RESUMEN
Inexpensive sodium sulfide trihydrate was found to promote unprecedented 6e-regio-predefined redox condensation of o-nitroanilines with α-tetralones to benzo[a]phenazines. The method was also successfully extended to acetophenones and higher homologs as reducing partners to provide 2-phenylquinoxalines. Compared to traditional approaches toward benzo[a]phenazine and quinoxaline cores starting with o-phenylenediamines, the present strategy could afford these heterocycles with well-defined regiochemistry based on the structure of starting o-nitroanilines.
RESUMEN
In four simple steps, a series of 5H-thiazolo[2',3':2,3]imidazo[4,5-b]indole and 11H-benzo[4',5']thiazolo[2',3':2,3]imidazo[4,5-b]indole derivatives were prepared with high yields. The key step in this procedure was demonstrated to be two-fold Cu-catalysed C-N coupling reactions of 5-bromo-6-(2-bromophenyl)imidazo[2,1-b]thiazole and 3-bromo-2-(2-bromophenyl)benzo[d]imidazo[2,1-b]thiazole with various amines.
RESUMEN
An Fe/S catalyst generated in situ from FeCl2·4H2O and elemental sulfur S8 in the presence of a tertiary amine as a base was found to catalyze efficiently a 6e- redox condensation of o-nitrophenols with acetophenones and methylquinolines. The condensed products 2-benzoylbenzoxazoles and 2-quinolylbenzoxazoles were obtained in reasonable yields with water as the only byproduct at a temperature as low as 80 °C.
RESUMEN
In our study, some newly synthesized aryl-substituted pyrazole derivatives mimicking cis-diphenylethylene scaffold of two apoptotic inducing agents celecoxib and combretastatin A-4 were found to have strong antiproliferative as well as antiinflammatory activities. Among these coxib-combretastatin hybrids, two lead compounds 8 and 6c simultaneously inhibited prostaglandin E2 (PGE2) production in LPS-activated murine macrophage RAW 264.7 cells and suppressed cell cycle progression of MCF7 cells at G2/M or G0/G1 phases, but only compound 8 induced apoptosis via caspase-3 activation. Both the lead compounds showed good docking energies with both protein targets COX-2 and tubulin in the molecule interaction modeling. The cis-diphenylethylene scaffold of celecoxib or combretastatin A-4 as well as functional groups such as the ethyl ester group and the sulfonamide could be considered as potential key features for the dual activity of studied compounds meanwhile the trimethoxybenzene remained the crucial characterization of the newly derived compounds of combretastatins.
Asunto(s)
BibencilosRESUMEN
In our efforts to discover novel multi-target agents having better antitumor activities than celecoxib, 21 new aryl-substituted pyrazole derivatives possessing cis-diphenylethylene scaffold were mostly synthesized by a one-pot approach to ethyl 1,4,5-triaryl-1H-pyrazole-3-carboxylates via an improved Claisen condensation - Knorr reaction sequence. The cytotoxic effects of these compounds against three human cancer cell lines HT-29, Hep-G2, MCF-7 as well as their inhibition of NO production were studied. Results showed that incorporation of the important pharmacophoric groups of two original molecules celecoxib and combretastatin A-4 in a single molecule plays an important role in determining a better biological activities of the new coxib-hybrided compounds.
Asunto(s)
Antineoplásicos/síntesis química , Bibencilos/química , Inhibidores de la Ciclooxigenasa 2/química , Diseño de Fármacos , Pirazoles/química , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Lipopolisacáridos/farmacología , Macrófagos/citología , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Ratones , Óxido Nítrico/metabolismo , Pirazoles/síntesis química , Pirazoles/farmacología , Células RAW 264.7RESUMEN
A new series of vinca-alkaloids derivatives containing various α,ß-unsaturated aromatic side chains was synthesized. Four new vinca-alkaloids derivatives showed selective cytotoxicities against KB tumor cell lines with IC50 value below 0.1 µM, thus comparable with vinblastine.
Asunto(s)
Antineoplásicos Fitogénicos/síntesis química , Antineoplásicos Fitogénicos/uso terapéutico , Neoplasias/tratamiento farmacológico , Vinblastina/uso terapéutico , Antineoplásicos Fitogénicos/química , Línea Celular Tumoral , Humanos , Concentración 50 Inhibidora , Estructura Molecular , Vinblastina/química , Alcaloides de la Vinca/químicaRESUMEN
In this Letter, we report a convenient and efficient method for the synthesis of new simplified derivatives of hemiasterlin in which the α,α-dimethylbenzylic moiety A is replaced by α,ß-unsaturated aryl groups as Michael acceptor. Most of these derivatives have a strong cytotoxic activity on three human tumor cell lines (KB, Hep-G2 and MCF7). Analogs 17b and 17f showed a high cytotoxicity against KB and Hep-G2 cancer cell lines comparable to paclitaxel and ellipticine.
Asunto(s)
Oligopéptidos/síntesis química , Ensayos de Selección de Medicamentos Antitumorales , Células Hep G2 , Humanos , Células KB , Células MCF-7 , Oligopéptidos/química , Oligopéptidos/farmacología , Relación Estructura-ActividadRESUMEN
In this Letter, the synthesis and the evaluation of the cytotoxicity of new hemiasterlin analogues were reported. The indole moiety was replaced respectively by benzofurane, naphthalene and 4-bromobenzene groups. Most of these derivatives possess strong cytotoxic activity on two human tumour cell lines (KB and Hep-G2), and some analogues showed comparable cytotoxic activity to that observed for paclitaxel and ellipticine, against KB and Hep-G2 cancer cell lines.
Asunto(s)
Citotoxinas/química , Citotoxinas/toxicidad , Oligopéptidos/química , Oligopéptidos/toxicidad , Muerte Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales/métodos , Células Hep G2 , Humanos , EstereoisomerismoRESUMEN
We disclose the synthesis of 3-arylquinoxalin-2-ones from o-phenylenediamines and readily available arylacetates. The method harnesses the selective oxidative property of elemental sulfur in the presence of amine base catalyst and DMSO. The reactions are operationally simple and tolerate a wide range of functional groups.
RESUMEN
Bis(3-indolyl)methanes (BIMs) are known for their important bioactivities, which include anti-cancer, anti-inflammatory, antibacterial, and antioxidant properties. In this study, we are disclosing a metal catalyst-free synthesis of BIMs in high yields via the alkylation reaction of indoles and alcohols in the presence of lithium tert-butoxide base. Notably, oxygen in air played an important role as an oxidant for the facilitation of this transformation. Interestingly, unactivated aliphatic alcohols could be successfully used as alkylating reagents in the alkylation reactions of indole. Especially, several chemical intermediates detected by GC-MS gave important information about the mechanism insights. This method demonstrated cost and environmental advantages for the development of green processes.
RESUMEN
Two new phenolic glycosides, 4-(3-hydroxypropyl)-2,6-dimethoxyphenol ß-D-apiofuranosyl-(1â6)-ß-D-glucopyranoside (1), trans-cinnamyl alcohol 9-O-(6'-O-ß-D-apiofuranosyl)-ß-D-glucopyranoside (2), together with nine known phenolic glycosides (3-11) were isolated from the roots of Pandanus tonkinensis. Their structures were determined by extensive analysis of HRESIMS and NMR spectral data, as well as by comparison of their spectral data (including CD spectra) with those reported in the literature. Compounds 1-4 and 6-11 inhibited NO production in LPS-activated RAW264.7 cells with IC50 values in the range from 0.80 ± 0.06 µM to 43.38 ± 3.92 µM, whereas compound 5 was inactive. The NO production inhibitory activities of compounds 1, 4, 8, and 10 with IC50 values of 10.16 ± 1.05, 0.80 ± 0.06, 1.10 ± 0.13, and 2.79 ± 0.21 µM, respectively, are as potent as that of the positive control of NG-monomethyl-L-arginine acetate (L-NMMA) with an IC50 value of 9.80 ± 0.78 µM.
RESUMEN
As frequently encountered byproducts of isocyanate chemistry, hydrogen sulfide and related sulfur containing compounds should be treated in a safe way to lower their adverse health and environmental effects, especially in large scale syntheses. As a proof of concept, we report herein an example of in situ recycling of sulfur byproduct to reductant in the synthesis of bioactive 2-aminobenzoxazoles 3. Using an Fe/S catalytic system, this heterocyclic scaffold could be obtained from o-nitrophenols 1 with isothiocyates 2 via direct redox condensation consisting of reduction of the nitro group of 1 by the sulfur moiety of 2.
Asunto(s)
Isotiocianatos , Nitrofenoles , Oxidación-Reducción , Azufre , Compuestos de Azufre , CatálisisRESUMEN
The ethylacetate extracts produced from the leaves of Stixis suaveolens (Roxb.) was characterized on the basis of NMR spectra combined with extensive mass spectroscopic techniques. The chemical characterization revealed presence of two new phenolic amides which were named as stixilamides A and B.
Asunto(s)
Amidas/aislamiento & purificación , Capparaceae/química , Hojas de la Planta/química , Amidas/química , Animales , Espectroscopía de Resonancia Magnética con Carbono-13 , Concentración 50 Inhibidora , Lipopolisacáridos/farmacología , Ratones , Óxido Nítrico/biosíntesis , Extractos Vegetales/química , Espectroscopía de Protones por Resonancia Magnética , Células RAW 264.7RESUMEN
Celecoxib is used widely for the acute treatment of pain and for pain relief in various diseases. Furthermore, it shows potential in chemoprevention, although chronic treatment with celecoxib could lead to adverse effects like cardiovascular events. New derivatives of celecoxib were synthesised that may be suitable as chemopreventive agent without inducing adverse effects. Critical endpoint for a safe use of pharmaceuticals is genotoxicity after application. A standard test for the assessment of genotoxicity is the cytokinesis-block micronucleus assay, that evaluates the number micronuclei after treatment of cells with a test compound as biomarker for DNA damage. Various promising derivatives of celecoxib have been assessed with the cytokinesis-block micronucleus assay in HeLa-H2B-GFP cells. It could be demonstrated, that neither celecoxib nor its derivatives were genotoxic in this assay and therefore celecoxib derivatives could be developed further for a safe use as chemopreventive agent.
RESUMEN
BACKGROUND: Vinca alkaloids are important cancer drugs belonging to the class of antimitotic agents. The most commonly used substances are vinblastine and vincristine, other compounds are vinorelbine and vinflunine. All of them are very effective drugs but their use is limited by severe side-effects including neurotoxicity and bone marrow depression. Therefore, it is very important to develop novel vinca alkaloids with similar efficacy but lower toxicity. METHODS: Here, we analyzed two new compounds, 4-chlorochablastine and 4-chlorochacristine, with regard to their biological activity. These novel compounds were applied to a leukemia cell line at clinically relevant concentrations. For comparison, the established vinca alkaloids vinblastine, vincristine, vinorelbine, and vinflunine were also tested. RESULTS: Both novel substances decreased cellular proliferation. Apoptosis was found to be increased using two different methods reflecting early and late apoptosis. Cell cycle analysis revealed a clear decrease in G1-cells and an increase in G2/M-cells indicating an arrest in mitosis. In general, 4- chlorochablastine and 4-chlorochacristine caused these effects at concentrations higher than those needed for vinblastine, vincristine, and vinorelbine, but the potency was approximately in the range of vinflunine. CONCLUSION: Taken together, the results show first indications that these novel vinca alkaloids might be effective and that they warrant further analysis.
Asunto(s)
Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/farmacología , Apoptosis , Proliferación Celular , Leucemia Promielocítica Aguda/patología , Alcaloides de la Vinca/química , Alcaloides de la Vinca/farmacología , Ciclo Celular , Humanos , Leucemia Promielocítica Aguda/tratamiento farmacológico , Células Tumorales CultivadasRESUMEN
This study characterized the carbon and phosphorus composition of buffalo manure, its compost and vermicompost and investigated if presence of bamboo biochar has an effect on their chemical and biological reactivity. The four substrates were characterized for chemical and biochemical composition and P forms. The biological stability of the four substrates and their mixtures were determined during an incubation experiment. Their chemical reactivity was analyzed after acid dichromate oxidation. Biological reactivity of these substrates was related to their soluble organic matter content, which decreased in the order buffalo manure>compost>vermicompost. Phosphorus was labile in all organic substrates and composting transformed organic P into plant available P. The presence of biochar led to a protection of organic matter against chemical oxidation and changed their susceptibility to biological degradation, suggesting that biochar could increase the carbon sequestration potential of compost, vermicompost and manure, when applied in mixture.
Asunto(s)
Carbón Orgánico/química , Estiércol/análisis , Oligoquetos/metabolismo , Fósforo/química , Suelo/química , Animales , Bambusa/química , Búfalos , Carbono/análisis , Compuestos Orgánicos , Oxidación-ReducciónRESUMEN
Nine simplified vinca alkaloids and phomospin A hybrids, in which vindoline moiety has been replaced by a simpler scaffold, have been elaborated to evaluate their activity on the inhibition of tubulin polymerization. This article deals with the synthesis of various simplified vinca alkaloids, using a stereoselective coupling of catharantine with reactive aromatic compounds and methanol as well as their subsequent condensation with a large peptide chain mimicking those of phomopsin A. Biological evaluation and molecular modeling studies are also reported.
Asunto(s)
Micotoxinas/química , Vinblastina/análogos & derivados , Alcaloides de la Vinca/química , Metanol/química , Micotoxinas/síntesis química , Estereoisomerismo , Termodinámica , Tubulina (Proteína)/química , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/síntesis química , Moduladores de Tubulina/química , Vinblastina/química , Alcaloides de la Vinca/síntesis química , Alcaloides de la Vinca/farmacologíaRESUMEN
Ten hybrids of vinca alkaloids and phomopsin A have been synthesized by linking the octahydrophomopsin lateral chain to the tertiary amine of the cleavamine moiety of anhydrovinblastine (AVLB) and vinorelbine. These compounds have been elaborated in order to obtain original products that may interfere with both binding sites of vinblastine (VLB) and phomopsin in tubulin. Although NMR and molecular modeling studies have shown that the orientation of the added peptide chains of these hybrids is not the same as those of phomopsin A, most of them are very potent inhibitors of microtubules assembly and they present good cytotoxicity against KB cell line. These interesting biological activities may eventually be explained by the fact that their lateral chain resides in a pocket distinct from that of the phomopsin A peptide, at the interface of tubulins beta and alpha.