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1.
Molecules ; 26(4)2021 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-33673007

RESUMO

Malaria remains a significant cause of morbidity and mortality in Sub-Saharan Africa and South Asia. While clinical antimalarials are efficacious when administered according to local guidelines, resistance to every class of antimalarials is a persistent problem. There is a constant need for new antimalarial therapeutics that complement parasite control strategies to combat malaria, especially in the tropics. In this work, nopol-based quinoline derivatives were investigated for their inhibitory activity against Plasmodium falciparum, one of the parasites that cause malaria. The nopyl-quinolin-8-yl amides (2-4) were moderately active against the asexual blood stage of chloroquine-sensitive strain Pf3D7 but inactive against chloroquine-resistant strains PfK1 and PfNF54. The nopyl-quinolin-4-yl amides and nopyl-quinolin-4-yl-acetates analogs were generally less active on all three strains. Interesting, the presence of a chloro substituent at C7 of the quinoline ring of amide 8 resulted in sub-micromolar EC50 in the PfK1 strain. However, 8 was more than two orders of magnitude less active against Pf3D7 and PfNF54. Overall, the nopyl-quinolin-8-yl amides appear to share similar antimalarial profile (asexual blood-stage) with previously reported 8-aminoquinolines like primaquine. Future work will focus on investigating the moderately active and selective nopyl-quinolin-8-yl amides on the gametocyte or liver stages of Plasmodium falciparum and Plasmodium vivax.


Assuntos
Antimaláricos/farmacologia , Compostos Bicíclicos com Pontes/farmacologia , Plasmodium/efeitos dos fármacos , Quinolinas/farmacologia , Antimaláricos/síntese química , Antimaláricos/química , Compostos Bicíclicos com Pontes/síntese química , Compostos Bicíclicos com Pontes/química , Células Hep G2 , Humanos , Quinolinas/síntese química , Quinolinas/química
2.
J Med Chem ; 64(3): 1454-1480, 2021 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-33492963

RESUMO

Sphingosine-1-phosphate (S1P) binds to a family of sphingosine-1-phosphate G-protein-coupled receptors (S1P1-5). The interaction of S1P with these S1P receptors has a fundamental role in many physiological processes in the vascular and immune systems. Agonist-induced functional antagonism of S1P1 has been shown to result in lymphopenia. As a result, agonists of this type hold promise as therapeutics for autoimmune disorders. The previously disclosed differentiated S1P1 modulator BMS-986104 (1) exhibited improved preclinical cardiovascular and pulmonary safety profiles as compared to earlier full agonists of S1P1; however, it demonstrated a long pharmacokinetic half-life (T1/2 18 days) in the clinic and limited formation of the desired active phosphate metabolite. Optimization of this series through incorporation of olefins, ethers, thioethers, and glycols into the alkyl side chain afforded an opportunity to reduce the projected human T1/2 and improve the formation of the active phosphate metabolite while maintaining efficacy as well as the improved safety profile. These efforts led to the discovery of 12 and 24, each of which are highly potent, biased agonists of S1P1. These compounds not only exhibited shorter in vivo T1/2 in multiple species but are also projected to have significantly shorter T1/2 values in humans when compared to our first clinical candidate. In models of arthritis, treatment with 12 and 24 demonstrated robust efficacy.


Assuntos
Compostos Bicíclicos com Pontes/síntese química , Compostos Bicíclicos com Pontes/farmacologia , Pró-Proteína Convertases/efeitos dos fármacos , Serina Endopeptidases/efeitos dos fármacos , Animais , Artrite Experimental/tratamento farmacológico , Doenças Autoimunes/tratamento farmacológico , Biotransformação , Compostos Bicíclicos com Pontes/efeitos adversos , Líquido da Lavagem Broncoalveolar , Quimiotaxia de Leucócito/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Meia-Vida , Humanos , Pneumopatias/induzido quimicamente , Pneumopatias/patologia , Masculino , Miócitos Cardíacos/efeitos dos fármacos , Fosforilação , Ratos , Ratos Endogâmicos Lew , Relação Estrutura-Atividade
3.
Chem Commun (Camb) ; 56(3): 415-418, 2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31821393

RESUMO

We report a novel 1,2-catechol based radioiodinated precursor for radioiodination of bicyclo[6.1.0]nonyne (BCN) installed biologically active molecules using a strain-promoted oxidation-controlled cyclooctyne-1,2-quinone cycloaddition reaction (SPOCQ) under ambient conditions. Compared to the reported methodologies, the new strategy demonstrates some clear advantages, including high in vitro and in vivo stability, high radiochemical yield, and exceptionally fast reaction kinetics at micro-molar concentration.


Assuntos
Reação de Cicloadição , Quinonas/química , Compostos Radiofarmacêuticos/química , Animais , Compostos Bicíclicos com Pontes/síntese química , Compostos Bicíclicos com Pontes/química , Catecóis/química , Coração/diagnóstico por imagem , Radioisótopos do Iodo/química , Marcação por Isótopo , Cinética , Camundongos , Camundongos Endogâmicos ICR , Oxirredução , Compostos Radiofarmacêuticos/síntese química , Tomografia Computadorizada com Tomografia Computadorizada de Emissão de Fóton Único
4.
J Org Chem ; 84(22): 14670-14678, 2019 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-31603325

RESUMO

Oxidopyrylium ylides are useful intermediates in synthetic organic chemistry because of their capability of forming structurally complex cycloadducts. They can also self-dimerize via [5 + 3] cycloaddition, which is an oft-reported side reaction that can negatively impact [5 + 2] cycloadduct yields and efficiency. In select instances, these dimers can be synthesized and used as the source of oxidopyrylium ylide, although the generality of this process remains unclear. Thus, how the substitution pattern governs both dimerization and cycloaddition reactions is of fundamental interest to probe factors to regulate them. The following manuscript details our findings that maltol-derived oxidopyrylium ylides (i.e., with ortho methyl substitution relative to oxide) can be trapped prior to dimerization more efficiently than the regioisomeric allomaltol-derived ylide (i.e., with a para methyl substitution relative to oxide). Density functional theory studies provide evidence in support of a sterically (kinetically) controlled mechanism, whereby gauche interactions between appendages of the approaching maltol-derived ylides are privileged by higher barriers for dimerization and thus are readily intercepted by dipolarophiles via [5 + 2] cycloadditions.


Assuntos
Compostos Bicíclicos com Pontes/síntese química , Pironas/química , Tropolona/síntese química , Compostos Bicíclicos com Pontes/química , Reação de Cicloadição , Dimerização , Cinética , Estrutura Molecular , Tropolona/química
5.
Yakugaku Zasshi ; 139(10): 1259-1265, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31582609

RESUMO

The first total synthesis of avenaol was achieved using a new robust strategy involving all-cis-substituted cyclopropane formation via an alkylidene cyclopropane. The keys to success for the total synthesis were (i) Rh-catalyzed intramolecular cyclopropanation of an allene; (ii) Ir-catalyzed stereoselective double-bond isomerization to form an all-cis cyclopropane; and (iii) differentiation of two hydroxymethyl groups via regioselective cyclization and oxidation of tetrahydropyran based on the reactivity of cyclopropyl group. This strategy effectively avoids cyclopropane ring opening and undesired formation of a cage structure. Additionally, the proposed structure of avenaol, especially unique all-cis-substituted cyclopropane was confirmed correct by this total synthesis.


Assuntos
Compostos Bicíclicos com Pontes/síntese química , Ciclopropanos/química , Alcadienos/química , Compostos Bicíclicos com Pontes/química , Catálise , Ciclização , Ciclopropanos/síntese química , Conformação Molecular , Fenômenos de Química Orgânica , Oxirredução , Estereoisomerismo
6.
Bioorg Med Chem ; 27(23): 115146, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31648876

RESUMO

In this study, the impact of one or two hydroxy moieties at the benzo[7]annulene scaffold on the GluN2B affinity and cytoprotective activity was analyzed. The key intermediate for the synthesis of OH-substituted benzo[7]annulenamines 11-13 and 17 was the epoxyketone 8. Reductive epoxide opening of 8 resulted with high regioselectivity in the 5-hydroxyketone 9 (Pd(OAc)2, HCO2H, phosphane ligand) or the 6-hydroxyketone 10 (H2, Pd/C), whereas hydrolysis in aqueous dioxane led to the dihydroxyketone 14. Reductive amination of these ketones with primary amines and NaBH(OAc)3 afforded the benzo[7]annulenamines 11-13 and 17. In receptor binding studies 5-OH derivatives 11 and 12 showed higher GluN2B affinity than 6-OH derivatives 13, which in turn were more active than 5,6-di-OH derivative 17a. The same order was found for the cytoprotective activity of the ligands. The tertiary amine 12a with one OH moiety in 5-position represents the most promising GluN2B negative allosteric modulator with a binding affinity of Ki = 49 nM and a cytoprotective activity of IC50 = 580 nM. In the binding pocket 12a shows a crucial H-bond between the benzylic OH moiety and the backbone carbonyl O-atom of Ser132 (GluN1b). It was concluded that a 5-OH moiety is essential for the inhibition of the NMDA receptor associated ion channel, whereas a OH moiety in 6-position is detrimental for binding and inhibition. An OH or CH2OH moiety at 2-position results in binding at the ifenprodil binding site, but very weak ion channel inhibition.


Assuntos
Compostos Bicíclicos com Pontes/química , Compostos Bicíclicos com Pontes/farmacologia , Receptores de N-Metil-D-Aspartato/metabolismo , Animais , Compostos Bicíclicos com Pontes/síntese química , Cristalografia por Raios X , Desenho de Fármacos , Humanos , Ligantes , Camundongos Endogâmicos C57BL , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Receptores de N-Metil-D-Aspartato/química , Relação Estrutura-Atividade
7.
Angew Chem Int Ed Engl ; 58(44): 15876-15882, 2019 10 28.
Artigo em Inglês | MEDLINE | ID: mdl-31476269

RESUMO

Inverse electron-demand Diels-Alder cycloadditions (iEDDAC) between tetrazines and strained alkenes/alkynes have emerged as essential tools for studying and manipulating biomolecules. A light-triggered version of iEDDAC (photo-iEDDAC) is presented that confers spatio-temporal control to bioorthogonal labeling in vitro and in cellulo. A cyclopropenone-caged dibenzoannulated bicyclo[6.1.0]nonyne probe (photo-DMBO) was designed that is unreactive towards tetrazines before light-activation, but engages in iEDDAC after irradiation at 365 nm. Aminoacyl tRNA synthetase/tRNA pairs were discovered for efficient site-specific incorporation of tetrazine-containing amino acids into proteins in living cells. In situ light activation of photo-DMBO conjugates allows labeling of tetrazine-modified proteins in living E. coli. This allows proteins in living cells to be modified in a spatio-temporally controlled manner and may be extended to photo-induced and site-specific protein labeling in animals.


Assuntos
Compostos Bicíclicos com Pontes/química , Ciclopropanos/química , Proteínas de Escherichia coli/química , Corantes Fluorescentes/química , Compostos Heterocíclicos com 1 Anel/química , Luz , Compostos Bicíclicos com Pontes/síntese química , Reação de Cicloadição , Corantes Fluorescentes/síntese química , Estrutura Molecular , Processos Fotoquímicos
8.
Bioorg Med Chem ; 27(17): 3879-3888, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31324566

RESUMO

The modulation of VDR signaling is important in regulating tumor-related signal transduction and protecting from microorganismal infection. In this study we discovered by luciferase reporter assay that several fused bicyclic derivatives of 1H-pyrrolo[1,2-c]imidazol-1-one with the assistance of calcitriol result in up to three-fold increases of VDR promoter activity. Preliminary SAR results from 20 compounds disclose that ideal VDR signaling regulators of these compounds are built up by the optimal combination of multiple factors. Western blot analysis indicates that compounds of ZD-3, ZD-4 and ZD-5 not only significantly upregulate p62 and LC3-II but also elevate the ratio of LC3-II/LC3-I, which possibly leads to activated autophagy. All of five compounds also significantly downregulate p65 and upregulate p-p65 and ZD-3 is the most active one to NF-κB signaling, suggesting a possible induction of apoptosis through the regulation of NF-κB signal transduction mediated by VDR signaling. Compounds of ZD-3, ZD-4 and ZD-5 significantly counteract the interference by VDR shRNA, in which ZD-3 gets the highest compensation of VDR expression and the highest ratio of LC3-II/LC3-I, indicating that ZD-3 very likely activates VDR-mediated autophagy. Taken together, these 1H-pyrrolo[1,2-c]imidazol-1-one derivatives can modulate VDR signaling, possibly resulting in the regulation of some signal pathways to induce autophagy and apoptosis.


Assuntos
Compostos Bicíclicos com Pontes/farmacologia , Descoberta de Drogas , Imidazóis/farmacologia , Receptores de Calcitriol/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Compostos Bicíclicos com Pontes/síntese química , Compostos Bicíclicos com Pontes/química , Relação Dose-Resposta a Droga , Células HeLa , Humanos , Imidazóis/síntese química , Imidazóis/química , Estrutura Molecular , RNA Interferente Pequeno/farmacologia , Receptores de Calcitriol/metabolismo , Relação Estrutura-Atividade
9.
Bioorg Chem ; 89: 103020, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31185392

RESUMO

Despite recent advancements in its control, malaria is still a deadly parasitic disease killing millions of people each year. Progresses in combating the infection have been made by using the so-called artemisinin combination therapies (ACTs). Natural and synthetic peroxides are an important class of antimalarials. Here we describe a new series of peroxides synthesized through a new elaboration of the scaffold of bicyclic-fused/bridged synthetic endoperoxides previously developed by us. These peroxides are produced by a straightforward synthetic protocol and are characterized by submicromolar potency when tested against both chloroquine-sensitive and chloroquine-resistant Plasmodium falciparum strains. To investigate their mode of action, the biomimetic reaction of the representative compound 6w with Fe(II) was studied by EPR and the reaction products were characterized by NMR. Rationalization of the observed structure-activity relationship studies was performed by molecular docking. Taken together, our data robustly support the hypothesized mode of activation of peroxides 6a-cc and led to the definition of the key structural requirements responsible for the antiplasmodial potency. These data will pave the way in future to the rational design of novel optimized antimalarials suitable for in vivo investigation.


Assuntos
Antimaláricos/farmacologia , Materiais Biomiméticos/farmacologia , Compostos Bicíclicos com Pontes/farmacologia , Compostos Férricos/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Antimaláricos/síntese química , Antimaláricos/química , Materiais Biomiméticos/síntese química , Materiais Biomiméticos/química , Compostos Bicíclicos com Pontes/síntese química , Compostos Bicíclicos com Pontes/química , Relação Dose-Resposta a Droga , Compostos Férricos/síntese química , Compostos Férricos/química , Estrutura Molecular , Testes de Sensibilidade Parasitária , Relação Estrutura-Atividade
10.
J Am Chem Soc ; 141(20): 8088-8092, 2019 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-31042866

RESUMO

The total synthesis of principinol D, a rearranged kaurane diterpenoid, is reported. This grayanane natural product is constructed via a convergent fragment coupling approach, wherein the central seven-membered ring is synthesized at a late stage. The bicyclo[3.2.1]octane fragment is accessed by a Ni-catalyzed α-vinylation reaction. Strategic reductions include a diastereoselective SmI2-mediated ketone reduction with PhSH and a new protocol for selective ester reduction in the presence of ketones. The convergent strategy reported herein may be an entry point to the larger class of kaurane diterpenoids.


Assuntos
Diterpenos de Caurano/síntese química , Compostos Bicíclicos com Pontes/síntese química , Ciclização , Cicloexanonas/química , Oxirredução , Estereoisomerismo
11.
Org Biomol Chem ; 17(22): 5615-5632, 2019 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-31120090

RESUMO

Routes to bicyclic tetramates derived from cysteine permitting ready incorporation of functionality at two different points around the periphery of a heterocyclic skeleton are reported. This has enabled the identification of systems active against Gram-positive bacteria, some of which show gyrase and RNA polymerase inhibitory activity. In particular, tetramates substituted with glycosyl side chains, chosen to impart polarity and aqueous solubility, show high antibacterial activity coupled with modest gyrase/polymerase activity in two cases. An analysis of physicochemical properties indicates that the antibacterially active tetramates generally occupy physicochemical space with MW of 300-600, clog D7.4 of -2.5 to 4 and rel. PSA of 11-22%. This work demonstrates that biologically active 3D libraries are readily available by manipulation of a tetramate skeleton.


Assuntos
Antibacterianos/farmacologia , Compostos Bicíclicos com Pontes/farmacologia , Cisteína/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Antibacterianos/síntese química , Antibacterianos/química , Compostos Bicíclicos com Pontes/síntese química , Compostos Bicíclicos com Pontes/química , Cisteína/química , Testes de Sensibilidade Microbiana , Estrutura Molecular
12.
J Med Chem ; 62(3): 1502-1522, 2019 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-30605331

RESUMO

(N)-Methanocarba ([3.1.0]bicyclohexyl) adenosines and corresponding ribosides were synthesized to identify novel A1 adenosine receptor (A1AR) agonists for CNS or peripheral applications. Human and mouse AR binding was determined to assess the constrained ring system's A1AR compatibility. N6-Dicyclobutylmethyl ribose agonist (9, MRS7469, >2000-fold selective for A1AR) and known truncated N6-dicyclopropylmethyl methanocarba 7 (MRS5474) were drug-like. The pure diastereoisomer of known riboside 4 displayed high hA1AR selectivity. Methanocarba modification reduced A1AR selectivity of N6-dicyclopropylmethyl and endo-norbornyladenosines but increased ribavirin selectivity. Most analogues tested (ip) were inactive or weak in inducing mouse hypothermia, despite mA1AR full agonism and variable mA3AR efficacy, but strong hypothermia by 9 depended on A1AR, which reflects CNS activity (determined using A1AR or A3AR null mice). Conserved hA1AR interactions were preserved in modeling of 9 and methanocarba equivalent 24 (∼400-fold A1AR-selective). Thus, we identified, and characterized in vivo, ribose and methanocarba nucleosides, including with A1AR-enhancing N6-dicyclobutylmethyl-adenine and 1,2,4-triazole-3-carboxamide (40, MRS7451) nucleobases.


Assuntos
Agonistas do Receptor A1 de Adenosina/farmacologia , Adenosina/análogos & derivados , Adenosina/farmacologia , Compostos Bicíclicos com Pontes/farmacologia , Adenosina/síntese química , Agonistas do Receptor A1 de Adenosina/síntese química , Agonistas do Receptor A1 de Adenosina/farmacocinética , Animais , Compostos Bicíclicos com Pontes/síntese química , Compostos Bicíclicos com Pontes/farmacocinética , Células CHO , Cricetulus , Desenho de Fármacos , Células HEK293 , Humanos , Macaca fascicularis , Masculino , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Estrutura Molecular , Receptor A1 de Adenosina/metabolismo , Relação Estrutura-Atividade
13.
Bioorg Med Chem Lett ; 29(2): 248-251, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30501964

RESUMO

An innovative and efficient reagent- and scaffold-based diversity oriented synthesis (DOS) of a fragment set was developed for fragment-based drug discovery (FBDD) programs. Twelve diverse, functionalized and bicyclic scaffolds were rapidly accessed by adopting a convenient synthetic toolkit around three privileged azine cores in order to effectively modulate biomolecules. These structures are characterized by both key motifs for interacting with diverse biological targets via hydrogen bonds and useful points of growth for subsequent fragment optimization.


Assuntos
Compostos Azo/síntese química , Compostos Bicíclicos com Pontes/síntese química , Compostos Azo/química , Compostos Bicíclicos com Pontes/química , Descoberta de Drogas , Ligação de Hidrogênio , Estrutura Molecular
14.
Chemistry ; 25(14): 3496-3500, 2019 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-30589135

RESUMO

The PYR/PYL/RCAR protein families have recently emerged as receptors of the phytohormone abscisic acid (ABA, 1), which regulates plant responses to environmental stress. These families have multiple members with different physiological actions, and so selective agonists or antagonists are needed both as tools to elucidate functional differences and as lead compounds for agrochemicals. We previously identified RK460 (rac-3 a) as a PYR1-selective antagonist, and showed that it possesses five stereocenters on a 6,5-cis-bicyclo skeleton. Here, we synthesized all the stereoisomers of RK460 and evaluated their activity towards a panel of receptors. Relative stereochemistry as well as absolute stereochemistry was important for selective action.


Assuntos
Ácido Abscísico/metabolismo , Proteínas de Arabidopsis/antagonistas & inibidores , Arabidopsis/efeitos dos fármacos , Compostos Bicíclicos com Pontes/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Reguladores de Crescimento de Planta/metabolismo , Receptores de Superfície Celular/antagonistas & inibidores , Arabidopsis/metabolismo , Proteínas de Arabidopsis/metabolismo , Compostos Bicíclicos com Pontes/síntese química , Compostos Bicíclicos com Pontes/química , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Reguladores de Crescimento de Planta/síntese química , Reguladores de Crescimento de Planta/química , Receptores de Superfície Celular/metabolismo , Estereoisomerismo
15.
Bioorg Med Chem ; 27(2): 338-342, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30545734

RESUMO

Isocarbacyclin is a valuable synthetic analogue of prostacyclin with potential neuroprotective effects for the treatment of ischemic stroke. Herein, we describe the synthesis of isocarbacyclin and bicyclic analogues in only 7-10 steps, with the ω-side chain diversified at a late stage. A combination of new reaction design, function-oriented synthesis, and late-stage diversification led to a series of compounds that were tested for their neuroprotective activities. Efforts toward the synthesis of tricyclic analogues of isocarbacyclin, using the same combination of metal-catalyzed reactions, is also described.


Assuntos
Compostos Bicíclicos com Pontes/farmacologia , Epoprostenol/análogos & derivados , Fármacos Neuroprotetores/farmacologia , Animais , Isquemia Encefálica/tratamento farmacológico , Compostos Bicíclicos com Pontes/síntese química , Compostos Bicíclicos com Pontes/química , Epoprostenol/síntese química , Epoprostenol/química , Epoprostenol/farmacologia , Camundongos , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Estereoisomerismo , Acidente Vascular Cerebral/tratamento farmacológico
16.
Angew Chem Int Ed Engl ; 58(3): 681-694, 2019 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-30378226

RESUMO

This Minireview is focused on an in-depth discussion of comparative strategies to construct the gelsemine and gelsedine classes of the gelsemium alkaloids. This document highlights the diversity of strategies used to access specific motifs found within these targets: a) the fused "[3.2.1]bicycle" (in gelsemine) and "oxabicycle" (in gelsedine class); b) the "piroxindole" moiety with C7 quaternary center; c) the "N-heterocycles" and d) the "THP" moiety with C20 quaternary center (in gelsemine).


Assuntos
Alcaloides/síntese química , Técnicas de Química Sintética/métodos , Gelsemium/química , Oxindois/síntese química , Compostos Policíclicos/síntese química , Alcaloides/química , Produtos Biológicos/síntese química , Produtos Biológicos/química , Compostos Bicíclicos com Pontes/síntese química , Compostos Bicíclicos com Pontes/química , Oxindois/química , Compostos Policíclicos/química
17.
Nat Prod Rep ; 36(2): 263-288, 2019 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-30215657

RESUMO

Covering: January 2012 to January 2018 Sesterterpenoids are a small family of terpenes that often possess intriguing biological profiles and complicated chemical structures. Their total syntheses are usually remarkably challenging, requiring methodological and strategic innovation. In this review, we summarize and discuss the total syntheses of sesterterpenoids published during the coverage period, and the key chemical transformations are highlighted.


Assuntos
Terpenos/síntese química , 4-Butirolactona/análogos & derivados , 4-Butirolactona/síntese química , Compostos Bicíclicos com Pontes/síntese química , Estrutura Molecular , Sesquiterpenos/síntese química , Sesterterpenos/síntese química
18.
Angew Chem Int Ed Engl ; 57(45): 14921-14925, 2018 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-30199596

RESUMO

The analysis of volatiles released by marine Salinispora bacteria uncovered a new class of natural compounds displaying an unusual bicyclic [3.1.0]-lactone skeleton. Although only sub-µg quantities of the compounds were available, the combination of analytical methods, computational spectroscopy, and synthesis allowed unambiguous structural identification of the compounds, called salinilactones, without the need for isolation. Orthogonal hyphenated methods, GC/MS and solid-phase GC/IR allowed to propose a small set of structures consistent with the data. A candidate structure was selected by comparison of DFT-calculated IR spectra and the experimental IR-spectrum. Synthesis confirmed the structure and absolute configuration of three bicyclic lactones, salinilactones A-C. The salinilactones are structurally closely related to the A-factor class of compounds, autoregulators from streptomycete bacteria. They exhibited inhibitory activity against Salinispora and Streptomyces strains.


Assuntos
Actinobacteria/química , Lactonas/química , 4-Butirolactona/análogos & derivados , 4-Butirolactona/química , Actinobacteria/efeitos dos fármacos , Antibacterianos/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Compostos Bicíclicos com Pontes/síntese química , Compostos Bicíclicos com Pontes/química , Compostos Bicíclicos com Pontes/farmacologia , Cromatografia Gasosa-Espectrometria de Massas , Lactonas/síntese química , Lactonas/farmacologia , Espectrofotometria Infravermelho , Streptomyces/química , Streptomyces/efeitos dos fármacos
19.
Chemistry ; 24(72): 19250-19257, 2018 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-30255960

RESUMO

The chemical synthesis of a bicycle inspired by the natural lasso peptide sungsanpin using a combination of solid-phase and in-solution chemistries is described. The bicyclic-derived topoisomer was designed by introducing a covalent linkage between the ring and the loop, which allowed the tying of these two parts of the peptide, rendering the bicyclic structure. Several structural techniques, such as MS fragmentation, ion-mobility and NMR spectroscopic analysis were used to characterize the bicycle. Ion-mobility spectroscopy studies revealed that it showed lasso-like behavior. Its 3D structure was predicted on the basis of the NMR restraints. In addition, the high proteolytic and thermal stability of the bicycle potentially make it a suitable scaffold for epitope grafting.


Assuntos
Compostos Bicíclicos com Pontes/química , Peptídeos/química , Compostos Bicíclicos com Pontes/síntese química , Modelos Moleculares , Peptídeos/síntese química , Conformação Proteica , Estabilidade Proteica
20.
Bioorg Med Chem Lett ; 28(15): 2605-2610, 2018 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-29970308

RESUMO

We describe the design, synthesis, X-ray studies, and biological evaluation of novel BACE1 inhibitors containing bicyclic isoxazoline carboxamides as the P3 ligand in combination with methyl cysteine, methylsulfonylalanine and Boc-amino alanine as P2 ligands. Inhibitor 3a displayed a BACE1 Ki value of 10.9 nM and EC50 of 343 nM. The X-ray structure of 3a bound to the active site of BACE1 was determined at 2.85 Šresolution. The structure revealed that the major molecular interactions between BACE1 and the bicyclic tetrahydrofuranyl isoxazoline heterocycle are van der Waals in nature.


Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Compostos Bicíclicos com Pontes/química , Compostos Bicíclicos com Pontes/farmacologia , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Alanina/análogos & derivados , Alanina/química , Amidas/química , Secretases da Proteína Precursora do Amiloide/metabolismo , Ácido Aspártico Endopeptidases/metabolismo , Compostos Bicíclicos com Pontes/síntese química , Ácidos Carboxílicos/química , Domínio Catalítico , Cristalografia por Raios X , Cisteína/análogos & derivados , Cisteína/química , Humanos , Isoxazóis/química , Estrutura Molecular , Inibidores de Proteases/síntese química
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