RESUMO
We described a copper(I)-catalyzed atom economic and selective hydroamination-cyclization of alkynyl-tethered quinazolinones to prepare a variety of indole-fused pyrazino[1,2-a]quinazolinones in good to excellent yields ranging from 39% to 99% under mild reaction conditions. Control experiments revealed that coordination-directed method of quinazolinone moiety with copper(I) was important for the selective hydroamination-cyclization of alkynes at the N1-atom instead of N3-atom of quinazolinone. The reaction could be easily performed at gram scales and some prepared indole-fused pyrazino[1,2-a]quinazolinones with donating groups on the indole moiety showed a distinct fluorescence emission wavelength with blue shift under the acid conditions.
RESUMO
We described an iron(III) and BF3·OEt2-promoted oxygen transfer reaction of N-aryl-α,ß-unsaturated nitrones to prepare various N,O-difluoroboron ß-ketoiminates in good yields ranging from 24% to 87%. Control experiments revealed that the enaminone was the vital intermediate for the formation of N,O-difluoroboron ß-ketoiminates, and iron(III) combined with BF3·OEt2 played as cocatalyst to promote the oxygen transfer reaction through intramolecular cyclization and N-O bond cleavage. More importantly, an estrone-derived N,O-difluoroboron ß-ketoiminate was easily prepared in 40% yield from estrone in four steps.
RESUMO
A variety of 4-(trichloromethyl)pyrido[2',1':3,4]pyrazino[2,1-b]quinazolinones were prepared in moderate to good yields with high regioselectivity through intramolecular 6-endo-dig cyclization and trichloromethylation of N3-alkynyl-2-pyridinyl-tethered quinazolinones in chloroform. Mechanistic studies revealed that chloroform might serve as a trichloromethyl anion precursor. Furthermore, the reaction could be easily performed on gram scales and an estrone-derived 4-(trichloromethyl)pyrido[2',1':3,4]pyrazino[2,1-b]quinazolinone was prepared over five steps. The present method features broad substrate scope, good functional group tolerance, new dearomatization of pyridine rings, and chloroform as the trichloromethylation reagent.
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Herein, we described a copper(I)-catalyzed dearomatization of benzofurans with 2-(chloromethyl)anilines to prepare various tetrahydrobenzofuro[3,2-b]quinolines and 2-(quinolin-2-yl)phenols in good to excellent yields through radical addition and an intramolecular cyclization process. Mechanistic studies revealed that 2-(chloromethyl)anilines served as radical precursors. The present method features broad substrate scope, good functional group tolerance, quinoline scaffold diversity, and radical addition dearomatization of benzofurans.
RESUMO
Conventional topoisomerase (Topo) inhibitors typically usually exert their cytotoxicity by damaging the DNAs, which exhibit high toxicity and tend to result in secondary carcinogenesis risk. Molecules that have potent topoisomerase inhibitory activity but involve less DNA damage provide more desirable scaffolds for developing novel chemotherapeutic agents. In this work, we broke the rigid pentacyclic system of luotonin A and synthesized thirty-three compounds as potential Topo inhibitors based on the devised molecular motif. Further investigation disclose that two compounds with the highest antiproliferation activity against cancer cells, 5aA and 5dD, had a distinct Topo I inhibitory mechanism different from those of the classic Topo I inhibitors CPT or luteolin, and were able to obviate the obvious cellular DNA damage typically associated with clinically available Topo inhibitors. The animal model experiments demonstrated that even in mice treated with a high dosage of 50 mg/kg 5aA, there were no obvious signs of toxicity or loss of body weight. The tumor growth inhibition (TGI) rate was 54.3 % when 20 mg/kg 5aA was given to the T24 xenograft mouse model, and 5aA targeted the cancer tissue precisely without causing damage to the liver and other major organs.
Assuntos
Antineoplásicos , Neoplasias , Humanos , Animais , Camundongos , Antineoplásicos/farmacologia , Quinonas , Pirróis , Inibidores da Topoisomerase I/farmacologia , Inibidores da Topoisomerase I/uso terapêutico , Dano ao DNA , DNA Topoisomerases Tipo I/metabolismo , Inibidores da Topoisomerase II/farmacologia , DNA Topoisomerases Tipo II , Linhagem Celular TumoralRESUMO
A variety of spirooxindole-1,2-oxazinan-5-one derivatives were prepared in moderate to excellent yields through 2,2,2-trifluoroethanol (TFE)-promoted [3 + 3] cycloaddition of N-vinyl oxindole nitrones with oxyallyl cations generated from α-tosyloxy ketones under mild reaction conditions. Mechanistic studies revealed that [3 + 3] cycloaddition might involve two possible reaction pathways, including direct [3 + 3] cycloaddition of N-vinyl oxindole ntirones with oxyallyl cations, or the addition of TFE to N-vinyl oxindole nitrones, sequential addition to oxyallyl cations, elimination, and cyclization. The present method features mild reaction conditions, broad substrate scope, good functional group tolerance, easy gram scalable preparation, and new applications of TFE.
RESUMO
Pseudo-natural products (PNPs) design strategy provides a great valuable entrance to effectively identify of novel bioactive scaffolds. In this report, novel pseudo-rutaecarpines were designed via the combination of several privileged structure units and 46 target compounds were synthesized. Most of them display moderate to potent inhibitory effect on LPS-induced NO production and low cytotoxicity in RAW264.7 macrophage. The results of the anti-inflammatory efficacy and action mechanism of compounds 7l and 8c indicated that they significantly reduced the release of IL-6, IL-1ß and TNF-α. Further studies revealed that they can strongly inhibit the activation of NF-κB and MAPK signal pathways. The LPS-induced acute liver injury mice model studies not only confirmed their anti-inflammatory efficacy in vivo but also could effectively relieve the liver injury in mice. The results suggest that compounds 7l and 8c might serve as lead compounds to develop therapeutic drugs for treatment of inflammation.
Assuntos
Lipopolissacarídeos , NF-kappa B , Animais , Camundongos , NF-kappa B/metabolismo , Lipopolissacarídeos/farmacologia , Células RAW 264.7 , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Fígado/metabolismoRESUMO
A variety of 1,2,4-oxadiazoline derivatives were synthesized in moderate to good yields through a deoxygenative cyclization cascade reaction of N-vinyl-α,ß-unsaturated nitrones and hydroxamoyl chlorides. Mechanistic studies revealed that the reaction underwent double additions of nitrile oxides to N-vinyl-α,ß-unsaturated nitrones, sequential elimination, and intramolecular cyclization to afford 1,2,4-oxadiazolines. Alternatively, 1,2,5-oxadiazolines were also obtained as major products in i-PrOH solvent through [3 + 3] cycloaddition and selective [3,3]-rearrangement. Moreover, the prepared 1,2,4-oxadiazolines were easily converted to polysubstituted pyrroles under thermal conditions.
RESUMO
A variety of tetrahydro-5H-indolo[2,3-b]quinolines were prepared in 40-97% yields through a copper(II)-catalyzed cascade reaction of aza-o-quinone methides generated in situ from 2-(chloromethyl)anilines and indoles. Experimental results showed that the reaction underwent double 1,4-additions and sequential intramolecular cyclization. The present method features broad substrate scope, good functional group tolerance, and easy gram scalable preparation of indolo[2,3-b]quinolines.
Assuntos
Indóis , Quinolinas , Indóis/química , Estrutura Molecular , Cobre/química , Quinolinas/química , CatáliseRESUMO
A variety of azetidine nitrones are prepared in moderate to good yields through copper(I) combined with 2-aminopyridine to catalyze skeletal rearrangement of O-propargylic oximes. Mechanistic studies reveal that the reaction undergoes a copper(I)-catalyzed tandem [2,3]-rearrangement, 4π-electrocyclization, ring opening, and recyclization over four steps in one pot. Substituents at the terminus of alkyne and oxime moieties have a significant impact on the formation of azetidine nitrones and exomethylene oxazolines, respectively. Furthermore, the obtained azetidine nitrone could easily participate in [3 + 2] cycloaddition with alkynoates, and a [2.2]-paracyclophane-derived azetidine nitrone is synthesized in 45% yield over five steps from bromo[2.2]-paracyclophane.
Assuntos
Azetidinas , Cobre , Óxidos de Nitrogênio , Oximas , CatáliseRESUMO
A type of quinoxaline-derived tridentate N,N,O-ligand was synthesized in good to excellent yields over three steps through iodination of 2-aryl indoles, sequential Kornblum-type oxidation with DMSO, and capture by 1,2-diaminobenzenes. The prepared atropisomeric N,N,O-ligand was successfully applied in the synthesis of N-vinyl cinnamaldehyde nitrones as only Z-isomers in good yields through the Chan-Lam reaction. The method features an easily accessed tunable tridentate N,N,O-ligand, broad substrate scope, good functional group tolerance, and high Z-isomer for N-vinyl nitrones.
RESUMO
As one of the most important structural units in pharmaceuticals and medicinal chemistry, quinazolinone and its derivatives exhibit a wide range of biological and pharmacological activities, including anti-inflammatory, antitubercular, antiviral, and anticancer activities, etc. In particular, 2,3-fused quinazolinones have attracted much attention because the rings fused to the 2,3-positions of quinazolinones improve their rigidity and planarity. Their synthetic strategies have made great advances in recent years. Therefore, this review focuses on novel strategies for the synthesis of 2,3-fused quinazolinone derivatives from 2017 to 2022, such as the difunctionalization of alkenes, the ring-opening of easily available small rings, dehydrogenative cross-coupling reactions, transition-metal catalyzed cyclizations, cycloadditions, and other cascade reactions.
Assuntos
Química Farmacêutica , Quinazolinonas , Reação de Cicloadição , Quinazolinonas/químicaRESUMO
A variety of oxazabicyclo[4.2.1]nonanone derivatives were prepared in good yields through a cinchonidine-catalyzed cascade reaction of N-aryl-α,ß-unsaturated nitrones and 1-ethynylnaphthalen-2-ols. Mechanistic studies show that the reaction undergoes a [4 + 3] cycloaddition of nitrones to vinylidene o-quinone methide generated in situ from 1-ethynylnaphthalen-2-ols in the presence of cinchonidine, 1,3-rearrangement of N-O vinyl moieties, ring-opening, and finally double intramolecular cyclizations to afford oxazabicyclo[4.2.1]nonanones over five steps in a one-pot reaction.
RESUMO
We describe the difunctionalization of arylboronic acids to prepare various N-(2-hydroxyaryl)pyridin-2-ones in good yields using N-hydroxypyridin-2-ones as the oxygen and nitrogen sources through a copper(II)-catalyzed Chan-Lam reaction and subsequent BF3-promoted selective 1,3-rearrangement of N-O bond in a one-pot procedure. Mechanistic studies reveal that the 1,3-rearrangement selectivity is controlled by the formation of the key aryloxypyridinium salt. The obtained products are easily converted to various useful pyridin-2-one scaffolds.
RESUMO
A variety of functionalized spiroindolenine-3,3'-pyrrolo[2,1-b]quinazolinones were prepared in good to excellent yields through a gold(I)-catalyzed dearomative cyclization of N-alkynyl quinazolinone-tethered C2-substituted indoles. This reaction features a broad substrate scope, good functional group tolerance, and easy gram-scale preparation and transformations. Furthermore, biological activity studies showed that most of the obtained spiroindolenine-3,3'-pyrrolo[2,1-b]quinazolinone scaffolds showed potential as good anti-inflammatory agents.
RESUMO
A variety of functionalized sulfonium ylides were prepared in good yields through MnSO4-promoted S-O bond cleavage from activated alkynes and sulfoxides. Experimental results showed that the MnSO4 catalyst played important roles in accelerating the reaction and promoting the [1,3]-rearrangement of the S-O bond. Furthermore, the product was easily obtained on a gram scale by simple recrystallization without column chromatography. The obtained product can be converted to new sulfonium ylides and undergo cycloaddition with an alkyne to afford a trisubstituted furan scaffold.
RESUMO
We describe a P-containing palladacycle-catalyzed regioselective Heck reaction of 2,3-dihydrofuran with diaryliodonium salts and aryl iodides to afford 2-aryl-2,5-dihydrofurans and 2-aryl-2,3-dihydrofurans, respectively, in good yields. Mechanistic studies revealed that the oxidative addition of diaryliodonium salts to palladacycles to form Pd(IV) species showed high chemoselectivity and that electron-rich aryl moieties were preferentially transferred to the Heck product. DFT calculations indicated that the regioselectivity-determining step is the reductive elimination reaction rather than the isomerization and reinsertion of Pd(IV)-hydride intermediates into the double bond.
RESUMO
A variety of N-vinylindoles and N-vinylpyrroles were prepared in moderate to good yields through the nickel(II)-catalyzed [3 + 2] cycloaddition of α,ß-unsaturated nitrones with allenoates under mild reaction conditions. A rational mechanism for the formation of N-vinylindoles was proposed based on the 18O-labeled experiments and key intermediates detected by high-resolution mass spectrometry trace experiments. The present method highlights a nickel(II)-controlled cyclization, atom-economical reaction, broad substrate scope, good functional group tolerance, and high Z-stereoselectivity for the enamine bond.
RESUMO
Thirty-eight new 3-arylaminoquinoxaline-2-carboxamide derivatives were in silico designed, synthesized and their cytotoxicity against five human cancer cell lines and one normal cells WI-38 were evaluated. Molecular mechanism studies indicated that N-(3-Aminopropyl)-3-(4-chlorophenyl) amino-quinoxaline-2-carboxamide (6be), the compound with the most potent anti-proliferation can inhibit the PI3K-Akt-mTOR pathway via down regulating the levels of PI3K, Akt, p-Akt, p-mTOR and simultaneously inhibit the phosphorylation of Thr308 and Ser473 residues in Akt kinase to servers as a dual inhibitor. Further investigation revealed that 6be activate the P53 signal pathway, modulated the downstream target gene of Akt kinase such p21, p27, Bax and Bcl-2, caused the fluctuation of intracellular ROS, Ca2+ and mitochondrial membrane potential to induce cell cycle arrest and apoptosis in MGC-803 cells. 6be also display moderate anti-tumor activity in vivo while displaying no obvious adverse signs during the drug administration. The results suggest that 3-arylaminoquinoxaline-2-carboxamide derivatives might server as new scaffold for development of PI3K-Akt-mTOR inhibitor.
Assuntos
Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Quinoxalinas/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Proteína Supressora de Tumor p53/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Estrutura Molecular , Proteínas Proto-Oncogênicas c-akt/metabolismo , Quinoxalinas/síntese química , Quinoxalinas/química , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade , Serina-Treonina Quinases TOR/metabolismoRESUMO
A variety of tetrahydroquinoline-fused bicycles bearing multiple stereocenters are prepared in good yields with high diastereoselectivity through Cu2O-catalyzed [4 + 2] cycloaddition of aza-ortho-quinone methides (ao-QMs) with bicyclic alkenes. Mechanistic studies reveal that the Cu(i) catalyst not only promotes the formation of ao-QMs through a radical process by single electron transfer but also accelerates [4 + 2] cycloaddition. The reaction was easily performed on gram scale and the obtained tetrahydroquinoline-fused bicycles can be converted to diverse tetrahydroquinoline scaffolds.