RESUMO
An efficient and high-yielding synthesis of penaresidin B is disclosed herein. The concise 8-step synthesis of azetidine aldehyde was devised by incorporating our novel strategy for ready access to 3-amino-2,3-dideoxysugars via regio- and stereoselective tandem hydroamination/glycosylation of glycal as the key step.
Assuntos
Aldeídos/química , Azetidinas/química , Azetidinas/síntese química , Álcoois Graxos/síntese química , Aldeídos/síntese química , Álcoois Graxos/química , Conformação Molecular , EstereoisomerismoRESUMO
A collective synthesis of 4-hydroxy-2-pyridone alkaloids--specifically, pretenellinâ B, prebassianinâ B, farinosoneâ A, militarioneâ D, pyridovericin, and torrubielloneâ C--has been achieved. Key steps include using a strategic convergent method to synthesize the densely substituted pyridone key intermediate by Suzuki-Miyaura cross-coupling reaction, a divergent synthesis approach of target molecules by aldol condensation of pyridone intermediate with homologous aldehydes, and an iterative synthesis of homologous aldehydes with all-trans-polyene backbones. Interestingly, among the six tumor cell lines investigated, torrubielloneâ C was found to induce potent and apoptotic inhibitory activities on Jurkatâ T cells with IC50 values of 7.05â µM. Hence, this approach could potentially contribute to the synthesis of bioactive small-molecule libraries as well as drug discovery.
Assuntos
Alcaloides/farmacologia , Piridinas/farmacologia , Alcaloides/síntese química , Alcaloides/química , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Células HCT116 , Células HeLa , Humanos , Concentração Inibidora 50 , Células Jurkat , Células MCF-7 , Estrutura Molecular , Neoplasias/patologia , Piridinas/síntese química , Piridinas/química , Relação Estrutura-AtividadeRESUMO
An efficient coupling reaction of allyl acetate with (O-azaaryl)carboxaldehyde by Pd-NHC dual catalysis has been developed. This reaction proceeds via direct coordination between the ortho nitrogen atom in the heterocycle and Pd(0). This dual catalysis is achieved under mild conditions to give 1,4-diones as products with up to 90% yield.
RESUMO
cis-2,6-Tetrahydropyran is an important structural skeleton of bioactive natural products. A facile synthesis of cis-2,6-disubstituted-3,6-dihydropyrans as cis-2,6-tetrahydropyran precursors has been achieved in high regio- and stereoselectivity with high yields. This reaction involves a palladium-catalyzed decarboxylative allylation of various 3,4-dihydro-2H-pyran substrates. Extending this reaction to 1,2-unsaturated carbohydrates allowed the achievement of challenging ß-C-glycosylation. Based on this methodology, the total syntheses of (±)-centrolobine and (+)-decytospolidesâ A and B were achieved in concise steps and overall high yields.
Assuntos
Compostos Alílicos/química , Antibacterianos/síntese química , Paládio , Piranos/síntese química , CatáliseRESUMO
A diverted total synthesis (DTS) approach to the total synthesis of pyridone alkaloids N-deoxymilitarinone A (8) and torrubiellone B (10) has been developed. The common intermediate 14 was first assembled by a dual directed orthometalation process using a methoxymethyl group as directed metalation group. Other crucial steps include the assembly of polyenes under aldol condensation for DTS using general and concise strategy and diastereoselective synthesis of the syn-dimethyl array by an Evans aldol reaction.
Assuntos
Alcaloides/síntese química , Piridonas/síntese química , Alcaloides/química , Conformação Molecular , Piridonas/químicaRESUMO
In the search for new estrogen receptor alpha (ERα) modulators, a trial molecular screening was conducted and 5,6-dihydroxybenzofuran was identified as a possible drug target for ERα. The target molecular modelling molecule 1 and a series of 5,6-dihydroxybenzofurans have been synthesized and evaluated for their anti-proliferation activities against MCF-7 and MDA-MB-231 cells. From the SAR studies, potential functional groups have been identified, the two hydroxyl groups at C-5 and C-6 and the phenyl ring at C-2, which showed considerable cytotoxicity in MCF-7 breast cancer cells. In addition, the apoptotic abilities of the compounds have been measured in both MCF-7 ER(+) and MDA-MB-231 ER(-) breast cancer cells. The results demonstrated that our compounds inhibit MCF-7 breast cancer cells via ER(+). These preliminary results provide valuable information towards the identification of important functional groups present on 5,6-dihydroxybenzofuran, which could be a promising scaffold for designing novel ER ligands.
Assuntos
Antineoplásicos/farmacologia , Benzofuranos/farmacologia , Moduladores de Receptor Estrogênico/farmacologia , Receptor alfa de Estrogênio/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Simulação por Computador , Humanos , Modelos MolecularesRESUMO
FKBP35, FK506 binding protein family member, in Plasmodium species displays a canonical peptidyl-prolyl isomerase (PPIase) activity and is intricately involved in the protein folding process. Inhibition of PfFKBP35 by FK506 or its analogues were shown to interfere with the in vitro growth of Plasmodium falciparum. In this study, we have synthesized adamantyl derivatives, Supradamal (SRA/4a) and its analogues SRA1/4b and SRA2/4c, which demonstrate submicromolar inhibition of Plasmodium falciparum FK506 binding domain 35 (FKBD35) PPIase activity. SRA and its analogues not only inhibit the in vitro growth of Plasmodium falciparum 3D7 strain but also show stage specific activity by inhibiting the trophozoite stage of the parasite. SRA/4a also inhibits the Plasmodium vivax FKBD35 PPIase activity and our crystal structure of PvFKBD35 in complex with the SRA provides structural insights in achieving selective inhibition against Plasmodium FKBPs.
RESUMO
A low-cost and highly sensitive biosensor system is designed to investigate carbohydrate-lectin interactions. This combination of glyco-gold nanoparticles and boronic acid biosensor system opens a way to study noncovalent drug delivery.
Assuntos
Técnicas Biossensoriais , Carboidratos/química , Sistemas de Liberação de Medicamentos , Lectinas/química , Nanopartículas , Espectrometria de FluorescênciaRESUMO
A facile synthesis of imidazo[1,2-α]pyridines has been achieved by copper(II) and iron(III) co-catalyzed C-N bond formation. This reaction involves an intermolecular oxidative diamination of alkynes with high chemoselectivity and regioselectivity.
Assuntos
Alcinos/química , Cobre/química , Compostos Férricos/química , Compostos Heterocíclicos com 2 Anéis/síntese química , Imidazóis/síntese química , Catálise , Técnicas de Química Combinatória , Compostos Heterocíclicos com 2 Anéis/química , Imidazóis/química , Oxirredução , Piridinas/síntese química , Piridinas/química , EstereoisomerismoRESUMO
Pyrrolidine derivatives were prepared in high diastereoselectivities and good yields via a [3 + 2] cycloaddition of a tert-butyldimethylsilyl protected carbohydrate-based allene with a diverse range of imines. The subsequent removal of the carbohydrate auxiliary afforded a variety of pyrrolidines with excellent enantioselectivities (up to 99% ee). Selective reduction of the pyrrolidines further demonstrated the potential of this strategy.
Assuntos
Carboidratos/química , Pirrolidinas/síntese química , Catálise , Estrutura Molecular , Oxirredução , Pirrolidinas/química , Silanos/química , EstereoisomerismoRESUMO
Molecular dynamics (MD) simulations were carried out to study the behavior of human receptor molecule in the hemagglutinin (HA) of 1918 and 2009 H1N1 influenza viruses respectively. The 2009 HA model was obtained by virtually mutating the 1918 HA crystal structure based on A/Mexico City/MCIG01/2009(H1N1) segment 4 sequence. We found that human receptor molecule has no binding preference between the 2009 HA and the 1918 HA. In addition, among the four sugar moieties in the human receptor molecule, sialic acid contributes the most to the electrostatic and non-polar interaction energy during binding. Furthermore, the hydrogen bonds between sialic acid and the surrounding residues in 1918 HA are preserved in 2009 HA. We also found that the mutated residues contribute to a more favorable binding of hemagglutinin to the human receptor molecule.
Assuntos
Glicoproteínas de Hemaglutininação de Vírus da Influenza/química , Vírus da Influenza A Subtipo H1N1/química , Simulação de Dinâmica Molecular , Receptores Virais/química , Sequência de Aminoácidos , Sítios de Ligação , Glicoproteínas de Hemaglutininação de Vírus da Influenza/genética , Humanos , Ligação de Hidrogênio , Vírus da Influenza A Subtipo H1N1/genética , Dados de Sequência Molecular , Ligação Proteica/fisiologia , Alinhamento de SequênciaRESUMO
A fast and highly efficient copper-catalyzed multicomponent synthesis of 1,4-dihydropyridines under microwave irradiation is described. The protocol utilizes mild reaction conditions with low catalytic loading, leading to high yields. This methodology provides us with biologically active 1,4-dihydropyridine library for medicinal chemistry applications.