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.
Assuntos
Compostos Organofosforados , Catálise , Compostos Organofosforados/química , Ligação de Hidrogênio , Ácidos/química , Estrutura MolecularRESUMO
Ureas are often thought of as "double amides" due to the obvious structural similarity of these functional groups. The main structural feature of an amide is its planarity, which is responsible for the conjugation between the nitrogen atom and carbonyl moiety and the decrease of amide nucleophilicity. Consequently, since amides are poor nucleophiles, ureas are often thought of as poor nucleophiles as well. Herein, we demonstrate that ureas can be distinctly different from amides. These differences can be amplified by rotation around one of the ureas' C-N bonds, which switches off the amide resonance and recovers the nucleophilicity of one of the nitrogen atoms. This conformational change can be further facilitated by the judicious introduction of steric bulk to disfavor the planar conformation. This change in reactivity is an example of "stereoelectronic deprotection," a concept when the desired reactivity of a functional group is produced by a conformational change rather than a chemical modification. This concept may be used complementarily to the traditional protecting groups. We also demonstrate both the viability and the utility of this concept by the synthesis of unusual 2-oxoimidazolium salts possessing quaternary nitrogen atoms at the urea moiety.
RESUMO
Herein, we report a highly regioselective one-pot synthesis of pyrazolo[3,4-b]pyridines via the reaction of 3-arylidene-1-pyrrolines with aminopyrazoles. The reaction proceeds through the sequential nucleophilic addition/electrophilic substitution/C-N bond cleavage and provides easy access to pyrazolo[3,4-b]pyridine derivatives featuring a primary amino group. Moreover, the reaction can be terminated at the electrophilic substitution stage, thus providing convenient entry to the hardly accessible pyrazolopyrrolopyridine scaffold.
RESUMO
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
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.
RESUMO
In this article, we report a highly regioselective method for the synthesis of new fused pyridine derivativesâ2,3-disubstituted quinolines and 1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one derivatives. The method is based on the reaction of 1,1-diethoxybutane derivatives with aromatic and heterocyclic nucleophiles. The isolated compounds are similar to the products formed as a result of the Debner-Miller reaction. However, we have shown that the interaction of 1,1-diethoxybutane derivatives with (hetero)aromatic amines proceeds according to a mechanism different from that of the Doebner-Miller reaction. The proposed method is distinguished by the possibility of obtaining a wide range of substituted quinolines and 1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one derivatives in one step, the absence of the need to use expensive metal-containing catalysts, and a high product yield.
RESUMO
The cooperative L-proline/Brønsted acid/base promoted reaction of 2-ethoxypyrrolidines or N-substituted 4,4-diethoxybutan-1-amines with methyl(alkyl/aryl)ketones for the synthesis of 2-(acylmethylene)pyrrolidine derivatives is reported. The key features of the developed protocol are gram-scale synthesis of the target compounds, easily available starting materials, operational simplicity and usage of non-expensive reagents.
Assuntos
Acetais , Alcaloides , Cetonas , Estrutura Molecular , Pirrolidinas , EstereoisomerismoRESUMO
The series of novel taurine-derived diarylmethanes and dibenzoxanthenes was synthesized starting from simple commercially available precursors via modular three-stage approach. All the newly synthesized compounds were screened for inâ vitro antibacterial and antifungal activity, as well as cytotoxicity towards normal and cancer cell lines. Some of the synthesized compounds exhibited 2-4-fold higher activity against S.â aureus, E.â faecalis and B.â cereus compared with Chloramphenicol. In contrast to Chloramphenicol, the tested compounds also showed bactericidal, rather than bacteriostatic effect, which makes them promising candidates for further studies.
Assuntos
Anti-Infecciosos , Antineoplásicos , Antibacterianos/farmacologia , Anti-Infecciosos/farmacologia , Antifúngicos/farmacologia , Antineoplásicos/farmacologia , Cloranfenicol , Testes de Sensibilidade Microbiana , Estrutura Molecular , Staphylococcus aureus , Relação Estrutura-Atividade , Taurina , XantenosRESUMO
New derivatives of benzofuroxan containing triazidoisobutyl fragments, opening the way for the creation of highly effective compositions with an increased value of energy characteristics, were synthesized for the first time. Such compounds are also an excellent platform for further modification and for the preparation of new biologically-active compounds containing tetrazole and triazole fragments. Calculations of heats of formation performed with the DFT (density functional theory) method showed that the studied compounds are high-energetic density ones, the enthalpies of formation of which are comparable to the enthalpies of formation of similar benzofuroxan derivatives and exceeds experimental enthalpy of formation of CL-14 (5,7-diamino-4,6-dinitrobenzofuroxan). The analysis of DSC indicates a sufficiently high thermal stability of the synthesized azidobenzofuroxans, which are acceptable for their use as components in the creation of highly efficient compositions with an increased value of energy characteristics.
Assuntos
Modelos Moleculares , Oxidiazóis/química , Tetrazóis/química , Teoria QuânticaRESUMO
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
Gold(I)-catalyzed reactions of electron-poor alkynes are still a challenging process. A straightforward synthesis of phosphorus-based heterocycles, namely, 2-phenyl 1H-isophosphinoline 2-oxides 1, is reported. The reaction used PPh3AuCl precatalyst in combination with triflic acid under microwave activation and afforded isophosphinoline 2-oxides 1 in moderate to quantitative yields through a fully regioselective 6-endo-dig hydroarylation cyclization, paving the way toward an effective synthesis of phosphorus heterocycles.
RESUMO
This research focuses on the X-ray structure of 4,6-dichloro-5-nitrobenzofuroxan 1 and of some of its amino derivatives (4a, 4e, 4g, and 4l) and on DFT calculations concerning the nucleophilic reactivity of 1. We have found that by changing the solvent used for crystallization, it is possible to obtain 4,6-dichloro-5-nitrobenzofuroxan (1) in different polymorphic structures. Moreover, the different torsional angles observed for the nitro group in 1 and in its amino derivatives (4a, 4e, 4g, and 4l) are strictly dependent on the steric hindrance of the substituent at C-4. DFT calculations on the course of the nucleophilic substitution confirm the role of the condensed furoxan ring in altering the aromaticity of the carbocyclic frame, while chlorine atoms strongly influence the dihedral angle and the rotational barrier of the nitro group. These results corroborate previous observations based on experimental kinetic data and give a deep picture of the reaction with amines, which proceeds via a "non-aromatic" nucleophilic substitution.
Assuntos
Oxidiazóis/química , Aminas , Teoria da Densidade Funcional , Estrutura Molecular , Nitrobenzenos/síntese química , Nitrobenzenos/química , Oxidiazóis/síntese química , SolventesRESUMO
A series of novel hybrid compounds containing benzofuroxan and 2-aminothiazole moieties are synthesized via aromatic nucleophilic substitution reaction. Possible reaction pathways have been considered quantum-chemically, which allowed us to suggest the most probable products. The quantum chemical results have been proved by X-ray data on one compound belonging to the synthesized series. It was shown that the introduction of substituents to both the thiazole and amine moieties of the compounds under study strongly influences their UV/Vis spectra. Initial substances and obtained hybrid compounds have been tested in vitro as anticancer agents. Target compounds showed selectivity towards M-HeLa tumor cell lines and were found to be more active than starting benzofuroxan and aminothiazoles. Furthermore, they are considerably less toxic to normal liver cells compared to Tamoxifen. The mechanism of action of the studied compounds can be associated with the induction of apoptosis, which proceeds along the mitochondrial pathway. Thus, new hybrids of benzofuroxan are promising candidates for further development as anticancer agents.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Benzoxazóis/química , Tiazóis/química , Neoplasias do Colo do Útero/tratamento farmacológico , Apoptose , Proliferação de Células , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Células HeLa , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Neoplasias do Colo do Útero/patologiaRESUMO
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
A series of novel 4-(het)arylimidazoldin-2-ones were obtained by the acid-catalyzed reaction of (2,2-diethoxyethyl)ureas with aromatic and heterocyclic C-nucleophiles. The proposed approach to substituted imidazolidinones benefits from excellent regioselectivity, readily available starting materials and a simple procedure. The regioselectivity of the reaction was rationalized by quantum chemistry calculations and control experiments. The anti-cancer activity of the obtained compounds was tested in vitro.
Assuntos
Antineoplásicos , Imidazolidinas/química , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Ciclização , Células HeLa , Humanos , Imidazolidinas/síntese química , Imidazolidinas/farmacologiaRESUMO
The reaction rates for the nucleophilic aromatic substitution of 4,6-dichloro-5-nitrobenzofuroxan 1 with eight aliphatic amines (characterized by very different basicities/nucleophilicities) and three anilines have been measured in both methanol and toluene. The obtained rates have been related to the basicity (pKaH in water and Kb in benzene) or nucleophilicity (N Mayr constants) of the tested amines. The whole of the obtained kinetic data has furnished useful information on the high nucleophilic reactivity of benzofuroxan derivatives, which has been related essentially to two factors: the high electron-drawing ability/power of the condensed furoxan ring and the low aromatic character of the benzofuroxan system.
RESUMO
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.