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New tetrahydropyrazino[2,3-c]quinolin-5(6H)-ones were prepared from 3-chloroquinoline-2,4(1H,3H)-diones and ethylene diamine. In their reaction with HNCO, an unprecedented molecular rearrangement produced new types of hydantoin derivatives. All prepared compounds were characterized on the basis of their 1H, 13C, and 15N NMR and ESI mass spectra and some were authenticated by X-ray analysis of single crystalline material. A proposed mechanism for rearrangement is discussed in this essay. The CDK and ABL inhibition activity as well as in vitro cytotoxicity of the prepared compounds was also tested.
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Espectroscopía de Resonancia Magnética , CianatosRESUMEN
The constant increase in the resistance of pathogenic bacteria to the commonly used drugs so far makes it necessary to search for new substances with antibacterial activity. Taking up this challenge, we obtained a series of rhodanine-3-carboxyalkyl acid derivatives containing 2- or 3- or 4-pyridinyl moiety at the C-5 position. These compounds were tested for their antibacterial and antifungal activities. They showed activity against Gram-positive bacteria while they were inactive against Gram-negative bacteria and yeast. In order to explain the relationship between the activity of the compounds and their structure, for selected derivatives crystal structures were determined using the X-ray diffraction method. Modeling of the isosurface of electron density was also performed. For all tested compounds their lipophilicity was determined by the RP-TLC method and by calculation methods. On the basis of the carried-out research, it was found that the derivatives with 1.5 N···S electrostatics interactions between the nitrogen atom in the pyridine moiety and the sulfur atom in the rhodanine system showed the highest biological activity.
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Rodanina , Antibacterianos/química , Antibacterianos/farmacología , Bacterias Gramnegativas , Bacterias Grampositivas , Pruebas de Sensibilidad Microbiana , Rodanina/química , Rodanina/farmacología , Relación Estructura-ActividadRESUMEN
The aryltellurenyl cation [2-(tBuNCH)C6 H4 Te]+ , a Lewis super acid, and the weakly coordinating carborane anion [CB11 H12 ]- , an extremely weak Brønsted acid (pKa =131.0 in MeCN), form an isolable ion pair complex [2-(tBuNCH)C6 H4 Te][CB11 H12 ], in which the Brønsted acidity (pKa 7.4 in MeCN) of the formally hydridic B-H bonds is dramatically increased by more than 120 orders of magnitude. The electrophilic activation of B-H bonds in the carborane moiety gives rise to a proton transfer from boron to nitrogen at slightly elevated temperatures, as rationalized by the isolation of a mixture of the zwitterionic isomers 12- and 7-[2-(tBuN{H}CH)C6 H4 Te(CB11 H11 )] in ratios ranging from 62 : 38 to 80 : 20.
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Human 17ß-hydroxysteroid dehydrogenase type 10 is a multifunctional protein involved in many enzymatic and structural processes within mitochondria. This enzyme was suggested to be involved in several neurological diseases, e.g., mental retardation, Parkinson's disease, or Alzheimer's disease, in which it was shown to interact with the amyloid-beta peptide. We prepared approximately 60 new compounds based on a benzothiazolyl scaffold and evaluated their inhibitory ability and mechanism of action. The most potent inhibitors contained 3-chloro and 4-hydroxy substitution on the phenyl ring moiety, a small substituent at position 6 on the benzothiazole moiety, and the two moieties were connected via a urea linker (4at, 4bb, and 4bg). These compounds exhibited IC50 values of 1-2 µM and showed an uncompetitive mechanism of action with respect to the substrate, acetoacetyl-CoA. These uncompetitive benzothiazolyl inhibitors of 17ß-hydroxysteroid dehydrogenase type 10 are promising compounds for potential drugs for neurodegenerative diseases that warrant further research and development.
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3-Hidroxiacil-CoA Deshidrogenasas/antagonistas & inhibidores , Benzotiazoles/química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Urea/química , Urea/farmacología , 3-Hidroxiacil-CoA Deshidrogenasas/química , Enfermedad de Alzheimer/tratamiento farmacológico , Activación Enzimática , Humanos , Cinética , Estructura Molecular , Proteínas Recombinantes , Relación Estructura-ActividadRESUMEN
The objective of the studies was to synthesize and characterize new mono- and diesters with an imidazoquinolin-2-one ring with the use of 2,3-dihydro-2-thioxo-1H-imidazo[4 ,5-c]-quinolin-4(5H)-ones and ethyl bromoacetate. The products were isolated at high yield and characterized by instrumental methods (IR, 1H-, 13C-, and 15N- NMR, MS-ESI, HR-MS, EA). In order to clarify the places of substitution and the structure of the derivatives obtained, molecular modeling of substrates and products was performed. Consideration of the possible tautomeric structures of the substrates confirmed the existence only the most stable keto form. Based on the free energy of monosubstituted ester derivatives, the most stable form were derivatives substituted at sulfur atom of enolic form the used imidazoquinolones. Enolic form referred only to nitrogen atom no 1. The modeling results were consistent with the experimental data. The HOMO electron densities at selected atoms of each substrate has shown that the most reactive atom is sulfur atom. It explained the formation of monoderivatives substituted at sulfur atom. The diester derivatives of the used imidazoquinolones had second substituent at nitrogen atom no. 3. The new diesters can be used as raw material for synthesis of thermally stable polymers, and they can also have biological activity.
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Ésteres/química , Modelos Moleculares , Quinolonas/química , Imidazoles/química , Conformación Molecular , Teoría Cuántica , Quinolonas/síntesis química , Tiocianatos/químicaRESUMEN
Racemic 2-(2-trifluoromethyl)-1H-benzo[d]imidazol-1-yl)benzoic acid (TBBA) was synthesized in three steps from 1-fluoro-2-nitrobenzene. Target (P)- and (M)-TBBA atropisomers were stable with a racemization barrier above 30 kcal/mol. As a chiral derivatizing agent, TBBA showed much higher differences in chemical shifts (ΔδPM) than the conventional Mosher's acid.
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We report on the synthesis, activity testing, docking, and quantum mechanical scoring of novel imidazo[1,2-c]pyrimidin-5(6H)-one scaffold for cyclin-dependent kinase 2 (CDK2) inhibition. A series of 26 compounds substituted with aromatic moieties at position 8 has been tested in in vitro enzyme assays and shown to inhibit CDK2. 2D structure-activity relationships have ascertained that small substituents at position 8 (up to the size of naphtyl or methoxyphenyl) generally lead to single-digit micromolar IC50 values, whereas bigger substituents (substituted biphenyls) decreased the compounds' activities. The binding modes of the compounds obtained using Glide docking have exhibited up to 2 hinge-region hydrogen bonds to CDK2 and differed in the orientation of the inhibitor core and the placement of the 8-substituents. Semiempirical quantum mechanics-based scoring identified probable favourable binding modes, which will serve for future structure-based design and synthetic optimization of substituents of the heterocyclic core. In summary, we have identified a novel core for CDK2 inhibition and will explore it further to increase the potencies of the compounds and also monitor selectivities against other protein kinases.
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Quinasa 2 Dependiente de la Ciclina/química , Inhibidores de Proteínas Quinasas/química , Pirimidinas/química , Quinasa 2 Dependiente de la Ciclina/antagonistas & inhibidores , Diseño de Fármacos , Humanos , Simulación del Acoplamiento Molecular , Unión Proteica , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/síntesis química , Pirimidinas/farmacología , Teoría Cuántica , Relación Estructura-ActividadRESUMEN
Treatment of the neutral pyridine-based ligands L1 -L3 , bearing either one or two RN=CH imine moieties {where L1 and L2 are N,N-chelating ligands 2-(RN=CH)C5 H4 N (R=Ph (L1 ) or R=2,4,6-Ph3 C6 H2 (L2 )) and L3 is the N,N,N-chelating ligand 2,6-(RN=CH)2 C5 H3 N (R=2,6-iPr2 C6 H3 )}, with HSiCl3 yielded NâSi-coordinated silicon(IV) amides 2-{Cl3 SiN(R)CH2 }C5 H4 N (1, R=Ph; 2, R=2,4,6-Ph3 C6 H2 ) and 2-{Cl3 SiN(R)CH2 }-6-(RN=CH)C5 H4 N (3, R=2,6-iPr2 C6 H3 ). The organosilicon amides 1-3 are the products of spontaneous hydrosilylation of the RN=CH imine moiety induced by NâSi coordination of the proposed N,N-chelated chlorosilanes L1 âSiHCl3 (1 a), L2 âSiHCl3 (2 a), and L3 âSiHCl3 (3 a). Furthermore, the reaction of L3 with an excess of HSiCl3 provided the intramolecularly coordinated chlorosilicon diamide cyclo-{(C5 H3 N)-1,3-(CH2 NR)2 }SiCl2 (4) (R=2,6-iPr2 C6 H3 ) as the product of spontaneous reduction of both RN=CH imine moieties. The compounds have been characterized by NMR spectroscopy (1-4) and single-crystal X-ray diffraction analysis (1, 3, and 4). The mechanism of the hydrosilylation of the second RN=CH imine moiety in 3 by an excess of SiHCl3 has also been studied. The experimental work is supplemented by DFT calculations.
RESUMEN
A set of (3,3')-bis(1-Ph-2-R-1H-2,1-benzazaborole) compounds, in which R=tBu (Bab-tBu)2 , R=Dipp (Bab-Dipp)2 or R=tBu and Dipp (Bab-Dipp)(Bab-tBu), was synthesized and fully characterized using 1 H, 11 B, 13 C, and 15 Nâ NMR spectroscopy as well as single-crystal X-ray diffraction analysis. The central HC(sp3 )-C(sp3 )H bond with restricted rotation at the junction of both 1H-2,1-benzazaborole rings displayed an intriguing reactivity. It was demonstrated that this bond is easily mesolytically cleaved using alkali metals to form the respective aromatic 1Ph-2R-1H-2,1-benzazaborolyl anions M+ (THF)n (Bab-tBu)- (M=Li, Na, K) and K+ (THF)n (Bab-Dipp)- . Furthermore, the central HC(sp3 )-C(sp3 )H bond of bis(1H-2,1-benzazaborole)s is also homolytically cleaved either by heating or photochemical means, giving corresponding 1Ph-2R-1H-2,1-benzazaborolyl radicals (Bab-tBu). and (Bab-Dipp). , which rapidly self-terminate. Nevertheless, their formation was unambiguously established by NMR analysis of the reaction mixtures containing products of the self-termination of the radicals after heating or irradiation. (Bab-Dipp). radical was also characterized using EPR spectroscopy. Importantly, it turned out that the essentially non-polarized HC(sp3 )-C(sp3 )H bond in (Bab-tBu)2 is also cleaved heterolytically with 2â equiv of MeLi, giving the mixture of Li+ (SOL)n (Bab-tBu)- (SOL=THF or Et2 O) and lithium methyl-substituted borate complex Li+ (SOL)n (Bab-tBu-Me)- in a diastereoselective fashion.
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An unprecedented transfer of an aryl group from boron to Sb and Bi is observed in the reaction of heteroboroxines of general formula ArM[(OBR)2O] [where M = Sb, Bi; Ar = C6H3-2,6-(CH2NMe2)2; R = Ph, 4-CF3C6H4, 4-BrC6H4] with corresponding boronic acid RB(OH)2. Using this procedure, ion pairs [ArMR](+)[R4B5O6](-) were obtained [where M = Sb and R = Ph (4), 4-CF3C6H4 (5), 4-BrC6H4 (6); where M = Bi and R = Ph (7), 4-CF3C6H4 (8), 4-BrC6H4 (9)]. All compounds were characterized using elemental analysis, electrospray ionization mass spectrometry, and multinuclear NMR spectroscopy, and molecular structures of 4 and 7 were determined by single-crystal X-ray diffraction analysis. The central metal atoms in 4-9 were arylated by respective boronic acids, which represents, to the best of our knowledge, unprecedented reaction path in the chemistry of heavier group 15 elements. Investigation of the mechanism of this transformation indicated that Lewis pairs consisting of monomeric oxides ArMO and boroxine rings are probably key intermediates. In this regard, molecular structures of ArSbO[(4-CF3C6H4)3B3O3]·(4-CF3C6H4)B(OH)2 (10) and {ArSbO[(3,5-(CF3)2C6H3)3B3O3]} (13) were established by single-crystal X-ray diffraction analysis, and compound 13 was also fully characterized in solution by multinuclear NMR spectroscopy. The bonding in 13 was analyzed in detail by using density functional theory and natural bond order calculations and compared with known adduct ArSbOB(C6F5)3 (14) and hypothetical ArSbO monomer.
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Our attempts to synthesize the NâSi intramolecularly coordinated organosilanes Ph2 L(1) SiH (1 a), PhL(1) SiH2 (2 a), Ph2 L(2) SiH (3 a), and PhL(2) SiH2 (4 a) containing a CH=N imine group (in which L(1) is the C,N-chelating ligand {2-[CH=N(C6 H3 -2,6-iPr2)]C6 H4}(-) and L(2) is {2-[CH=N(tBu)]C6 H4}(-)) yielded 1-[2,6-bis(diisopropyl)phenyl]-2,2-diphenyl-1-aza-silole (1), 1-[2,6-bis(diisopropyl)phenyl]-2-phenyl-2-hydrido-1-aza-silole (2), 1-tert-butyl-2,2-diphenyl-1-aza-silole (3), and 1-tert-butyl-2-phenyl-2-hydrido-1-aza-silole (4), respectively. Isolated organosilicon amides 1-4 are an outcome of the spontaneous hydrosilylation of the CH=N imine moiety induced by NâSi intramolecular coordination. Compounds 1-4 were characterized by NMR spectroscopy and X-ray diffraction analysis. The geometries of organosilanes 1 a-4 a and their corresponding hydrosilylated products 1-4 were optimized and fully characterized at the B3LYP/6-31++G(d,p) level of theory. The molecular structure determination of 1-3 suggested the presence of a Si-N double bond. Natural bond orbital (NBO) analysis, however, shows a very strong donor-acceptor interaction between the lone pair of the nitrogen atom and the formal empty p orbital on the silicon and therefore, the calculations show that the Si-N bond is highly polarized pointing to a predominantly zwitterionic Si(+) N(-) bond in 1-4. Since compounds 1-4 are hydrosilylated products of 1 a-4 a, the free energies (ΔG298), enthalpies (ΔH298), and entropies (ΔH298) were computed for the hydrosilylation reaction of 1 a-4 a with both B3LYP and B3LYP-D methods. On the basis of the very negative ΔG298 values, the hydrosilylation reaction is highly exergonic and compounds 1 a-4 a are spontaneously transformed into 1-4 in the absence of a catalyst.
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Six organotin(IV) complexes, viz., [Me2Sn(L)] (1), [n-Bu2Sn(L)] (2), [n-Oct2Sn(L)] (3), [Bz2Sn(L)]·0.5C7H8 (4), [n-BuSn(L)Cl] (5), and [PhSn(L)Cl] (6), were synthesized using a 2,6-diacetylpyridine bis(2-hydroxybenzoylhydrazone), H2L. Compounds were characterized by Fourier transform infrared (FT-IR), High-resolution mass spectrometry (HRMS), and solutions Fourier transform nuclear magnetic resonance (FT-NMR) spectroscopies. The structures 1-6 were established by single-crystal X-ray diffraction (SC-XRD) analysis. Diffraction results evidenced that complexes 1-6 were seven-coordinated mononuclear species with the equatorial plane comprising the pentagonal N3O2 chelate ring of the doubly deprotonated L and two axial ligands, either R (R = Me, n-Bu, n-Oct, Bz) or R (n-Bu or Ph) and Cl ligands. Additionally, the photophysical properties were examined due to the enhanced conjugation and rigidity of the molecules while thermogravimetric analysis was carried out to evaluate the thermal stabilities of compounds. The anti-proliferative activity of the complexes 1-6 was tested against prostate cancer cells (DU-145) and normal human embryonic kidney cells (HEK-293). Among the compounds, dibutyltin compound 2 exhibited increased anti-proliferative activity, with an IC50 value of 6.16 ± 1.56 µM. The investigation of its mechanism of action involves using AO/EB (acridine orange/ethidium bromide) and ROS (reactive oxygen species) generation assays. This likely detects apoptotic morphological alterations in the nucleus of the cells, with ROS generation ultimately leading to apoptosis and cell death. The superior activity of 2 may be attributed to the C···H contacts and respective higher de outside and di inside distances from the Hirshfeld surface. Thus, these compounds could be a promising alternative to classical chemotherapy agents.
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Put the right spin on it: Mixed monomeric organotin(IV) chalcogenides of the general formula L(2)Sn(2)EX(2) containing two terminal Sn-X (X = Se, Te) bonds were prepared and were tested as potential single-source precursors for the deposition of semiconducting thin films. Spin-coating deposition of [{2,6-(Me(2)NCH(2))(2)C(6)H(3)}SnSe](2)(µ-S), as the useful single-source precursor, provided amorphous Sn-S-Se semiconducting thin films.
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The identification and quantitation of a wide range of lipids in complex biological samples is an essential requirement for the lipidomic studies. High-performance liquid chromatography-mass spectrometry (HPLC/MS) has the highest potential to obtain detailed information on the whole lipidome, but the reliable quantitation of multiple lipid classes is still a challenging task. In this work, we describe a new method for the nontargeted quantitation of polar lipid classes separated by hydrophilic interaction liquid chromatography (HILIC) followed by positive-ion electrospray ionization mass spectrometry (ESI-MS) using a single internal lipid standard to which all class specific response factors (RFs) are related to. The developed method enables the nontargeted quantitation of lipid classes and molecules inside these classes in contrast to the conventional targeted quantitation, which is based on predefined selected reaction monitoring (SRM) transitions for selected lipids only. In the nontargeted quantitation method described here, concentrations of lipid classes are obtained by the peak integration in HILIC chromatograms multiplied by their RFs related to the single internal standard (i.e., sphingosyl PE, d17:1/12:0) used as common reference for all polar lipid classes. The accuracy, reproducibility and robustness of the method have been checked by various means: (1) the comparison with conventional lipidomic quantitation using SRM scans on a triple quadrupole (QqQ) mass analyzer, (2) (31)P nuclear magnetic resonance (NMR) quantitation of the total lipid extract, (3) method robustness test using subsequent measurements by three different persons, (4) method transfer to different HPLC/MS systems using different chromatographic conditions, and (5) comparison with previously published results for identical samples, especially human reference plasma from the National Institute of Standards and Technology (NIST human plasma). Results on human plasma, egg yolk and porcine liver extracts are presented and discussed.
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The step-wise oxidation of an organotin(I) compound with elemental tellurium gave a variety of unprecedented organotin tellurides containing tin atoms in the oxidation states +II and +IV.
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Axially chiral 2-(2-(trifluoromethyl)-1H-benzo[d]imidazole-1-yl)benzoic acid (TBBA) was used as a chiral derivatizing agent to evaluate the limits of absolute configuration assignment for ß-chiral aminoalcohols. Seven Boc-aminoalcohols and eight variously N-substituted (S)-phenylglycinols were prepared, and their TBBA esters were analyzed by NMR spectroscopy. Diverse substitution at the ß-position was employed to demonstrate the effect of structure on the general conformational model and reliability of the absolute configuration assignment. It was concluded that hydrogen bond formation and steric hindrance were the main factors affecting the correct assignment for Boc-aminoalcohols.
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.Organoantimony(III) and organobismuth(III) phosphates (LM)(3)(PO(4))(2) [M = Sb (3) and Bi (4)], containing the NCN-chelating ligand L [L = 2,6-(CH(2)NMe(2))(2)C(6)H(3)], were prepared by the simple treatment of parent oxides 1 and 2 with H(3)PO(4). Both compounds were characterized by elemental analysis, electrospray ionization mass spectrometry, and IR and NMR spectroscopy and in the case of 3 by X-ray diffraction techniques. Compound 3 has an interesting behavior in solution, i.e., the formation of two possible conformational isomers, which was studied by (1)H, (13)C, and (31)P NMR spectroscopy.
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3-Chloroquinoline-2,4-diones react with cyanide ions in dimethyl formamide to give 3-cyanoquinoline-2,4-diones in small yields due to the strong hindrance of the substituent at the C-3 atom. Good yields can be achieved if the substituent at this position is the methyl group. In the methanol solution, the reaction proceeds by an addition mechanism to form 2-oxo-1a,2,3,7b-tetrahydrooxireno[2,3-c]quinoline-7b-carbonitriles, from which 4-hydroxy-3-methoxy-2-oxo-1,2,3,4-tetrahydroquinoline-4-carbonitriles are subsequently formed by opening of the epoxide ring with methanol. Some minor products of these reactions have also been isolated. The 1 H, 13 C and 15 N NMR spectra of the prepared compounds were measured, and all resonances were assigned using appropriate two-dimensional spectra.
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Pharmacological inhibition of cyclin-dependent kinases has emerged as a possible treatment option for various cancer types. We recently identified substituted imidazo[1,2-c]pyrimidin-5(6H)-ones as inhibitors of cyclin-dependent kinase 2 (CDK2). Here, we report the synthesis of derivatives modified at positions 2, 3, 6 or 8 prepared using Suzuki-Miyaura cross-coupling, halogenation, Dimroth-type rearrangement and alkylation as the main synthetic methods. The compounds displayed micro- to submicromolar inhibition of CDK2/cyclin E activity. Binding of the most potent compound 3b to CDK2 was determined using isothermal titration calorimetry. The co-crystal structure of 3b in complex with fully active CDK2 was solved, revealing the binding mode of 3b in the ATP pocket and a hydrogen bonding interaction with hinge region residue Leu83. Evaluation against leukaemia cell lines revealed low cytotoxicity, which is in line with the high selectivity towards CDK2. This study demonstrates that substituted imidazo[1,2-c]pyrimidines can be exploited for future kinase inhibitor development.
Asunto(s)
Quinasa 2 Dependiente de la Ciclina/antagonistas & inhibidores , Imidazoles/química , Inhibidores de Proteínas Quinasas/síntesis química , Pirimidinas/química , Antineoplásicos/síntesis química , Antineoplásicos/metabolismo , Antineoplásicos/farmacología , Sitios de Unión , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cristalografía por Rayos X , Quinasa 2 Dependiente de la Ciclina/metabolismo , Humanos , Enlace de Hidrógeno , Imidazoles/metabolismo , Imidazoles/farmacología , Simulación de Dinámica Molecular , Unión Proteica , Inhibidores de Proteínas Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/metabolismo , Pirimidinas/farmacología , Relación Estructura-ActividadRESUMEN
BACKGROUND: A series of rare-earth bisphthalocyanines of praseodymium, samarium and gadolinium bearing 5-bromo-2-thienyl substituents were prepared for the first time. RESULTS: Three bis[octakis(5-bromo-2-thienyl)] rare-earth metal(III) bisphthalocyanine complexes (Pr, Sm, Gd) were synthesized for the first time. The new compounds were characterized by UV-vis, NIR, FT-IR, mass spectroscopy and thermogravimetry as well as elementary analysis and electrochemistry. Production of singlet oxygen was also estimated using 9,10-dimethylanthracene method. CONCLUSIONS: The bromine substituent causes significant changes in molecule paramagnetism, singlet oxygen production, HOMO position and spectral characteristics. The compounds in solutions exist in two forms (neutral and/or reduced) depending on the solvent and rare-earth metal. Moreover, the compounds exhibit much increased stability under acid conditions compared with non-brominated derivatives. Graphical abstract Prepared compounds for the study of their chemical and other properties.