RESUMO
A family of bifunctional dihetarylmethanes and dibenzoxanthenes is assembled via a reaction of acetals containing a 2-chloroacetamide moiety with phenols and related oxygen-containing heterocycles. These compounds demonstrated selective antitumor activity associated with the induction of cell apoptosis and inhibition of the process of glycolysis. In particular, bis(heteroaryl)methane containing two 4-hydroxy-6-methyl-2H-pyran-2-one moieties combine excellent in vitro antitumor efficacy with an IC50 of 1.7 µM in HuTu-80 human duodenal adenocarcinoma models with a high selectivity index of 73. Overall, this work highlights the therapeutic potential of dimeric compounds assembled from functionalized acetals and builds a starting point for the development of a new family of anticancer agents.
Assuntos
Antineoplásicos , Apoptose , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Metano/análogos & derivados , Metano/química , Metano/farmacologia , Proliferação de Células/efeitos dos fármacos , Xantenos/farmacologia , Xantenos/químicaRESUMO
The electrophilic activation of various substrates via double or even triple protonation in superacidic media enables reactions with extremely weak nucleophiles. Despite the significant progress in this area, the utility of organophosphorus compounds as superelectrophiles still remains limited. Additionally, the most common superacids require a special care due to their high toxicity, exceptional corrosiveness and moisture sensitivity. Herein, we report the first successful application of the "Brønsted acid assisted Brønsted acid" concept for the superelectrophilic activation of 2-hydroxybenzo[e][1,2]oxaphosphinine 2-oxides (phosphacoumarins). The pivotal role is attributed to the tendency of the phosphoryl moiety to form hydrogen-bonded complexes, which enables the formation of dicationic species and increases the electrophilicity of the phosphacoumarin. This unmasks the reactivity of phosphacoumarins towards non-activated aromatics, while requiring only relatively non-benign trifluoroacetic acid as the reaction medium.
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Compostos Organofosforados , Catálise , Compostos Organofosforados/química , Ligação de Hidrogênio , Ácidos/química , Estrutura MolecularRESUMO
We report an unusual transformation where the transient formation of a nitrene moiety initiates a sequence of steps leading to remote oxidative C-H functionalization (R-CH3 to R-CH2OC(O)R') and the concomitant reduction of the nitrene into an amino group. No external oxidants or reductants are needed for this formal molecular comproportionation. Detected and isolated intermediates and computational analysis suggest that the process occurs with pyrazole ring opening and recyclization.
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The utility of sterically hindered phenols (SHPs) in drug design is based on their chameleonic ability to switch from an antioxidant that can protect healthy tissues to highly cytotoxic species that can target tumor cells. This work explores the biological activity of a family of 45 new hybrid molecules that combine SHPs equipped with an activating phosphonate moiety at the benzylic position with additional urea/thiourea fragments. The target compounds were synthesized by reaction of iso(thio)cyanates with C-arylphosphorylated phenols containing pendant 2,6-diaminopyridine and 1,3-diaminobenzene moieties. The SHP/urea hybrids display cytotoxic activity against a number of tumor lines. Mechanistic studies confirm the paradoxical nature of these substances which combine pronounced antioxidant properties in radical trapping assays with increased reactive oxygen species generation in tumor cells. Moreover, the most cytotoxic compounds inhibited the process of glycolysis in SH-SY5Y cells and caused pronounced dissipation of the mitochondrial membrane of isolated rat liver mitochondria. Molecular docking of the most active compounds identified the activator allosteric center of pyruvate kinase M2 as one of the possible targets. For the most promising compounds, 11b and 17b, this combination of properties results in the ability to induce apoptosis in HuTu 80 cells along the intrinsic mitochondrial pathway. Cyclic voltammetry studies reveal complex redox behavior which can be simplified by addition of a large excess of acid that can protect some of the oxidizable groups by protonations. Interestingly, the re-reduction behavior of the oxidized species shows considerable variations, indicating different degrees of reversibility. Such reversibility (or quasi-reversibility) suggests that the shift of the phenol-quinone equilibrium toward the original phenol at the lower pH may be associated with lower cytotoxicity.
Assuntos
Neuroblastoma , Fenóis , Humanos , Animais , Ratos , Fenóis/farmacologia , Antioxidantes/farmacologia , Fenol , Ureia , Espécies Reativas de Oxigênio , Simulação de Acoplamento Molecular , ApoptoseRESUMO
Herein, we report the design and synthesis of novel 7-aza-coumarine-3-carboxamides via scaffold-hopping strategy and evaluation of their in vitro anticancer activity. Additionally, the improved non-catalytic synthesis of 7-azacoumarin-3-carboxylic acid is reported, which features water as the reaction medium and provides a convenient alternative to the known methods. The anticancer activity of the most potent 7-aza-coumarine-3-carboxamides against the HuTu 80 cell line is equal to that of reference Doxorubicin, while the selectivity towards the normal cell line is 9-14 fold higher.
Assuntos
Antineoplásicos , Antineoplásicos/farmacologia , Relação Estrutura-Atividade , Doxorrubicina , Cumarínicos/farmacologia , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos AntitumoraisRESUMO
Combining two pharmacophores in a molecule can lead to useful synergistic effects. Herein, we show hybrid systems that combine sterically hindered phenols with dinitrobenzofuroxan fragments exhibit a broad range of biological activities. The modular assembly of such phenol/benzofuroxan hybrids allows variations in the phenol/benzofuroxan ratio. Interestingly, the antimicrobial activity only appears when at least two benzofuroxan moieties are introduced per phenol. The most potent of the synthesized compounds exhibit high cytotoxicity against human duodenal adenocarcinoma (HuTu 80), human breast adenocarcinoma (MCF-7), and human cervical carcinoma cell lines. This toxicity is associated with the induction of apoptosis via the internal mitochondrial pathway and an increase in ROS production. Encouragingly, the index of selectivity relative to healthy tissues exceeds that for the reference drugs Doxorubicin and Sorafenib. The biostability of the leading compounds in whole mice blood is sufficiently high for their future quantification in biological matrices.
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A new biopreparation is developed to clean soils from oil pollution in the arid climate of the Republic of Kazakhstan. The biopreparation includes bacterial strains R. qingshengii F2-1, R. qingshengii F2-2, and P. alloputida BS3701. When using the biopreparation in a liquid mineral medium with 15% crude oil, laboratory studies have revealed degradation of 48% n-alkanes and 39% of PAHs after 50 days. The effectiveness of the biopreparation has been demonstrated in field experiments in the soil contaminated with 10% crude oil at the K-Kurylys landfill, Republic of Kazakhstan. During the six-month field experiment, the number of oil degraders reached 107 CFU/g soil, which degraded 70% of crude oil by the end of the experiment.
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A series of novel water-soluble salts of benzofuroxans was achieved via aromatic nucleophilic substitution reaction of 4,6-dichloro-5-nitrobenzofuroxan with various amines. The salts obtained showed good effectiveness of the pre-sowing treatment of seeds of agricultural crops at concentrations of 20-40 mmol. In some cases, the seed treatment with salts leads not only to improved seed germination, but also to the suppression of microflora growth. Additionally, their anti-cancer activityin vitrohas been researched. The compounds with morpholine fragments or a fragment of N-dimethylpropylamine, demonstrated the highest cytotoxic activity, which is in good correlation with the ability to inhibit the glycolysis process in tumor cells. Two compounds 4e and 4g were selected for further experiments using laboratory animals. It was found that the lethal dose of 50% (LD50) is 22.0 ± 1.33 mg/kg for 4e and 13.75 ± 1.73 mg/kg for 4g, i.e., compound 4e is two times less toxic than 4g, according to the mouse model in vivo. It was shown that the studied compounds exhibit antileukemia activity after a single intraperitoneal injection at doses from 1.25 to 5 mg/kg, as a result of which the average lifespan of animals with a P388 murine leukemia tumor increases from 20 to 28%. Thus, the water-soluble salts of benzofuroxans can be considered as promisingcandidates for further development, both as anti-cancer agents and as stimulants for seed germination and regulators of microflora crop growth.
Assuntos
Antineoplásicos , Benzoxazóis , Animais , Camundongos , Benzoxazóis/farmacologia , Sementes , Sais , Relação Dose-Resposta a Droga , Antineoplásicos/farmacologia , Água , GerminaçãoRESUMO
Herein we present the regio- and diastereoselective synthesis of novel pyrrolidine-fused spiro-dihydrophosphacoumarins via intermolecular [3 + 2] cycloaddition reaction. The presented approach is complementary to existing ones and provides an easy entry to the otherwise inaccessible derivatives. Additionally, the unprecedented pathway of the reaction of 4-hydroxycoumarin with azomethine ylides is described. The anti-cancer activity of the obtained compounds was tested in vitro, the most potent compound being 2.6-fold more active against the HuTu 80 cell line than the reference 5-fluorouracil, with a selectivity index > 32.
Assuntos
Compostos de Espiro , Compostos de Espiro/farmacologia , Estereoisomerismo , Reação de CicloadiçãoRESUMO
The dimensional effect of electric charge storage with a density of up to 270 µF/g by the hydrated ZrO2-nanoparticles system was determined. It was found that the place of localization of different charge carriers is the generalized heterophase boundary-nanoparticles surface. The supposed mechanism of the effect was investigated using the theory of dispersed systems, the band theory, and the theory of contact phenomena in semiconductors, which consists of the formation of localized electronic states in the nanoparticle material due to donor-acceptor interaction with the adsorption ionic atmosphere. The effect is relevant for modern nanoelectronics, microsystem technology, and printed electronics because it allows overcoming the basic physical restrictions on the size, temperature, and operation frequency of the device, caused by leakage currents.
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Herein, we report on the reaction of nitro-substituted azidobenzofuroxans with 1,3-dicarbonyl compounds in basic media. The known reactions of benzofuroxans and azidofuroxans with 1,3-dicarbonyl compounds in the presence of bases are the 1,3-dipolar cycloaddition and the Beirut reaction. In contrast with this, azidonitrobenzofuroxan reacts with 1,3-carbonyl compounds through Regitz diazo transfer, which is the first example of this type of reaction for furoxan derivatives. This difference is seemingly due to the strong electron-withdrawing effect of the superelectrophilic azidonitrobenzofuroxan, which serves as the azido transfer agent rather than 1,3-dipole in this case.
Assuntos
Compostos Azo/química , Benzoxazóis/química , Química Farmacêutica/métodos , Reação de Cicloadição , Animais , Humanos , Espectroscopia de Ressonância Magnética/métodos , Espectrometria de Massas/métodos , Modelos Químicos , Estrutura Molecular , EstereoisomerismoRESUMO
This study examines the adhesive properties and cytotoxicity of polyelectrolyte nanofilms from polyethyleneimine (PEI), polyallylamine hydrochloride (PAH) and sodium polystyrene sulfonate (PSS) on human bone marrow mesenchymal stromal cells (h-MSCs) and mouse adipose tissue (m-MSC) in vitro. Films are formed on 24- and 96-well culture plates in the combinations: PEI, PAH, PEI-PSS, PEI-PSS-PAH, PEI-PSS-PEI. An analysis of the culture results show that direct contact of h-MSCs with the PEI surface promotes adhesion (93-95% of adhesive cells versus 40% in the control). On the PEI surface, h-MSCs are evenly distributed, form colonies and 80% monolayer after 72 h of culture, as in the control on culture plastic. On nanofilms from PAH and PEI-PSS-PAH, cells grow in the form of rosette-like colonies with long and thin processes similar to neurites. The cytotoxic properties of PSS were revealed in direct contact with h-MSCs (more than 40% of nonviable cells with damaged plasma membranes). On the PSS surface, cells lost their adhesiveness. To culture and stably grow the cell mass of h-MSCs, it is better to use monolayer nanofilms made of highly adhesive and non-toxic PEI polyelectrolyte, which can bind the growth factors of blood serum and platelet lysate, ensuring the growth of h-MSCs under in vitro deprivation conditions.
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A series of novel 4-aminobenzofuroxan derivatives containing aromatic/aliphatic amines fragments was achieved via aromatic nucleophilic substitution reaction of 4,6-dichloro-5-nitrobenzofuroxan. The quantum chemistry calculations were performed to identify the factors affecting the regioselectivity of the reaction. The formation of 4-substituted isomer is favored both by its greater stability and the lower activation barrier. Antimicrobial activity of the obtained compounds has been evaluated and some of them were found to suppress effectively bacterial biofilm growth. Fungistatic activity of 4-aminobenzofuroxans were tested on two genetically distinct isolates of M. nivale. The effect of some benzofuroxan derivatives is likely to be more universal against different varieties of M. nivale compared with benzimidazole and carbendazim. Additionally, their anti-cancer activity in vitro has been tested. 4-aminofuroxans possessing aniline moiety showed a high selectivity towards MCF-7 and M-HeLa tumor cell lines. Moreover, they exhibit a significantly lower toxicity towards normal liver cells compared to Doxorubicin and Tamoxifen. Thus, benzofuroxans containing aromatic amines fragments in their structure are promising candidates for further development both as anti-cancer and anti-microbial agents.
Assuntos
Anti-Infecciosos/síntese química , Antineoplásicos/síntese química , Benzoxazóis/síntese química , Descoberta de Drogas , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Benzoxazóis/química , Relação Dose-Resposta a Droga , Desenho de Fármacos , Descoberta de Drogas/métodos , Ensaios de Seleção de Medicamentos Antitumorais , Drogas em Investigação/síntese química , Drogas em Investigação/química , Células HeLa , Humanos , Concentração Inibidora 50 , Células MCF-7 , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
Many plants have medicinal properties due to substances known as phytochemicals. To utilize these plants in practice, numerous procedures, such as extraction, isolation and characterization methods and toxicology and bioactivity studies, must be designed and implemented. Integrated approach to process Carpobrotus edulis, a weed medicinal plant widely spread in Portugal, was developed into a closed loop of two processes: microwave assisted extraction (MAE) and activation (MAA), to produce both phytochemicals and biochar. The use of MAE for phytochemical extraction was shown to be more energy efficient than conventional Soxhlet extraction: the process time was decreased by 7-8 times, and the energy efficiency was increased by up to 97%. The yield of the extracts is of 27%. Qualitative and quantitative identification/characterization of the phytochemicals were performed by LC-MS and phytochemical screening assays. The results clearly indicated that Carpobrotus edulis is rich by flavonoids (up to 24%). The use of MAA to process the residual biomass could shorten the activation time, resulting in reduced energy consumption. Biochar with a high yield of 65% (on a biomass basis) and a well-developed texture (surface area of 68.9 m2/g; total pore volume of 0.10 cm3/g; micropore volume of 0.07 cm3/g) is obtained.