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1.
Molecules ; 29(9)2024 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-38731629

RESUMO

This work presents the design, synthesis and biological activity of novel N-substituted benzimidazole carboxamides bearing either a variable number of methoxy and/or hydroxy groups. The targeted carboxamides were designed to investigate the influence of the number of methoxy and/or hydroxy groups, the type of substituent placed on the N atom of the benzimidazole core and the type of substituent placed on the benzimidazole core on biological activity. The most promising derivatives with pronounced antiproliferative activity proved to be N-methyl-substituted derivatives with hydroxyl and methoxy groups at the phenyl ring and cyano groups on the benzimidazole nuclei with selective activity against the MCF-7 cell line (IC50 = 3.1 µM). In addition, the cyano-substituted derivatives 10 and 11 showed strong antiproliferative activity against the tested cells (IC50 = 1.2-5.3 µM). Several tested compounds showed significantly improved antioxidative activity in all three methods compared to standard BHT. In addition, the antioxidative activity of 9, 10, 32 and 36 in the cells generally confirmed their antioxidant ability demonstrated in vitro. However, their antiproliferative activity was not related to their ability to inhibit oxidative stress nor to their ability to induce it. Compound 8 with two hydroxy and one methoxy group on the phenyl ring showed the strongest antibacterial activity against the Gram-positive strain E. faecalis (MIC = 8 µM).


Assuntos
Antineoplásicos , Antioxidantes , Benzimidazóis , Proliferação de Células , Desenho de Fármacos , Benzimidazóis/química , Benzimidazóis/farmacologia , Benzimidazóis/síntese química , Humanos , Proliferação de Células/efeitos dos fármacos , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Células MCF-7 , Antioxidantes/farmacologia , Antioxidantes/síntese química , Antioxidantes/química , Relação Estrutura-Atividade , Antibacterianos/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Amidas/química , Amidas/farmacologia , Amidas/síntese química , Estrutura Molecular , Testes de Sensibilidade Microbiana , Estresse Oxidativo/efeitos dos fármacos
2.
Eur J Med Chem ; 259: 115705, 2023 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-37544182

RESUMO

A series of BODIPY compounds with a methylphenol substituent at the meso-position and halogen atoms on the BODIPY core, or OCH3 or OAc substituents at the phenolic moiety was synthesized. Their spectral and photophysical properties and the photochemical reactivity upon irradiation in CH3OH were investigated. The molecules with the phenolic substituent at the meso-position undergo more efficient photo-methanolysis at the boron atom, while the introduction of the OCH3 group at the phenolic moiety changes the reaction selectivity towards the cleavage at the meso-position. The introduction of the halogen atoms into the BODIPY increases the photo-cleavage reaction efficiency, as well as the ability of the molecules to sensitize oxygen and form reactive oxygen species (ROS). The efficiency of the ROS formation was measured in comparison with that of tetraphenylporphyrin. The antiproliferative effect of BODIPY molecules was investigated against three human cancer cell lines MCF-7 (breast carcinoma), H460 (lung carcinoma), HCT116 (colon carcinoma), and two non-cancer cell lines, HEK293T (embryonic kindey) and HaCaT (keratinocytes), with the cells kept in the dark or irradiated with visible light. For most of the compounds a modest or no antiproliferative activity was observed for cells in the dark. However, when cells were irradiated, a dramatic increase in cytotoxicity was observed (more than 100-fold), with IC50 values in the submicromolar concentration range. The enhancement of the cytotoxic effect was explained by the formation of ROS, which was studied for cells in vitro. However, for some BODIPY compounds, the effects due to the formation of electrophilic species (carbocations and quinone methides, which react with biomolecules) cannot be disregarded. Confocal fluorescence microscopy images of H460 cells and HEK293T show that the compounds enter the cells and are retained in the cytoplasm and membranes of the various organelles. When the cells treated with the compounds are irradiated, photo-processes lead to cell death by apoptosis. The study performed is important because it provides bases for the development of novel photo-therapeutics capable of exerting photo-cytotoxic effects in both oxygenated and hypoxic cells.


Assuntos
Carcinoma , Oxigênio Singlete , Humanos , Oxigênio Singlete/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Fármacos Fotossensibilizantes/química , Células HEK293 , Compostos de Boro/farmacologia , Compostos de Boro/química , Halogênios
3.
ChemMedChem ; 18(18): e202300261, 2023 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-37376962

RESUMO

Novel benzo[b]thienyl- and 2,2'-bithienyl-derived benzothiazoles and benzimidazoles were synthesized to study their antiproliferative and antitrypanosomal activities in vitro. Specifically, we assessed the impact that amidine group substitutions and the type of thiophene backbone have on biological activity. In general, the benzothiazole derivatives were more active than their benzimidazole analogs as both antiproliferative and antitrypanosomal agents. The 2,2'-bithienyl-substituted benzothiazoles with unsubstituted and 2-imidazolinyl amidine showed the most potent antitrypanosomal activity, and the greatest selectivity was observed for the benzimidazole derivatives bearing isopropyl, unsubstituted and 2-imidazolinyl amidine. The 2,2'-bithiophene derivatives showed most selective antiproliferative activity. Whereas the all 2,2'-bithienyl-substituted benzothiazoles were selectively active against lung carcinoma, the benzimidazoles were selective against cervical carcinoma cells. The compounds with an unsubstituted amidine group also produced strong antiproliferative effects. The more pronounced antiproliferative activity of the benzothiazole derivatives was attributed to different cytotoxicity mechanisms. Cell cycle analysis, and DNA binding experiments provide evidence that the benzimidazoles target DNA, whereas the benzothiazoles have a different cellular target because they are localized in the cytoplasm and do not interact with DNA.


Assuntos
Antineoplásicos , Carcinoma , Humanos , Antineoplásicos/química , Linhagem Celular Tumoral , Benzotiazóis/química , DNA/metabolismo , Benzimidazóis/química , Amidinas/farmacologia , Amidinas/química , Relação Estrutura-Atividade , Proliferação de Células
4.
Molecules ; 28(1)2022 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-36615231

RESUMO

A series of cyano- and amidino-substituted imidazo[4,5-b]pyridines were synthesized using standard methods of organic synthesis, and their biological activity was evaluated. Biological evaluation included in vitro assessment of antiproliferative effects on a diverse selection of human cancer cell lines, antibacterial activity against chosen Gram-positive and Gram-negative bacterial strains, and antiviral activity on a broad panel of DNA and RNA viruses. The most pronounced antiproliferative activity was observed for compound 10, which contained an unsubstituted amidino group, and compound 14, which contained a 2-imidazolinyl amidino group; both displayed selective and strong activity in sub-micromolar inhibitory concentration range against colon carcinoma (IC50 0.4 and 0.7 µM, respectively). All tested compounds lacked antibacterial activity, with the exception of compound 14, which showed moderate activity against E. coli (MIC 32 µM). Bromo-substituted derivative 7, which contained an unsubstituted phenyl ring (EC50 21 µM), and para-cyano-substituted derivative 17 (EC50 58 µM) showed selective but moderate activity against respiratory syncytial virus (RSV).


Assuntos
Antineoplásicos , Piridinas , Humanos , Linhagem Celular Tumoral , Piridinas/farmacologia , Escherichia coli , Antineoplásicos/farmacologia , Antibacterianos/farmacologia , Relação Estrutura-Atividade , Proliferação de Células
5.
Org Biomol Chem ; 19(22): 4891-4903, 2021 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-34106112

RESUMO

A series of BODIPY dyes were synthesized, that were at the 3, or 3 and 5 positions, substituted by photochemically reactive quinone methide (QM) precursor moieties. Fluorescence properties of the molecules were investigated and we demonstrated that the molecules undergo wavelength dependent photochemistry. Photodeamination to deliver QMs takes place only upon excitation to higher excited singlet states, showing unusual anti-Kasha photochemical reactivity. The findings were corroborated by TD-DFT computations. Laser flash photolysis experiments could not reveal QMs due to the low efficiency of their formation, but enabled the detection of phenoxyl radicals. The applicability of the molecules for the fluorescent labeling of bovine serum albumin as a model protein upon photoexcitation at 350 nm was demonstrated.


Assuntos
Compostos de Boro
6.
ACS Appl Mater Interfaces ; 12(1): 347-351, 2020 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-31829548

RESUMO

A novel approach for the photolabeling of proteins by a BODIPY fluorophore is reported that is based on an anti-Kasha photochemical reaction from an upper singlet excited state (Sn) leading to the deamination of the BODIPY quinone methide precursor. On the other hand, the high photochemical stability of the dye upon excitation by visible light to S1 allows for the selective fluorescence detection from the dye or dye-protein adduct, without concomitant bleaching or hydrolysis of the protein-dye adduct. Therefore, photolabeling and fluorescence monitoring can be uncoupled by using different excitation wavelengths. Combined theoretical and experimental studies by preparative irradiations, fluorescence, and laser flash photolysis fully disclose the photophysical properties of the dye and its anti-Kasha photochemical reactivity. The application of the dye was demonstrated on photolabeling of bovine serum albumin.


Assuntos
Compostos de Boro/química , Indolquinonas/química , Fotoquímica/métodos , Fluorescência , Fotólise , Estrutura Secundária de Proteína
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