modelos Moleculares , Dados de Sequência Molecular
13.
J Enzyme Inhib Med Chem ; 30(2): 180-8, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24697298

RESUMO

Four series of carbazole derivatives, including N-substituted-hydroxycarbazoles, oxazinocarbazoles, isoxazolocarbazolequinones, and pyridocarbazolequinones, were studied using diverse biological test methods such as a CE-based assay for CK2 activity measurement, a cytotoxicity assay with IPC-81 cell line, determination of MIC of carbazole derivatives as antibacterial agents, a Plasmodium falciparum susceptibility assay, and an ABCG2-mediated mitoxantrone assay. Two oxazinocarbazoles Ib and Ig showed CK2 inhibition with IC50 = 8.7 and 14.0 µM, respectively. Further chemical syntheses were realized and the 7-isopropyl oxazinocarbazole derivative 2 displayed a stronger activity against CK2 (IC50 = 1.40 µM). Oxazinocarbazoles Ib, Ig, and 2 were then tested against IPC-81 leukemia cells and showed the ability to induce leukemia cell death with IC50 values between 57 and 62 µM. Further investigations were also reported on antibacterial and antiplasmodial activities. No significant inhibitory activity on ABCG2 efflux pump was detected.


Assuntos
Antibacterianos/síntese química , Antimaláricos/síntese química , Antineoplásicos/síntese química , Carbazóis/síntese química , Oxazinas/síntese química , Inibidores de Proteínas Quinases/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Antimaláricos/química , Antimaláricos/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Carbazóis/química , Carbazóis/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Negativas/crescimento & desenvolvimento , Bactérias Gram-Positivas/efeitos dos fármacos , Bactérias Gram-Positivas/crescimento & desenvolvimento , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Oxazinas/química , Oxazinas/farmacologia , Testes de Sensibilidade Parasitária , Plasmodium falciparum/efeitos dos fármacos , Proteína Quinase C/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia
14.
Bioorg Med Chem Lett ; 24(16): 3748-52, 2014 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-25022204

RESUMO

A novel series of (7-aryl-1,5-naphthyridin-2-yl)ureas was discovered as dual ERK2 and Aurora B kinases inhibitors. Several analogues were active at micromolar and submicromolar range against ERK2 and Aurora B, associated with very promising antiproliferative activity toward various cancer cell lines. Synthesis, structure activity relationship and docking study are reported. In vitro ADME properties and safety data are also discussed.


Assuntos
Antineoplásicos/farmacologia , Aurora Quinase B/antagonistas & inibidores , Descoberta de Drogas , Proteína Quinase 1 Ativada por Mitógeno/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Ureia/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Aurora Quinase B/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HCT116 , Humanos , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade , Ureia/análogos & derivados , Ureia/química
15.
Magn Reson Chem ; 51(12): 837-41, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24123338

RESUMO

The complete (1)H and (13)C assignments of eight bioactive indeno[1,2-b]indole-10-one derivatives were accomplished by the combined use of one-dimensional and two-dimensional NMR experiments.


Assuntos
Indenos/química , Indóis/química , Isótopos de Carbono , Espectroscopia de Ressonância Magnética/normas , Estrutura Molecular , Prótons , Padrões de Referência
16.
Eur J Med Chem ; 248: 115070, 2023 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-36628850

RESUMO

Human breast cancer resistance protein (BCRP), known also as ABCG2, plays a major role in multiple drug resistance (MDR) in tumor cells. Through this ABC transporter, cancer cells acquire the ability of resistance to structurally and functionally unrelated anticancer drugs. Nowadays, the design of ABCG2 inhibitors as potential agents to enhance the chemotherapy efficacy is an interesting strategy. In this context, we have used computer-aided drug design (CADD) based on available data of a large series of potent inhibitors from our groups as an approach in guiding the design of effective ABCG2 inhibitors. We report therein the results on the use of the FLAPpharm method to elucidate the pharmacophoric features of one of the ABCG2 binding sites involved in the regulation of the basal ATPase activity of the transporter. The predictivity of the model was evaluated by testing three predicted compounds which were found to induce high inhibitory activity of BCRP, in the nanomolar range for the best of them.


Assuntos
Antineoplásicos , Proteínas de Neoplasias , Humanos , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Resistência a Múltiplos Medicamentos , Antineoplásicos/farmacologia , Antineoplásicos/química , Desenho de Fármacos , Resistencia a Medicamentos Antineoplásicos
17.
Pharmaceutics ; 15(12)2023 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-38140042

RESUMO

The aim of this study was to formulate and characterize CK2 inhibitor-loaded alginate microbeads via the polymerization method. Different excipients were used in the formulation to improve the penetration of an active agent and to stabilize our preparations. Transcutol® HP was added to the drug-sodium alginate mixture and polyvinylpyrrolidone (PVP) was added to the hardening solution, alone and in combination. To characterize the formulations, mean particle size, scanning electron microscopy analysis, encapsulation efficiency, swelling behavior, an enzymatic stability test and an in vitro dissolution study were performed. The cell viability assay and permeability test were also carried out on the Caco-2 cell line. The anti-oxidant and anti-inflammatory effects of the formulations were finally evaluated. The combination of Transcutol® HP and PVP in the formulation of sodium alginate microbeads could improve the stability, in vitro permeability, anti-oxidant and anti-inflammatory effects of the CK2 inhibitor.

18.
Pharmaceuticals (Basel) ; 17(1)2023 Dec 25.
Artigo em Inglês | MEDLINE | ID: mdl-38256866

RESUMO

The syntheses of novel 2,4-bis[(substituted-aminomethyl)phenyl]phenylquinazolines 12 and 2,4-bis[(substituted-aminomethyl)phenyl]phenylquinolines 13 are reported here in six steps starting from various halogeno-quinazoline-2,4-(1H,3H)-diones or substituted anilines. The antiproliferative activities of the products were determined in vitro against a panel of breast (MCF-7 and MDA-MB-231), human adherent cervical (HeLa and SiHa), and ovarian (A2780) cell lines. Disubstituted 6- and 7-phenyl-bis(3-dimethylaminopropyl)aminomethylphenyl-quinazolines 12b, 12f, and 12i displayed the most interesting antiproliferative activities against six human cancer cell lines. In the series of quinoline derivatives, 6-phenyl-bis(3-dimethylaminopropyl)aminomethylphenylquinoline 13a proved to be the most active. G-quadruplexes (G4) stacked non-canonical nucleic acid structures found in specific G-rich DNA, or RNA sequences in the human genome are considered as potential targets for the development of anticancer agents. Then, as small aza-organic heterocyclic derivatives are well known to target and stabilize G4 structures, their ability to bind G4 structures have been determined through FRET melting, circular dichroism, and native mass spectrometry assays. Finally, telomerase inhibition ability has been also assessed using the MCF-7 cell line.

19.
Biochem Biophys Res Commun ; 424(1): 71-5, 2012 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-22728884

RESUMO

We previously reported indeno[1,2-b]indoles as a novel class of potent inhibitors of the human protein kinase CK2. In the present study we prepared two novel quinoid derivatives, the indeno[1,2-b]indoloquinones 6b and 6c, and demonstrated inhibition of the human CK2 by the compounds. Furthermore, we showed substantial antiproliferative activity of both compounds towards a broad panel of human cancer cell lines in the low micromolar range. Whereas the earlier indeno[1,2-b]indoles have been shown to be selective for CK2, the indeno[1,2-b]indoloquinones 6b and 6c also inhibited the AMPK activated protein kinase ARK5, potentially contributing to the anti-cancer effects of the compounds. In addition, with compound 6b we found a very potent inhibitor of the leukemia-associated receptor tyrosine kinase FLT3, with an IC(50) of 0.18 µM.


Assuntos
Antineoplásicos/farmacologia , Caseína Quinase II/antagonistas & inibidores , Indenos/farmacologia , Indolquinonas/farmacologia , Indóis/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Antineoplásicos/química , Linhagem Celular Tumoral , Humanos , Indenos/química , Indolquinonas/química , Indóis/química , Concentração Inibidora 50 , Inibidores de Proteínas Quinases/química
20.
Bioorg Med Chem ; 20(7): 2282-9, 2012 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-22377675

RESUMO

Herein we describe the synthesis and properties of indeno[1,2-b]indole derivatives as a novel class of potent inhibitors of the human protein kinase CK2. A set of 19 compounds was obtained using a convenient and straightforward synthesis protocol. The compounds were tested for inhibition of human protein kinase CK2, which was recombinantly expressed in Escherichia coli. New inhibitors with IC(50) in the micro- and sub-micromolar range were identified. Compound 4b (5-isopropyl-7,8-dihydroindeno[1,2-b]indole-9,10(5H,6H)-dione) inhibited human CK2 with an IC(50) of 0.11 µM and did not significantly inhibit 22 other human protein kinases, suggesting selectivity towards CK2. ATP-competitive inhibition by compound 4b was shown and a K(i) of 0.06 µM was determined. Our findings indicate that indeno[1,2-b]indoles are a promising starting point for further development and optimization of human protein kinase CK2 inhibitors.


Assuntos
Caseína Quinase II/antagonistas & inibidores , Indóis/química , Inibidores de Proteínas Quinases/química , Caseína Quinase II/metabolismo , Permeabilidade da Membrana Celular/efeitos dos fármacos , Humanos , Indóis/síntese química , Indóis/farmacologia , Cinética , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Estereoisomerismo
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