RESUMO
A photocatalyst-free visible-light induced arylation of 2-aryl-2H-indazoles with aryl iodides has been developed for the first time to produce 3,2-diaryl-2H-indazoles in good to moderate yields. In this transformation, potassium tert-butoxide acts as an activator of the C-I bond and also as a scavenger of in situ generated HI in the reaction. This method exhibits high functional group tolerance with a wide substrate scope and it has been successfully applied to the synthesis of liver X receptor agonists and also for fluorescent probes. This is the first report on the photoarylation of 2-arylindazoles at the C3-position with aryl iodides under catalyst-free conditions.
RESUMO
Rhodium(III)-catalyzed [3 + 2]-spiroannulation of 2-aryl-1,4-benzoxazines with 4-hydroxy-2-alkynoates has been developed for the synthesis of highly rigid spirolactones in good yields with high regioselectivity. The reaction proceeds through a cascade of C-H activation followed by C-H annulation and lactonization. In this approach, two C-C and C-O bonds are formed in a single step. This is the first report on the spiroannulation of 2,3-dihydro-1,4-benzoxazines with 4-hydroxy-2-alkynoates.
RESUMO
An oxidative annulation of N-arylbenzimidamides with maleimides has been developed for the first time using a catalytic amount of the [Cp*RhCl2]2 complex for the synthesis of a diverse range of 1H-benzo[4,5]imidazo[2,1-a]pyrrolo[3,4-c]isoquinoline-1,3(2H)-dione derivatives. This method is versatile and atom-economical for producing polycyclic benzo[4,5]imidazo[2,1-a]pyrrolo[3,4-c] isoquinoline-1,3(2H)-dione scaffolds in a single step.
RESUMO
A chiral Cu(i)-bisoxazoline complex catalyzed enantioselective electrophilic fluorination of 3-indolinone-2-carboxylates with NFSI has been accomplished to produce chiral 2-fluoro-3-indolinone-2-carboxylates in good yields with excellent enantioselectivities. This is the first report on the enantioselective fluorination of 2-substituted 3-indolinones using a chiral Cu(i)-bisoxazoline complex.
RESUMO
The vital role played by microtubules in the cell division process, marks them as a potential druggable target to decimate cancer. A novel furan-2-carboxamide based small molecule, is a selective microtubule stabilizing agent (MSA) with IC50 ranging from 4 µM to 8 µM in different cancer cell lines. Inhibition of tubulin polymerization or stabilization of tubulin polymers abrogates chromosomal segregation during cell division, results in cell cycle arrest and leads to cell death due to the delayed repair mechanism. A novel furan-2-carboxamide based small molecule exhibited potent anti-proliferative and anti-metastatic property In-Vitro against the panel of cancer cells. Annexin V-FITC/PI, double staining reveals potent cytotoxic effect of SH09 against HeLa cells. FACS analysis displays induction of G2/M arrest and accumulation of subG1 population of cells upon treatment with SH09. Molecular docking study unveils SH09 binding affinity to the Taxol binding pocket of tubulin proteins and MM-GBSA also confirms strong binding energies of SH09 with tubulin proteins.
Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Furanos/farmacologia , Microtúbulos/efeitos dos fármacos , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Furanos/síntese química , Furanos/química , Humanos , Mitose/efeitos dos fármacos , Estrutura Molecular , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
Correction for 'A multi-component reaction for the synthesis of pyrido [1,2-b] isoquinoline derivatives via the [3 + 2] cycloaddition reaction between alkynes and in situ generated isoquinolinium ylides' by Sundar S. Shinde et al., Org. Biomol. Chem., 2019, 17, 4121-4128, DOI: 10.1039/C9OB00560A.
RESUMO
Diphenyl ether derivatives inhibit mycobacterial cell wall synthesis by inhibiting an enzyme, enoyl-acyl carrier protein reductase (InhA), which catalyses the last step in the fatty acid synthesis cycle of genus Mycobacterium. To select and validate a protein crystal structure of enoyl-acyl carrier protein reductase of Mycobacterium tuberculosis for designing inhibitors using molecular modelling, a cross-docking and correlation study was performed. A series of novel 1-(3-(3-hydroxy-4-phenoxyphenyl)-5-phenyl-4,5-dihydro-1H-pyrazol-1-yl) ethan-1-ones were synthesized from this model and screened for their antitubercular activity against M. tuberculosis H37Rv. Compound PYN-8 showed good antitubercular activity on M. tuberculosis H37Rv (MIC = 4-7 µM) and Mycobacterium bovis (% inhibition at 10 µM = 95.91%). Cytotoxicity of all the synthesized derivatives was assessed using various cell lines, and they were found to be safe. Structure of PYN-8 was also confirmed by single-crystal X-ray diffraction. The molecular modelling studies also corroborated the biological activity of the compounds. Further, in silico findings revealed that all these tested compounds exhibited good ADME properties and drug likeness and thus may be considered as potential candidates for further drug development.
Assuntos
Antituberculosos/síntese química , Antituberculosos/farmacologia , Éteres Fenílicos/síntese química , Éteres Fenílicos/farmacologia , Tuberculose/tratamento farmacológico , Proteínas de Bactérias/metabolismo , Linhagem Celular , Linhagem Celular Tumoral , Simulação por Computador , Cristalografia por Raios X , Desenho de Fármacos , Células HEK293 , Células HeLa , Humanos , Células MCF-7 , Testes de Sensibilidade Microbiana/métodos , Simulação de Acoplamento Molecular , Mycobacterium tuberculosis/efeitos dos fármacos , Células PC-3 , Relação Estrutura-Atividade , Tuberculose/metabolismoRESUMO
An efficient and one-pot tandem procedure for the synthesis of fused ethanopyrido [1,2-b] isoquinoline derivatives from ninhydrin, proline and alkynes has been developed. This strategy exhibits an unprecedented [3 + 2] cycloaddition reaction between alkynes and isoquinolinium ylide (1,3 dipole) generated in situ from proline and ninhydrin. This newly developed methodology features simple operation and is metal free. In this methodology overall three new C-C bonds, two C-N bonds, and three new rings are formed in a single step process.
RESUMO
Considering the importance of ultra-performance liquid chromatography-electrospray ionization-quadrupole time of flight-tandem mass spectrometry (UPLC-ESI-QTOF-MS/MS) hyphenated techniques for analysis of secondary metabolites from crude extracts, the present study was aimed at identification of secondary metabolites in acetone extract of the lichen Usnea longissima. From our study, 19 compounds were tentatively identified through comparison of exact molecular masses from their MS/MS spectra, mass fragmentation studies and comparison with literature data. In addition, potent cytotoxic activity of U. longissima extract prompted us to isolate four compounds, 18R-hydroxy-dihydroalloprotolichesterinic acid (19), neuropogolic acid (20), barbatic acid (21), and usnic acid (22) from this extract which were adequately identified through mass spectrometry and NMR spectroscopy. All four compounds displayed cytotoxic activity. Barbatic acid (21) manifested doxorubicin equivalent activity against A549 lung cancer cell line with IC50 of 1.78 µM and strong G0/G1 accumulation of cells. Poly ADP-ribose polymerase (PARP) cleavage confirmed that it induced cytotoxic activity via apoptosis. Finally, our work has discerned the depside, barbatic acid (21) from crude extract as a candidate anti-cancer molecule, which induces cell death by stepping up apoptosis.
Assuntos
Ascomicetos/efeitos dos fármacos , Ascomicetos/metabolismo , Cromatografia Líquida de Alta Pressão , Metabolômica , Ácidos Ftálicos/farmacologia , Metabolismo Secundário , Espectrometria de Massas por Ionização por Electrospray , Acetona , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular , Cromatografia Líquida de Alta Pressão/métodos , Relação Dose-Resposta a Droga , Humanos , Metabolômica/métodos , Conformação Molecular , Estrutura Molecular , Ácidos Ftálicos/química , Espectrometria de Massas por Ionização por Electrospray/métodosRESUMO
An intramolecular annulation strategy has been developed for the synthesis of tetrahydrobenzo[e]pyrano[4,3-c][1,2]thiazine derivatives by means of coupling of aldehydes with 2-(4-hydroxybut-1-yn-1-yl)-N-arylsulfonamides using a catalytic amount of silver hexafluoroantimonate in toluene at 80 °C. This is the first report on the synthesis of fused benzo-δ-sultam derivatives through C-N, C-O, and C-C bond formations. The reaction proceeds through a cascade of hydroamination and Prins type cyclization.
RESUMO
UNLABELLED: The occurrence of recurrent, unprovoked seizures is the hallmark of human epilepsy. Currently, only two-thirds of this patient population has adequate seizure control. New epilepsy models provide the potential for not only understanding the development of spontaneous seizures, but also for testing new strategies to treat this disorder. Here, we characterize a primary generalized seizure model of epilepsy following repeated exposure to the GABAA receptor antagonist, flurothyl, in which mice develop spontaneous seizures that remit within 1 month. In this model, we expose C57BL/6J mice to flurothyl until they experience a generalized seizure. Each of these generalized seizures typically lasts <30 s. We induce one seizure per day for 8 d followed by 24 h video-electroencephalographic recordings. Within 1 d following the last of eight flurothyl-induced seizures, â¼50% of mice have spontaneous seizures. Ninety-five percent of mice tested have seizures within the first week of the recording period. Of the spontaneous seizures recorded, the majority are generalized clonic seizures, with the remaining 7-12% comprising generalized clonic seizures that transition into brainstem seizures. Over the course of an 8 week recording period, spontaneous seizure episodes remit after â¼4 weeks. Overall, the repeated flurothyl paradigm is a model of epileptogenesis with spontaneous seizures that remit. This model provides an additional tool in our armamentarium for understanding the mechanisms underlying epileptogenesis and may provide insights into why spontaneous seizures remit without anticonvulsant treatment. Elucidating these processes could lead to the development of new epilepsy therapeutics. SIGNIFICANCE STATEMENT: Epilepsy is a chronic disorder characterized by the occurrence of recurrent, unprovoked seizures in which the individual seizure-ictal events are self-limiting. Remission of recurrent, unprovoked seizures can be achieved in two-thirds of cases by treatment with anticonvulsant medication, surgical resection, and/or nerve/brain electrode stimulation. However, there are examples in humans of epilepsy with recurrent, unprovoked seizures remitting without any intervention. While elucidating how recurrent, unprovoked seizures develop is critical for understanding epileptogenesis, an understanding of how and why recurrent, unprovoked seizures remit may further our understanding and treatment of epilepsy. Here, we describe a new model of recurrent, unprovoked spontaneous seizures in which the occurrence of spontaneous seizures naturally remits over time without any therapeutic intervention.
Assuntos
Convulsivantes/toxicidade , Flurotila/toxicidade , Convulsões/induzido quimicamente , Análise de Variância , Animais , Anticonvulsivantes/uso terapêutico , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Esquema de Medicação , Eletroencefalografia , Fluoresceínas/metabolismo , Hipocampo/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Convulsões/tratamento farmacológico , Convulsões/patologia , Fatores de Tempo , Gravação em VídeoRESUMO
A novel strategy has been developed for the synthesis of chromeno[3,4-b]pyrrol-4(3H)-one and substituted pyrrole derivatives through 1,5-electrocyclization of conjugated azomethine ylides. This is the first example of the preparation of highly substituted pyrrole derivatives from chromene-3-carboxaldehydes (non-enolizable aldehydes) and N-alkyl amino acids/esters. This method is simple and applicable to a diverse range of substrates.
RESUMO
An operationally facile and high yielding one-pot, three-component protocol has been developed for the preparation of selectively trans-2,3-dihydrofuro[3,2-c]coumarins and trans-1,2-dihydrobenzo[h]furo[3,2-c]quinolinones. This protocol proceeds through a domino Knoevenagel condensation, a Michael addition followed by intramolecular SN2 cyclisation. All the synthesized compounds have been evaluated for their in vitro cytotoxic activity against selected human cancer cell lines. Interestingly, most of the compounds have exhibited considerable cytotoxicity with IC50 values <10 µM in all the tested cell lines. Moreover, these compounds showed higher activity against MCF-7 (breast cancer) cell lines compared to other tested cell lines. Compounds 1g and 1r displayed significant cytotoxicity against all four tested cell lines. Cytotoxicity studies indicated that the toxicity of the synthesized compounds was considerably higher in tumor cells compared to normal cells. The structure-activity relationship studies revealed that the activating groups in these compounds preferably improved the activity compared to the deactivating groups. For a better understanding of the mechanism of action of these compounds, we performed the binding studies with calf thymus DNA (CT-DNA). Both molecular docking studies as well as biophysical studies indicate that these compounds may possess DNA binding affinity through intercalation. Through photocleavage studies, it is evident that they have the potential to cleave pBR322 plasmid DNA strands in a concentration and time dependent manner. In addition, compounds 1g and 1r showed significant topoisomerase II inhibitory activities. Moreover, an in silico study of these synthesized compounds revealed that they possess drug-like properties.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Cumarínicos/síntese química , Cumarínicos/farmacologia , DNA/química , Quinolonas/farmacologia , Animais , Antineoplásicos/química , Bovinos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cumarínicos/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Simulação de Acoplamento Molecular , Estrutura Molecular , Células NIH 3T3 , Quinolonas/síntese química , Quinolonas/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A novel bicyclization strategy has been developed for the stereoselective synthesis of bicyclic lactones, i.e. 7-aryl or alkyl-2,6-dioxabicyclo[3.3.1]nonan-3-ones through a domino cyclization of (R)-3-hydroxyhex-5-enoic acid with an aldehyde in the presence of 10 mol% trimethylsilyltriflate under mild conditions. The salient features of this methodology are high yields, excellent selectivity, low catalyst loading and faster reaction times. This method has been successfully applied to the total synthesis of pyranopyran, tetraketide and polyrhacitide A.
Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Cicloexanonas/síntese química , Dissacarídeos/síntese química , Lactonas/síntese química , Piranos/síntese química , Aldeídos/síntese química , Aldeídos/química , Compostos Bicíclicos Heterocíclicos com Pontes/química , Catálise , Ciclização , Cicloexanonas/química , Dissacarídeos/química , Lactonas/química , Modelos Moleculares , Piranos/química , Estereoisomerismo , Compostos de Trimetilsilil/síntese química , Compostos de Trimetilsilil/químicaRESUMO
A novel cascade strategy has been developed for the synthesis of tetrahydrospiro[chroman-2,4'-pyran] derivatives by condensation of aldehydes with 2-(5-hydroxy-3-methylenepentyl)phenol. The reaction proceeds smoothly in the presence of BF3·OEt2 under mild conditions in a highly stereoselective manner leading to a single diastereomer. This approach is simple and convenient for the synthesis of pharmacologically relevant spirochroman scaffolds.
RESUMO
An efficient and simple approach has been developed for the regio-selective synthesis of iodo-substituted dihydrofurans from amine substituted alkynols. The resulting iodo-substituted dihydrofurans have been further diversified by C-C couplings and C-N coupling reactions to afford a diverse range of substituted dihydrofuran derivatives.
RESUMO
A novel tandem cyclization strategy has been developed for the synthesis of hexahydro-1H-spiro[isoquinoline-4,4'-pyran] derivatives through the condensation of 3-((benzylamino)methyl)but-3-en-1-ol with aldehydes using BF3·OEt2. The reaction proceeds in a highly stereoselective manner, leading to a single diastereoisomer. This approach is a simple and efficient alternative for the synthesis of pharmacologically important spiroisoquinoline scaffolds.
Assuntos
Aldeídos/química , Boranos/química , Isoquinolinas/síntese química , Piranos/síntese química , Ciclização , Isoquinolinas/química , Estrutura Molecular , Piranos/química , EstereoisomerismoRESUMO
A domino cyclization of 3-((3-(2-aminophenyl)prop-2-ynylamino)methyl)but-3-en-1-ol with aldehydes has been accomplished employing 5 mol % of the Ph3PAuCl/AgSbF6/In(OTf)3 system to afford the corresponding octahydrospiro[pyran-4,4'-pyrido[3,4-b]indole] derivatives in good yields with high selectivity. This is the first report on the synthesis of spiro-ß-carbolines through a multicatalytic cascade process.
RESUMO
A domino reaction has been developed for the synthesis of oxygen bridged bicyclic ethers through the coupling of 4-(2-hydroxyethyl)cyclohex-3-enols with aldehydes in the presence of 10 mol% of molecular iodine in dichloromethane at 25 °C. This method is highly diastereoselective affording the corresponding bicyclic ethers, i.e. octahydro-4a,7-epoxyisochromenes in good yields with high selectivity. It is the first report on the synthesis of oxygen bridged bicyclic ethers using a domino Prins strategy.
Assuntos
Compostos Bicíclicos com Pontes/síntese química , Éteres/síntese química , Iodo/química , Oxigênio/química , Compostos Bicíclicos com Pontes/química , Catálise , Éteres/química , EstereoisomerismoRESUMO
A wide array of aldehydes undergo smooth cross-coupling with 3-hydroxy-3-(4-hydroxybut-1-en-2-yl)-1-methylindolin-2-one in the presence of 10 mol% BF3·OEt2 at 0 °C in dichloromethane to afford the corresponding 2,3,5,6-tetrahydro-1'H-spiro[pyran-4,4'-quinoline]-2',3'-dione derivatives in good yields with excellent diastereoselectivity. This is the first report on the synthesis of tetrahydro-1'H-spiro[pyran-4,4'-quinoline]-2',3'-dione scaffolds through a cascade of Prins/pinacol reactions.