RESUMO
A visible-light-induced radical cascade regioselective acylation/cyclization of 1,7-dienes with acyl oxime esters for the preparation of acylation polycyclic compounds via NCR-mediated C-C σ-bond cleavage is established. The transformation involves the cleavage of the C-C σ-bond in acyl oxime esters and selective addition of the electron neutral CâC bonds in 1,7-dienes for the synthesis of acyl polycyclic quinolinone derivatives, not the traditional seven-membered ring products. The strategy offers several advantages, including broad substrate tolerance, no need for bases, hyperstoichiometric radical initiators, and other auxiliaries.
RESUMO
A novel strategy for the difunctionalization of electron-deficient alkenes with aryl sulfonium salts to access remote sulfur-containing oxindole derivatives by using in situ-formed copper(I)-based complexes as a photoredox catalyst is presented. This method enables the generation of the C(sp3)-centered radicals through site selective cleavage of the C-S bond of aryl sulfonium salts under mild conditions. Moreover, the oxidation reactions of desired products provide a new strategy for the preparation of sulfoxide or sulfone-containing compounds. Importantly, this approach can be easily applied to late-stage modification of pharmaceuticals molecules.
RESUMO
An oxidant-assisted tandem sulfonylation/cyclization of electron-deficient alkenes with 4-alkyl-substituted Hantzsch esters and Na2S2O5 for the preparation of 3-alkylsulfonylated oxindoles under mild conditions in the absence of a photocatalyst and transition metal catalyst is established. The mechanism studies show that the alkyl radicals, which come from the cleavage of the C-C bond in 4-substituted Hantzsch esters under oxidant conditions, subsequently undergo the in situ insertion of sulfur dioxide to generate the crucial alkylsulfonyl radical intermediates. This three-component reaction provides an efficient and facile route for the construction of alkylsulfonylated oxindoles and avoids the use of highly toxic alkylsulfonyl chlorides or alkylsulfonyl hydrazines as alkylsulfonyl sources.
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2-Aminobenzothiazoles are commonly encountered in various functional compounds. Herein, we disclose an electro-oxidative three-component reaction for the effective synthesis of 2-aminobenzothiazoles under mild conditions, utilizing non-toxic and abundant elemental sulfur as the sulfur source. Both aliphatic amines and aryl amines demonstrate good compatibility at room temperature, highlighting the broad functional group tolerance of this approach. Additionally, elemental selenium demonstrated reactivities comparable to those of elemental sulfur.
RESUMO
An efficient strategy for visible-light-promoted decarboxylative alkylation of vinylcyclopropanes with alkyl N-(acyloxy)phthalimide esters through the dual C-C bond and single N-O bond cleavage, employing triphenylphosphine and lithium iodide as the photoredox system to synthesize 2-alkylated 3,4-dihydronaphthalenes, has been established. This alkylation/cyclization involves a radical process and undergoes a sequence of N-(acyloxy)phthalimide ester single-electron reduction, N-O bond cleavage, decarboxylative, alkyl radical addition, C-C bond cleavage, and intramolecular cyclization. Moreover, using the photocatalyst Na2-Eosin Y instead of triphenylphosphine and lithium iodide, the vinyl transfer products are acquired when vinylcyclobutanes or vinylcyclopentanes are utilized as alkyl radical receptors.
Assuntos
Iodetos , Lítio , Ciclização , Alquilação , Ésteres , FtalimidasRESUMO
Cyclobutanone oximes and their derivatives are pivotal core structural motifs in organic chemistry. Iminyl-radical-triggered C-C bond cleavage of cyclobutanone oximes delivers an efficient strategy to produce stable distal cyano-substituted alkyl radicals, which can capture SO2, CO or O2 to form cyanoalkylsulfonyl radicals, cyanoalkylcarbonyl radicals or cyanoalkoxyl radicals under mild conditions. In the past several years, cyanoalkylsulfonylation/cyanoalkylcarbonyaltion/cyanoalkoxylation has attracted a lot of interest. In this updated report, the strategies for trapping SO2, CO or O2via iminyl-radical-triggered ring-opening of cyclobutanone oximes are summarized.
RESUMO
A new biocatalyst PCL@UiO-67(Zr) was successfully synthesized by immobilized lipases on metal-organic frameworks (MOFs) materials. Compare with free lipases, zirconium foundation organic framework material UiO-67(Zr) modification on immobilized lipases Pseudomonas cepacia lipase (PCL) great boosts their enantioselectivity in the kinetic resolution racemic 4-chloro-mandelic acid (4-ClMA) on the organic solvent. The acquired bio-composite PCL@UiO-67(Zr) was fully characterized by powder X-ray diffraction (PXRD), Fourier transform infrared (FT-IR) spectroscopy, N2 adsorption-desorption isotherm and aperture distribution map, and scanning electron microscopy (SEM). The catalytic performance of PCL@UiO-67(Zr), such as temperature, reaction time, and lipase quantity, were deeply explored. The experiment results showed resolution racemic 4-ClMA optimum conditions that 20 mmol/L of (R, S)-4-chloromandelic acid, 120 mmol/L vinyl acetate, 30-mg immobilized lipases PCL@UiO-67(Zr), 2 mL of MTBE, 500 rpm, and under the 55°C reaction 18 h. In this optimum conditions, c and eep could reach up to 47.6% and 98.7%, respectively.
Assuntos
Estruturas Metalorgânicas , Estruturas Metalorgânicas/química , Zircônio/química , Lipase/química , Espectroscopia de Infravermelho com Transformada de Fourier , Estereoisomerismo , SolventesRESUMO
A copper-catalyzed remote benzylic C-H functionalization strategy enabling 1,2-difunctionalization of alkenes with 2-methylbenzeneamides and nucleophiles, including alcohols, indoles, pyrroles, and the intrinsic amino groups, is reported, which is characterized by its redox-neutral conditions, exquisite site-selectivity, broad substrate scope, and wide utilizations of late-stage modifying bioactive molecules. This reaction proceeds through nitrogen-centered radical generation, hydrogen atom transfer, benzylic radical addition across the alkenes, single-electron oxidation, and carbocation electrophilic course cascades. While using external nucleophiles manipulates three-component alkene alkylalkoxylation and alkyl-heteroarylation with 2-methylbenzeneamides to access dialkyl ethers, 3-alkylindoles, and 3-alkylpyrroles, omitting the external nucleophiles results in two-component alkylamidation ([5+2] annulation) of alkenes with 2-methylbenzeneamides to benzo-[f][1,2]thiazepine 1,1-dioxides.
RESUMO
A new protocol is herein described for the direct generation of alkylated indolo/benzoimidazo[2,1-a]isoquinolin-6(5H)-one derivatives by using Hantzsch esters as alkylation radical precursors using a photoredox/K2S2O8 system. This oxidative alkylation of active alkenes involves a radical cascade cyclization process and a sequence of Hantzsch ester single electron oxidation, C-C bond cleavage, alkylation, arylation and oxidative deprotonation.
RESUMO
An efficient photocatalytic dual decarboxylative alkenylation of α,ß-unsaturated carboxylic acids and alkyl N-hydroxyphthalimide (NHP) esters mediated by triphenylphosphine and sodium iodide has been developed. This protocol proceeds under 456-nanometer irradiation by visible blue light in the absence of transition metals or organic dye based photoredox catalysts. The reaction is successfully applied to a wide range of redox-active esters derived from aliphatic carboxylic acids (1°, 2° and 3°) and α-amino acids, enabling transformations of diverse α,ß-unsaturated carboxylic acids to α,ß-alkylated styrenes with high efficiency and excellent selectivity under mild conditions.
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Acute myeloid leukemia (AML) is the most common form of acute leukemia with dismal long-term prognosis with age. The most aggressive subtype of AML is MLL-AML that is characterized by translocations of the mixed-lineage leukemia gene (MLL) and resistance to conventional chemotherapy. Cyclin dependent kinase 9 (CDK9) plays a crucial role in the MLL-driven oncogenic transcription, and hence, inhibiting activity of CDK9 has been proposed as a promising strategy for treatment of AML. We investigated the therapeutic potential of CDKI-73, one of the most potent CDK9 inhibitors, against a panel of AML cell lines and samples derived from 97 patients. CDKI-73 induced cancer cells undergoing apoptosis through transcriptional downregulation of anti-apoptotic proteins Bcl-2, Mcl-1 and XIAP by majorly targeting CDK9. Contrastively, it was relatively low toxic to the bone marrow cells of healthy donors. In MV4-11 xenograft mouse models, oral administration of CDKI-73 resulted in a marked inhibition of tumor growth (p < 0.0001) and prolongation of animal life span (P < 0.001) without causing body weight loss and other overt toxicities. The study suggests that CDKI-73 can be developed as a highly efficacious and orally deliverable therapeutic agent for treatment of AML.
Assuntos
Antineoplásicos/uso terapêutico , Quinase 9 Dependente de Ciclina/antagonistas & inibidores , Leucemia Mieloide Aguda/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Sulfonamidas/uso terapêutico , Administração Oral , Adulto , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Disponibilidade Biológica , Células da Medula Óssea/efeitos dos fármacos , Linhagem Celular Tumoral , Feminino , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , Sulfonamidas/farmacocinética , Sulfonamidas/farmacologia , Carga Tumoral/efeitos dos fármacosRESUMO
As the magic methyl effect is well acknowledged in pharmaceutical molecules, the development of simple and efficient methods for the installment of methyl groups on complex molecules is highly coveted. Hence, we provide a general strategy for radical cascade cyclization of N-(o-cyanobiaryl)acrylamides by utilizing sulfonium salts as the sources of methyl radical and merging photoredox and copper catalysis. This novel protocol can access a wide variety of methylation or remote thioether-substituted benzo-fused N-heterocycle derivatives, which can be easily transformed into diverse highly valuable sulfone and sulfoximine compounds via late-stage diversification. Moreover, to further demonstrate the synthetic utility of this conversion, the methyl(phenyl)sulfide, which serves as both raw material and byproduct, can be recovered and reused in this transformation. The scale-up experiment for the one-pot two-step process directly offers the target product in good yield under the standard conditions.
RESUMO
A convenient method for oxidant-promoted radical cascade acylation or decarbonylative alkylation of 1,7-dienes with aldehydes has been established. This method allows for the rapid construction of N-containing polycyclic skeletons in a highly regio- and stereoselective manner. This transformation provides a simple and efficient method for the preparation of a range of tetrahydro-6H-indeno[2,1-c]quinolinone derivatives by sequential formation of three new carbon-carbon bonds. Additionally, this radical cascade cyclization can selectively convert aldehydes into aroyl/primary aliphatic acyl radicals and secondary or tertiary alkyl radicals.
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A visible-light-induced radical alkylarylation of N-aryl bicyclobutyl amides with α-carbonyl alkyl bromides for the synthesis of functionalized 3-spirocyclobutyl oxindoles is described in which ß-selective radical addition of the alkyl radical to N-aryl bicyclobutyl amides forms a key radical intermediate followed by interception with intrinsic arene functional group. This approach can be applicable to a wide range of α-carbonyl alkyl bromides, including primary, secondary, and tertiary α-bromoalkyl esters, ketones, nitriles, and nitro compounds.
RESUMO
Praziquantel, the only drug in clinical use for the treatment and control of schistosomiasis, is inactive against developing infections. Ozonides are synthetic peroxide derivatives inspired by the naturally occurring artemisinin and show particularly promising activity against juvenile schistosomes. We conducted an in-depth characterization of the in vitro and in vivo antischistosomal activity and pharmacokinetics of lead ozonide carboxylic acid OZ418 and four of its active analogs. In vitro, the ozonides featured rapid and consistent activity against schistosomula and adult schistosomes at double-digit micromolar EC50 values. Potency did not vary considerably between Schistosoma spp. The zwitterionic OZ740 and OZ772 were more active in vivo compared to their non-amphoteric carboxylic acids OZ418 and OZ748, despite their much lower systemic plasma exposure (AUC). The most active compound in vivo was ethyl ester OZ780, which was rapidly transformed to its parent zwitterion OZ740 and achieved ED50 values of 35 ± 2.4 and 29 ± 2.4 mg/kg against adult and juvenile Schistosoma mansoni, respectively. Ozonide carboxylic acids represent promising candidates for further optimization and development due to their good efficacy against both life stages together with their broad activity range against all relevant parasite species.
Assuntos
Compostos Heterocíclicos , Esquistossomose , Animais , Ácidos Carboxílicos , Schistosoma mansoni , Esquistossomose/tratamento farmacológicoRESUMO
We discovered dibenzannulated medium-ring keto lactams (11,12-dihydro-5H-dibenzo[b,g]azonine-6,13-diones) as a new antimalarial chemotype. Most of these had chromatographic LogD7.4 values ranging from <0 to 3 and good kinetic solubilities (12.5 to >100 µg/mL at pH 6.5). The more polar compounds in the series (LogD7.4 values of <2) had the best metabolic stability (CLint values of <50 µL/min/mg protein in human liver microsomes). Most of the compounds had relatively low cytotoxicity, with IC50 values >30 µM, and there was no correlation between antiplasmodial activity and cytotoxicity. The four most potent compounds had Plasmodium falciparum IC50 values of 4.2 to 9.4 nM and in vitro selectivity indices of 670 to >12,000. They were more than 4 orders-of-magnitude less potent against three other protozoal pathogens (Trypanosoma brucei rhodesiense, Trypanosoma cruzi, and Leishmania donovani) but did have relatively high potency against Toxoplasma gondii, with IC50 values ranging from 80 to 200 nM. These keto lactams are converted into their poorly soluble 4(1H)-quinolone transannular condensation products in vitro in culture medium and in vivo in mouse blood. The similar antiplasmodial potencies of three keto lactam-quinolone pairs suggest that the quinolones likely contribute to the antimalarial activity of the lactams.
Assuntos
Antimaláricos , Quinolonas , Trypanosoma cruzi , Camundongos , Animais , Humanos , Antimaláricos/farmacologia , Antimaláricos/química , Lactamas , Trypanosoma brucei rhodesienseRESUMO
Novel 3,3'-disubstituted-5,5'-bi(1,2,4-triazine) compounds with potent in vitro activity against Plasmodium falciparum parasites were recently discovered. To improve the pharmacokinetic properties of the triazine derivatives, a new structure-activity relationship (SAR) investigation was initiated with a focus on enhancing the metabolic stability of lead compounds. These efforts led to the identification of second-generation highly potent antimalarial bis-triazines, exemplified by triazine 23, which exhibited significantly improved in vitro metabolic stability (8 and 42 µL/min/mg protein in human and mouse liver microsomes). The disubstituted triazine dimer 23 was also observed to suppress parasitemia in the Peters 4-day test with a mean ED50 value of 1.85 mg/kg/day and exhibited a fast-killing profile, revealing a new class of orally available antimalarial compounds of considerable interest.
Assuntos
Antimaláricos/uso terapêutico , Malária/tratamento farmacológico , Triazinas/uso terapêutico , Animais , Antimaláricos/síntese química , Antimaláricos/farmacocinética , Células CACO-2 , Feminino , Humanos , Masculino , Camundongos Endogâmicos NOD , Camundongos SCID , Microssomos Hepáticos/efeitos dos fármacos , Estrutura Molecular , Testes de Sensibilidade Parasitária , Plasmodium berghei/efeitos dos fármacos , Plasmodium falciparum/efeitos dos fármacos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Triazinas/síntese química , Triazinas/farmacocinéticaRESUMO
A visible light initiated α-C(sp3)-H arylation of N-(benzyloxy)phthalimides with cyanopyridines for the construction of highly valuable pyridinyl-containing diarylmethanols, including bioactive motif-based analogues, is reported. This method enables arylation of the C(sp3)-H bonds adjacent to an oxygen atom through alkoxy radical formation by O-N bond cleavage, 1,2-hydrogen atom transfer (HAT), arylation and C-CN bond cleavage cascades, and offers a means to exploit 1,2-HAT modes to incorporate functional groups for constructing functionalized alcohols.
RESUMO
Colorectal cancer (CRC) remains one of the most lethal human malignancies, and pursuit of new therapeutic targets for treatment has been a major research focus. Cyclin-dependent kinase 9 (CDK9), which plays a crucial role in transcription, has emerged as a target for cancer treatment. CDKI-73, one of the most potent and pharmacologically superior CDK9 inhibitors, has demonstrated excellent anti-tumour efficacy against several types of cancers. In this study, we evaluated its therapeutic potential against CRC. CDKI-73 elicited high cytotoxicity against all colon cancer cell lines tested. Cell cycle and apoptosis analysis in HCT 116 and HT29 cells revealed that CDKI-73 induced cell death without accumulation of DNA at any phase of the cell cycle. Moreover, it caused depolarisation of mitochondrial membrane, leading to caspase-independent apoptosis. Knockdown by shRNA demonstrated the CDK9-targeted mechanism of CDKI-73, which also affected the Mnk/eIF4E signalling axis. In addition, RT-qPCR analysis showed that CDKI-73 down-regulated multiple pro-survival factors at the mRNA level. Its in vivo anti-tumour efficacy was further evaluated in Balb/c nude mice bearing HCT 116 xenograft tumours. CDKI-73 significantly inhibited tumour growth (***P < 0.001) without overt toxicity. Analysis of the tumour tissues collected from the xenografted animals confirmed that the in vivo anti-tumour efficacy was associated with CDK9 targeting of CDKI-73. Overall, this study provides compelling evidence that CDKI-73 is a promising drug candidate for treating colorectal cancer.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Quinase 9 Dependente de Ciclina/antagonistas & inibidores , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Sulfonamidas/uso terapêutico , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/metabolismo , Quinase 9 Dependente de Ciclina/metabolismo , Feminino , Células HCT116 , Células HT29 , Humanos , Camundongos Endogâmicos BALB C , Camundongos Nus , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Sulfonamidas/farmacologiaRESUMO
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Mycophenolic acid (MPA) undergoes enterohepatic circulation (EHC) in the body and several population models have been proposed to describe this process using sparse data. Recent studies in Whites have found that polymorphism in UGT1A9 could partly explain the large interindividual variability associated with the pharmacokinetics of MPA. WHAT THIS STUDY ADDS: A new population pharmacokinetic model for EHC combining MPA and its main glucuronide metabolite (MPAG) simultaneously was established based on physiological aspects of biliary excretion using intensive sampling data. Pharmacokinetic profiles of MPA and MPAG with the UGT1A9 polymorphism in healthy Chinese were characterized. AIMS To establish a population pharmacokinetic model that describes enterohepatic circulation (EHC) of mycophenolic acid (MPA) based on physiological considerations and to investigate the influence of polymorphisms of UGT1A9 on the pharmacokinetics of MPA. METHODS: Pharmacokinetic data were obtained from two comparative bioavailability studies of oral mycophenolic mofetil formulations. Nonlinear mixed effects modelling was employed to develop an EHC model including both MPA and its main glucuronide metabolite (MPAG) simultaneously. Demographic characteristics and UGT1A9 polymorphisms were screened as covariates. RESULTS: In total, 590 MPA and 589 MPAG concentration-time points from 42 healthy male volunteers were employed in this study. The chain compartment model included an intestinal compartment, a gallbladder compartment, a central and a peripheral compartment for MPA and a central compartment for MPAG. The typical population clearance (CL/F) estimates with its relative standard error for MPA and MPAG were 10.2 l h(-1) (5.7%) and 1.38 l h(-1) (6.9%), respectively. The amount of MPA recycled in the body was estimated to be 29.1% of the total amount absorbed. Covariate analysis showed that body weight was positively correlated with CL/F of MPA, intercompartment CL/F of MPA and distribution volume of MPA peripheral compartment. Polymorphisms of UGT1A9 did not show any effect on the pharmacokinetics of MPA and MPAG. The model evaluation tests indicated that the proposed model can describe the pharmacokinetic profiles of MPA and MPAG in healthy Chinese subjects. CONCLUSIONS: The proposed model may provide a valuable approach for planning future pharmacokinetic-pharmacodynamic studies and for designing proper dosage regimens of MPA.