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1.
Molecules ; 29(11)2024 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-38893361

RESUMO

A versatile family of quaternary propargylamines was synthesized employing the KA2 multicomponent reaction, through the single-step coupling of a number of amines, ketones, and terminal alkynes. Sustainable synthetic procedures using transition metal catalysts were employed in all cases. The inhibitory activity of these molecules was evaluated against human monoaminoxidase (hMAO)-A and hMAO-B enzymes and was found to be significant. The IC50 values for hMAO-B range from 152.1 to 164.7 nM while the IC50 values for hMAO-A range from 765.6 to 861.6 nM. Furthermore, these compounds comply with Lipinski's rule of five and exhibit no predicted toxicity. To understand their binding properties with the two target enzymes, key interactions were studied using molecular docking, all-atom molecular dynamics (MD) simulations, and MM/GBSA binding free energy calculations. Overall, herein, the reported family of propargylamines exhibits promise as potential treatments for neurodegenerative disorders, such as Parkinson's disease. Interestingly, this is the first time a propargylamine scaffold bearing an internal alkyne has been reported to show activity against monoaminoxidases.


Assuntos
Alcinos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Inibidores da Monoaminoxidase , Monoaminoxidase , Pargilina , Alcinos/química , Alcinos/farmacologia , Monoaminoxidase/metabolismo , Monoaminoxidase/química , Inibidores da Monoaminoxidase/química , Inibidores da Monoaminoxidase/farmacologia , Inibidores da Monoaminoxidase/síntese química , Humanos , Pargilina/química , Pargilina/análogos & derivados , Pargilina/farmacologia , Propilaminas/química , Relação Estrutura-Atividade , Estrutura Molecular
2.
Biomacromolecules ; 25(2): 890-902, 2024 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-38180887

RESUMO

Both biochemical and mechanical cues could regulate the function of stem cells, but the interaction mechanism of their signaling pathway remains unclear, especially in the three-dimensional (3D) culture mode. Higher matrix stiffness promotes osteogenic differentiation of stem cells, and bone morphogenic protein-2 (BMP-2) has been clinically applied to promote bone regeneration. Here, the crosstalk of extracellular mechanical signals on BMP-2 signaling was investigated in rat bone marrow stromal cells (rMSCs) cultured inside cryogels with interconnective pores. Stiff cryogel independently promoted osteogenic differentiation and enhanced the autocrine secretion of BMP-2, thus stimulating increased phosphorylation levels of the Smad1/5/8 complex. BMP-2 mimetic peptide (BMMP) and high cryogel stiffness jointly guided the osteogenic differentiation of rMSCs. Inhibition of rho-associated kinase (ROCK) by Y-27632 or inhibition of nonmuscle myosin II (NM II) by blebbistatin showed that osteogenesis induction by BMP-2 signaling, as well as autocrine secretion of BMP-2 and phosphorylation of the Smad complex, requires the involvement of cytoskeletal tension and ROCK pathway signaling. An interconnective microporous cryogel scaffold promoted rMSC osteogenic differentiation by combining matrix stiffness and BMMP, and it accelerated critical cranial defect repair in the rat model.


Assuntos
Células-Tronco Mesenquimais , Osteogênese , Pargilina/análogos & derivados , Ratos , Animais , Criogéis , Gelatina , Diferenciação Celular , Proteína Morfogenética Óssea 2/farmacologia , Proteína Morfogenética Óssea 2/metabolismo , Células da Medula Óssea/metabolismo , Células Cultivadas
3.
J Org Chem ; 87(10): 6812-6823, 2022 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-35509227

RESUMO

We report a cascaded oxidative sulfonylation of N-propargylamine via a three-component coupling reaction using DABCO·(SO2)2 (DABSO). 3-Arylsulfonylquinolines were obtained by mixing diazonium tetrafluoroborate, N-propargylamine, and DABSO under argon atmosphere in dichloroethane (DCE) for 1 h. In a radical pathway, DABSO was utilized as the sulfone source and an oxidant in this radical-mediated cascaded reaction.


Assuntos
Pargilina , Propilaminas , Estresse Oxidativo , Pargilina/análogos & derivados , Sulfonas
4.
Bioorg Med Chem Lett ; 67: 128746, 2022 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-35447344

RESUMO

Monoamine oxidase B (MAO-B) inhibitors are established therapy for Parkinson's disease and act, in part, by blocking the MAO-catalysed metabolism of dopamine in the brain. Two propargylamine-containing MAO-B inhibitors, selegiline [(R)-deprenyl] and rasagiline, are currently used in the clinic for this purpose. These compounds are mechanism-based inactivators and, after oxidative activation, form covalent adducts with the FAD co-factor. An important consideration is that selegiline and rasagiline display specificity for MAO-B over the MAO-A isoform thus reducing the risk of tyramine-induced changes in blood-pressure. In the interest of discovering new propargylamine MAO inhibitors, the present study synthesises racemic N-propargylamine-2-aminotetralin (2-PAT), a compound that may be considered as both a six-membered ring analogue of rasagiline and a semi-rigid N-desmethyl ring-closed analogue of selegiline. The in vitro human MAO inhibition properties of this compound were measured and the results showed that 2-PAT is a 20-fold more potent inhibitor of MAO-A (IC50 = 0.721 µM) compared to MAO-B (IC50 = 14.6 µM). Interestingly, dialysis studies found that 2-PAT is a reversible MAO-A inhibitor, while acting as an inactivator of MAO-B. Since reversible MAO-A inhibitors are much less liable to potentiate tyramine-induced side effects than MAO-A inactivators, it is reasonable to suggest that 2-PAT could be a useful and safe therapeutic agent for disorders such as Parkinson's disease and depression.


Assuntos
Doença de Parkinson , Selegilina , Humanos , Indanos/farmacologia , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/farmacologia , Inibidores da Monoaminoxidase/uso terapêutico , Pargilina/análogos & derivados , Doença de Parkinson/tratamento farmacológico , Propilaminas , Selegilina/farmacologia , Tetra-Hidronaftalenos , Tiramina/farmacologia
5.
J Org Chem ; 87(9): 5795-5803, 2022 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-35442039

RESUMO

An efficient copper-catalyzed cascade annulation of o-hydroxyphenyl propargylamines and pyrazolin-5-ones is described. This methodology leads to the rapid assembly of a series of valuable pyrano[2,3-c]pyrazoles with good yields across a wide range of substrates in a simple fashion. This novel reaction involves the formation of alkynyl ortho-quinone methides, a 1,4-conjugate addition, and a subsequent 6-endo cyclization process. The mechanistic elucidation is well supported by control experiment and literature precedents.


Assuntos
Pirazolonas , Catálise , Cobre , Pargilina/análogos & derivados , Propilaminas , Pirazóis
6.
J Org Chem ; 87(9): 5916-5924, 2022 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-35394780

RESUMO

An interaction of 1,5-diaryl-3-X-pent-4-yn-1-ones (where X stands for piperidin-1-yl, morpholin-4-yl, 4-methylpiperazin-1-yl) with arylhydrazines proceeds at room temperature and results in 3-aryl-5-arylethynyl-1-phenyl-4,5-dihydro-1H-pyrazoles with up to 57-73% yields. Under similar conditions, the cyclocondensation of conjugated 2,4,1-enynones with arylhydrazine proceeds only in the presence of cyclic amines. 1,5-Diaryl-3-X-pent-4-yn-1-ones are reported as synthetic equivalents of conjugated 2,4,1-enynones in reactions with arylhydrazines. On the basis of obtained data, there are highly efficient methods developed for the synthesis of 5-arylethynyl-substituted 4,5-dihydro-1H-pyrazoles, as well as for similarly structured 1H-pyrazoles prepared by oxidation in AcOH. Presented products possess quite marked fluorescent abilities. Emission maximum wavelengths are located at 453-465 and 363-400 nm, respectively; certain compounds show extremely large Stokes shifts that may reach 91,000 cm-1.


Assuntos
Acetileno , Alcinos , Cetonas , Pargilina/análogos & derivados , Propilaminas , Pirazóis
7.
Org Biomol Chem ; 20(18): 3755-3762, 2022 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-35420116

RESUMO

A highly regio- and chemoselective synthesis of 1H-isoindoliums through a facile and novel cascade cyclization reaction of propargylamine-based 1,6-diynes under mild conditions has been developed. Different functional groups were compatible under the optimized reaction conditions, giving the corresponding products in up to 94% yields. Upon treatment with a base, the alkyne moiety of 1H-isoindoliums could be further transformed to allenes in excellent yields.


Assuntos
Di-Inos , Halogenação , Catálise , Ciclização , Estrutura Molecular , Pargilina/análogos & derivados , Propilaminas
8.
Bioorg Chem ; 122: 105724, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35305483

RESUMO

A series of N-propargylamine-hydroxamic acid/o-aminobenzamide hybrids inhibitors combining the typical pharmacophores of hydroxamic acid/o-aminobenzamide and propargylamine were designed and synthesized as HDAC1/MAO-B dual inhibitors for the treatment of Alzheimer's disease. Most of the hybrids displayed moderate to good MAO-B inhibitory activities. Among them, Hybrid If exhibited the most potent activity against MAO-B and HDAC1 (MAO-B, IC50 = 99.0 nM; HDAC1, IC50 = 21.4 nM) and excellent MAO selectively (MAO-A, IC50 = 9923.0 nM; SI = 100.2). Moreover, compound If significantly reversed Aß1-42-induced PC12 cell damage and decreased the production of intracellular ROS, exhibiting favorable antioxidant activity. More importantly, hybrid If instantly penetrated the BBB and accumulated in brain tissue as well as markedly ameliorated cognitive dysfunction in a Morris water maze ICR mice model. In summary, HDAC1/MAO-B dual inhibitor If is a promising potential agent for the therapy of Alzheimer's disease.


Assuntos
Doença de Alzheimer , Doença de Alzheimer/tratamento farmacológico , Animais , Inibidores da Colinesterase/farmacologia , Desenho de Fármacos , Ácidos Hidroxâmicos , Camundongos , Camundongos Endogâmicos ICR , Estrutura Molecular , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/farmacologia , Pargilina/análogos & derivados , Propilaminas , Relação Estrutura-Atividade
9.
J Med Chem ; 65(3): 2208-2224, 2022 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-35005974

RESUMO

Glioma treatment remains a challenge with a low survival rate due to the lack of effective therapeutics. Monoamine oxidase A (MAO A) plays a role in glioma development, and MAO A inhibitors reduce glioma growth. Histone deacetylase (HDAC) inhibition has emerged as a promising therapy for various malignancies including gliomas. We have synthesized and evaluated N-methylpropargylamine-conjugated hydroxamic acids as dual inhibitors of MAO A and HDAC. Compounds display potent MAO A inhibition with IC50 from 0.03 to <0.0001 µM and inhibit HDAC isoforms and cell growth in the micromolar to nanomolar IC50 range. These selective MAO A inhibitors increase histone H3 and α-tubulin acetylation and induce cell death via nonapoptotic mechanisms. Treatment with 15 reduced tumor size, reduced MAO A activity in brain and tumor tissues, and prolonged the survival. This first report on dual inhibitors of MAO A and HDAC establishes the basis of translational research for an improved treatment of glioma.


Assuntos
Inibidores Enzimáticos/química , Histona Desacetilases/química , Ácidos Hidroxâmicos/química , Monoaminoxidase/química , Acetilação/efeitos dos fármacos , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Desenho de Fármacos , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Glioma/tratamento farmacológico , Glioma/mortalidade , Histona Desacetilases/metabolismo , Histonas/metabolismo , Humanos , Ácidos Hidroxâmicos/metabolismo , Ácidos Hidroxâmicos/farmacologia , Ácidos Hidroxâmicos/uso terapêutico , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Estimativa de Kaplan-Meier , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Monoaminoxidase/metabolismo , Pargilina/análogos & derivados , Pargilina/química , Propilaminas/química , Relação Estrutura-Atividade , Transplante Heterólogo
10.
Bioorg Chem ; 116: 105301, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34492558

RESUMO

A combination of several pharmacophores in one molecule has been successfully used for multi-target-directed ligands (MTDL) design. New propargylamine substituted derivatives combined with salicylic and cinnamic scaffolds were designed and synthesized as potential cholinesterases and monoamine oxidases (MAOs) inhibitors. They were evaluated invitro for inhibition of acetyl- (AChE) and butyrylcholinesterase (BuChE) using Ellman's method. All the compounds act as dual inhibitors. Most of the derivatives are stronger inhibitors of AChE, the best activity showed 5-bromo-N-(prop-2-yn-1-yl)salicylamide 1e (IC50 = 8.05 µM). Carbamates (4-bromo-2-[(prop-2-yn-1-yl)carbamoyl]phenyl ethyl(methyl)carbamate 2d and 2,4-dibromo-6-[(prop-2-yn-1-yl)carbamoyl]phenyl ethyl(methyl)carbamate 2e were selective and the most active for BuChE (25.10 and 26.09 µM). 4-Bromo-2-[(prop-2-yn-1-ylimino)methyl]phenol 4a was the most potent inhibitor of MAOs (IC50 of 3.95 and ≈10 µM for MAO-B and MAO-A, respectively) along with a balanced inhibition of both cholinesterases being a real MTDL. The mechanism of action was proposed, and binding modes of the hits were studied by molecular docking on human enzymes. Some of the derivatives also exhibited antioxidant properties. Insilico prediction of physicochemical parameters affirm that the molecules would be active after oral administration and able to reach brain tissue.


Assuntos
Antioxidantes/farmacologia , Inibidores da Colinesterase/farmacologia , Simulação de Acoplamento Molecular , Inibidores da Monoaminoxidase/farmacologia , Pargilina/análogos & derivados , Propilaminas/farmacologia , Animais , Antioxidantes/síntese química , Antioxidantes/química , Butirilcolinesterase/metabolismo , Células Cultivadas , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Colinesterases/metabolismo , Relação Dose-Resposta a Droga , Electrophorus , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Cavalos , Humanos , Masculino , Estrutura Molecular , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/síntese química , Inibidores da Monoaminoxidase/química , Pargilina/síntese química , Pargilina/química , Pargilina/farmacologia , Propilaminas/síntese química , Propilaminas/química , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-Atividade
11.
ACS Chem Biol ; 16(9): 1615-1621, 2021 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-34403242

RESUMO

Ubiquitin activity-based probes have proven invaluable in elucidating structural mechanisms in the ubiquitin system by stabilizing transient macromolecular complexes of deubiquitinases, ubiquitin-activating enzymes, and the assemblies of ubiquitin-conjugating enzymes with ubiquitin ligases of the RING-Between-RING and RING-Cysteine-Relay families. Here, we demonstrate that an activity-based probe, ubiquitin-propargylamine, allows for the preparative reconstitution and structural analysis of the interactions between ubiquitin and certain HECT ligases. We present a crystal structure of the ubiquitin-linked HECT domain of HUWE1 that defines a catalytically critical conformation of the C-terminal tail of the ligase for the transfer of ubiquitin to an acceptor protein. Moreover, we observe that ubiquitin-propargylamine displays selectivity among HECT domains, thus corroborating the notion that activity-based probes may provide entry points for the development of specific, active site-directed inhibitors and reporters of HECT ligase activities.


Assuntos
Enzimas de Conjugação de Ubiquitina/química , Ubiquitina-Proteína Ligases/química , Ubiquitina/química , Sequência de Aminoácidos , Catálise , Domínio Catalítico , Cisteína/química , Humanos , Modelos Moleculares , Pargilina/análogos & derivados , Pargilina/química , Propilaminas/química , Conformação Proteica , Relação Estrutura-Atividade , Especificidade por Substrato , Ubiquitinação
12.
Org Lett ; 23(14): 5448-5451, 2021 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-34180676

RESUMO

We report here a three-component, Cu(I)-catalyzed hexadehydro-Diels-Alder (HDDA) benzyne 1,2-difunctionalization reaction. This protocol allowed the introduction of two different carbon-based substituents onto the in situ-generated benzyne. These substituents were terminal monoynes or diynes partnered with propargylic, benzylic, or allylic chlorides. An example of a sequential HDDA reaction is demonstrated using the product of a 1,3-diyne and a propargylic halide, itself a newly created HDDA precursor.


Assuntos
Derivados de Benzeno/química , Di-Inos/química , Pargilina/química , Catálise , Cobre/química , Reação de Cicloadição , Estrutura Molecular , Pargilina/análogos & derivados
13.
Bioorg Chem ; 113: 105013, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34062405

RESUMO

AD is a progressive brain disorder. Because of the lack of remarkable single-target drugs against neurodegenerative disorders, the multitarget-directed ligand strategy has received attention as a promising therapeutic approach. Herein, we rationally designed twenty-nine hybrids of N-propargylamine-hydroxypyridinone. The designed hybrids possessed excellent iron-chelating activity (pFe3+ = 17.09-22.02) and potent monoamine oxidase B inhibitory effects. Various biological evaluations of the optimal compound 6b were performed step by step, including inhibition screening of monoamine oxidase (hMAO-B IC50 = 0.083 ± 0.001 µM, hMAO-A IC50 = 6.11 ± 0.08 µM; SI = 73.5), prediction of blood-brain barrier permeability and mouse behavioral research. All of these favorable results proved that the N-propargylamine-hydroxypyridinone scaffold is a promising structure for the discovery of multitargeted ligands for AD therapy.


Assuntos
Inibidores da Monoaminoxidase/química , Pargilina/análogos & derivados , Propilaminas/química , Piridinas/química , Doença de Alzheimer/tratamento farmacológico , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Modelos Animais de Doenças , Desenho de Fármacos , Estabilidade de Medicamentos , Humanos , Concentração de Íons de Hidrogênio , Concentração Inibidora 50 , Quelantes de Ferro/síntese química , Quelantes de Ferro/química , Quelantes de Ferro/farmacologia , Quelantes de Ferro/uso terapêutico , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos ICR , Monoaminoxidase/química , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/síntese química , Inibidores da Monoaminoxidase/farmacologia , Inibidores da Monoaminoxidase/uso terapêutico , Pargilina/química , Relação Estrutura-Atividade
14.
Org Biomol Chem ; 19(18): 4060-4066, 2021 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-33978054

RESUMO

An Ag(i)-catalyzed tandem addition-cyclization of isothiocyanate and propargylamine was successfully applied to the synthesis of 2-amino-4-methylenethiazolines. This route features an unprecedented fast reaction rate with full conversion reached within 10 min at room temperature for aromatic isothiocyanates and excellent chemoselectivity for exocyclic products. The application of this strategy is further highlighted by the accelerated bioconjugation of propargylamine with fluorescein isothiocyanate (FITC) under Ag(i)-catalysis.


Assuntos
Pargilina/análogos & derivados , Propilaminas
15.
Bioorg Med Chem Lett ; 45: 128135, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34044119

RESUMO

Twenty six propargylamine mycophenolate analogues were designed and synthesized from mycophenolic acid 1 employing a key step A3-coupling reaction. Their cytotoxic activity was examined against six cancer cell lines. Compounds 6a, 6j, 6t, 6u, and 6z exhibited selective cytotoxicity towards neuroblastoma (SH-SY5Y) cancer cells and were less toxic to normal cells in comparison to the lead compound, MPA 1 and a standard drug, ellipticine. Molecular docking results suggested that compound 6a is fit well in the key amino acid of three proteins (CDK9, EGFR, and VEGFR-2) as targets in cancer therapy. The propargylamine mycophenolate scaffold might be a valuable starting point for development of new neuroblastoma anticancer drugs.


Assuntos
Antineoplásicos/farmacologia , Ácido Micofenólico/farmacologia , Neuroblastoma/tratamento farmacológico , Pargilina/análogos & derivados , Propilaminas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Ácido Micofenólico/síntese química , Ácido Micofenólico/química , Neuroblastoma/patologia , Pargilina/síntese química , Pargilina/química , Pargilina/farmacologia , Propilaminas/síntese química , Propilaminas/química , Relação Estrutura-Atividade
16.
J Am Chem Soc ; 143(17): 6423-6433, 2021 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-33885283

RESUMO

Terminal unactivated alkynes are nowadays considered the golden standard for cysteine-reactive warheads in activity-based probes (ABPs) targeting cysteine deubiquitinating enzymes (DUBs). In this work, we study the versatility of the thiol-alkyne addition reaction in more depth. Contrary to previous findings with UCHL3, we now show that covalent adduct formation can progress with substituents on the terminal or internal alkyne position. Strikingly, acceptance of alkyne substituents is strictly DUB-specific as this is not conserved among members of the same subfamily. Covalent adduct formation with the catalytic cysteine residue was validated by gel analysis and mass spectrometry of intact ABP-treated USP16CDWT and catalytically inactive mutant USP16CDC205A. Bottom-up mass spectrometric analysis of the covalent adduct with a deuterated propargyl ABP provides mechanistic understanding of the in situ thiol-alkyne reaction, identifying the alkyne rather than an allenic intermediate as the reactive species. Furthermore, kinetic analysis revealed that introduction of (bulky/electron-donating) methyl substituents on the propargyl moiety decreases the rate of covalent adduct formation, thus providing a rational explanation for the commonly lower level of observed covalent adduct compared to unmodified alkynes. Altogether, our work extends the scope of possible propargyl derivatives in cysteine targeting ABPs from unmodified terminal alkynes to internal and substituted alkynes, which we anticipate will have great value in the development of ABPs with improved selectivity profiles.


Assuntos
Alcinos/química , Cisteína Proteases/química , Pargilina/análogos & derivados , Compostos de Sulfidrila/química , Enzimas Desubiquitinantes/química , Células HEK293 , Humanos , Pargilina/química , Propilaminas/química , Ubiquitina Tiolesterase/química
17.
J Org Chem ; 86(5): 4182-4192, 2021 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-33625853

RESUMO

A novel and versatile approach to construct 12-phenacyl-11H-benzo[b]xanthene-6,11(12H)-dione derivatives through copper-catalyzed cascade reaction of propargylamines with 2-hydroxynaphthalene-1,4-diones has been developed. The procedure is proposed to go through a sequence of 1,4-conjugate addition, intramolecular nucleophilic addition/dehydration, and hydrolysis of alkyne followed by an enol-ketone tautomerization. The reaction provides a new and highly efficient method for the synthesis of 12-phenacyl-11H-benzo[b]xanthene-6,11(12H)-diones by formation of three new bonds and one heterocycle from readily available starting materials in good to high yields (70-88%) with broad functional group compatibility in a single step.


Assuntos
Cobre , Xantenos , Catálise , Hidrólise , Naftóis , Pargilina/análogos & derivados , Propilaminas
18.
Org Biomol Chem ; 19(9): 2044-2054, 2021 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-33599667

RESUMO

Described herein is the first example of glycosidation of thioglycosides in the presence of palladium(ii) bromide. While the activation with PdBr2 alone was proven feasible, higher yields and cleaner reactions were achieved when these glycosylations were performed in the presence of propargyl bromide as an additive. Preliminary mechanistic studies suggest that propargyl bromide assists the reaction by creating an ionizing complex, which accelerates the leaving group departure. A variety of thioglycoside donors in reactions with different glycosyl acceptors were investigated to determine the initial scope of this new reaction. Selective and chemoselective activation of thioglycosides over other leaving groups has also been explored.


Assuntos
Paládio/química , Tioglicosídeos/química , Catálise , Dissacarídeos/síntese química , Glicosilação , Pargilina/análogos & derivados , Pargilina/química
19.
J Org Chem ; 86(3): 2667-2681, 2021 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-33448846

RESUMO

The stereoselective synthesis of terminal bromo-substituted propargylamines via in situ generation of lithium bromoacetylide from 1,2-dibromoethene and addition to Ellman chiral N-tert-butanesulfinyl aldimines is reported. Modest to good yields (43-85%) and diastereoselectivity (dr = 3:1 to >20:1) were achieved for a range of aryl, heteroaryl, alkyl, and α,ß-unsaturated substrates. Terminal bromo-substituted propargylamines prepared via this method can be directly used in the frequently employed Cadiot-Chodkiewicz coupling to produce functionalized diynes. The method reported here increases the structural diversity of chiral terminal bromo-substituted propargylamines that can be readily synthesized as previous methods for the stereoselective synthesis of these compounds rely on amino acid precursors from the chiral pool.


Assuntos
Iminas , Lítio , Pargilina/análogos & derivados , Propilaminas , Estereoisomerismo
20.
Macromol Rapid Commun ; 42(6): e2000633, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33314555

RESUMO

Multicomponent polymerizations (MCPs) are a group of fascinating polymer synthesis approaches that are developed rapidly in the recent decade. As a popular alkyne-based MCP, the A3 -polycouplings of alkynes, aldehydes, and amines are developed for the synthesis of poly(propargylamine)s under the catalysis of metal catalysts. In this work, through the design of carboxylic acid group-activated alkyne monomers, a catalyst-free, four-component polymerization of propiolic acids, benzylamines, organoboronic acids, and formaldehyde is reported under mild condition at 45 °C in dichloroethane. This four-component polymerization is applicable to different monomer structures, which can afford seven poly(propargylamine)s with up to 94% yields and molecular weights of up to 13 900 g mol-1 . Moreover, the poly(propargylamine)s demonstrate good solubility and processibility, high thermal stability and light refractivity, unique photophysical property, and so on. The simple monomers, mild condition, low cost, high efficiency, and procedure simplicity of this catalyst-free four-component polymerization demonstrates an elegant example of functional polymer synthesis.


Assuntos
Alcinos , Benzilaminas , Catálise , Formaldeído , Pargilina/análogos & derivados , Polimerização , Propilaminas
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