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1.
Int J Mol Sci ; 22(5)2021 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-33803437

RESUMO

Melanoma is the deadliest form of skin cancer and accounts for about three quarters of all skin cancer deaths. Especially at an advanced stage, its treatment is challenging, and survival rates are very low. In previous studies, we showed that the constituents of the roots of Onosma paniculata as well as a synthetic derivative of the most active constituent showed promising results in metastatic melanoma cell lines. In the current study, we address the question whether we can generate further derivatives with optimized activity by synthesis. Therefore, we prepared 31, mainly novel shikonin derivatives and screened them in different melanoma cell lines (WM9, WM164, and MUG-Mel2 cells) using the XTT viability assay. We identified (R)-1-(1,4-dihydro-5,8-dihydroxy-1,4-dioxonaphthalen-2-yl)-4-methylpent-3-enyl 2-cyclopropyl-2-oxoacetate as a novel derivative with even higher activity. Furthermore, pharmacological investigations including the ApoToxGloTM Triplex assay, LDH assay, and cell cycle measurements revealed that this compound induced apoptosis and reduced cells in the G1 phase accompanied by an increase of cells in the G2/M phase. Moreover, it showed hardly any effects on the cell membrane integrity. However, it also exhibited cytotoxicity against non-tumorigenic cells. Nevertheless, in summary, we could show that shikonin derivatives might be promising drug leads in the treatment of melanoma.


Assuntos
Antineoplásicos , Apoptose/efeitos dos fármacos , Ciclopropanos , Melanoma/tratamento farmacológico , Naftoquinonas , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Ciclopropanos/síntese química , Ciclopropanos/química , Ciclopropanos/farmacologia , Humanos , Melanoma/metabolismo , Naftoquinonas/síntese química , Naftoquinonas/química , Naftoquinonas/farmacologia
2.
Molecules ; 26(4)2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33671969

RESUMO

The fractionation of an ethanol extract of the bark of Trichilia adolfi yielded four novel limonoids (trichilinones A-D, 1-4), with five fused rings and related to the hortiolide-type limonoids. Starting with an ε-lactone, which is α,ß-unsaturated in trichilinones A and D (1 and 4), attached to a tetrahydrofuran ring that is connected to an unusual bicyclo [5.1.0] hexane system, joined with a cyclopentanone with a 3-furanyl substituent [(2-oxo)-furan-(5H)-3-yl in trichilinone D (4)], the four compounds isolated display a new 7/5/3/5/5 limonoid ring system. Their structures were established based on extensive analysis of NMR spectroscopic data. As the crude extract possessed anti-leishmanial properties, the compounds were assayed for cytotoxic and anti-parasitic activities in vitro in murine macrophages cells (Raw 264.7) and leishmania promastigotes (L. amazoniensis and L. braziliensis), respectively. The compounds showed moderate cytotoxicity (approximately 70 µg/mL), but are not responsible for the leishmanicidal effect of the extract.


Assuntos
Ciclopropanos/análise , Limoninas/análise , Meliaceae/química , Animais , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Ciclopropanos/química , Ciclopropanos/farmacologia , Leishmania/efeitos dos fármacos , Limoninas/química , Limoninas/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/parasitologia , Camundongos , Espectroscopia de Prótons por Ressonância Magnética , Células RAW 264.7
4.
J Med Chem ; 64(1): 677-694, 2021 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-33370104

RESUMO

A search for structurally diversified Tyk2 JH2 ligands from 6 (BMS-986165), a pyridazine carboxamide-derived Tyk2 JH2 ligand as a clinical Tyk2 inhibitor currently in late development for the treatment of psoriasis, began with a survey of six-membered heteroaryl groups in place of the N-methyl triazolyl moiety in 6. The X-ray co-crystal structure of an early lead (12) revealed a potential new binding pocket. Exploration of the new pocket resulted in two frontrunners for a clinical candidate. The potential hydrogen bonding interaction with Thr599 in the pocket was achieved with a tertiary amide moiety, confirmed by the X-ray co-crystal structure of 29. When the diversity search was extended to nicotinamides, a single fluorine atom addition was found to significantly enhance the permeability, which directly led to the discovery of 7 (BMS-986202) as a clinical Tyk2 inhibitor that binds to Tyk2 JH2. The preclinical studies of 7, including efficacy studies in mouse models of IL-23-driven acanthosis, anti-CD40-induced colitis, and spontaneous lupus, will also be presented.


Assuntos
Ciclopropanos/farmacologia , Descoberta de Drogas , Oxazóis/farmacologia , Inibidores de Proteínas Quinases/farmacologia , TYK2 Quinase/antagonistas & inibidores , Animais , Catálise , Cristalografia por Raios X , Ciclopropanos/química , Humanos , Camundongos , Oxazóis/química , Ligação Proteica , Inibidores de Proteínas Quinases/química , Psoríase/tratamento farmacológico , Relação Estrutura-Atividade , TYK2 Quinase/metabolismo
5.
Arch Biochem Biophys ; 692: 108516, 2020 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-32745463

RESUMO

Ketol-acid reductoisomerase (KARI), the second enzyme in the branched-chain amino acid (BCAA) biosynthesis pathway, is an emerging target for the discovery of biocides. Here, we demonstrate that cyclopropane-1,1-dicarboxylate (CPD) inhibits KARIs from the pathogens Mycobacterium tuberculosis (Mt) and Campylobacter jejuni (Cj) reversibly with Ki values of 3.03 µM and 0.59 µM, respectively. Another reversible inhibitor of both KARIs, Hoe 704, is more potent than CPD with Ki values of 300 nM and 110 nM for MtKARI and CjKARI, respectively. The most potent inhibitor tested here is N-hydroxy-N-isopropyloxamate (IpOHA). It has a Ki of ~26 nM for MtKARI, but binds rather slowly (kon ~900 M-1s-1). In contrast, IpOHA binds more rapidly (kon ~7000 M-1s-1) to CjKARI and irreversibly.


Assuntos
Proteínas de Bactérias/antagonistas & inibidores , Campylobacter jejuni/enzimologia , Inibidores Enzimáticos/química , Cetol-Ácido Redutoisomerase/antagonistas & inibidores , Mycobacterium tuberculosis/enzimologia , Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Campylobacter jejuni/química , Ciclopropanos/química , Ácidos Dicarboxílicos/química , Ácidos Hidroxâmicos/química , Cetol-Ácido Redutoisomerase/química , Cetol-Ácido Redutoisomerase/metabolismo , Mycobacterium tuberculosis/química , Compostos Organofosforados/química
6.
Eur J Med Chem ; 194: 112244, 2020 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-32224380

RESUMO

Three series of novel 4-phenoxypyridine derivatives containing 4-methyl-6-oxo-1,6-dihydropyridazine- 3-carboxamide, 5-methyl-4-oxo-1,4-dihydropyridazine-3-carboxamide and 4-methyl-3,5-dioxo-2,3,4,5- tetrahydro-1,2,4-triazine-6-carboxamide moieties were synthesized and evaluated for their in vitro inhibitory activitives against c-Met kinase and cytotoxic activitives against A549, H460, HT-29 cancer cell lines. The results indicated that most of the compounds showed moderate to good antitumor activitives. The most promising compound 26a (with c-Met IC50 value of 0.016 µM) showed remarkable cytotoxicity against A549, H460, and HT-29 cell lines with IC50 values of 1.59 µM, 0.72 µM and 0.56 µM, respectively. Their preliminary structure-activity relationships (SARs) studies indicate that 4-methyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide was more preferred as linker part, and electron-withdrawing groups on the terminal phenyl rings are beneficial for improving the antitumor activitives. Furthermore, the colony formation, acridine orange/ethidium bromide (AO/EB) staining, apoptosis, and wound-healing assay of 26a were performed on HT-29 and/or A549 cell lines.


Assuntos
Amidas/farmacologia , Antineoplásicos/farmacologia , Ciclopropanos/farmacologia , Desenho de Fármacos , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Células A549 , Amidas/síntese química , Amidas/química , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ciclopropanos/síntese química , Ciclopropanos/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HT29 , Humanos , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Proteínas Proto-Oncogênicas c-met/metabolismo , Relação Estrutura-Atividade , Cicatrização/efeitos dos fármacos
7.
Yakugaku Zasshi ; 140(3): 329-344, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32115550

RESUMO

I have engaged in medicinal chemical studies based on the theoretical design of bioactive compounds. First, I present a three-dimensional structural diversity-oriented conformational restriction strategy for developing bioactive compounds based on the characteristic steric and stereoelectronic features of cyclopropane. Using this strategy, various biologically active small molecule compounds, such as receptor agonists/antagonists and enzyme inhibitors, were effectively developed. The strategy was also applied to develop versatile peptidomimetics and membrane-permeable cyclic peptides. Next, studies on Ca2+-mobilizing second messengers, cyclic ADP-ribose (cADPR) and myo-inositol trisphosphates (IP3), are described. In these studies, stable equivalents of cADPR were developed, since biological studies of cADPR have been limited due to its instability. Various potent IP3 receptor ligands, which were designed using the d-glucose structure as a bioisostere of the myo-inositol moiety of IP3, have been identified. Organic chemistry studies have also been extensively performed, because excellent organic chemistry is essential for promoting high-level medicinal chemical studies. For examples, new methods for the synthesis of chiral cyclopropanes, new radical reactions with silicon tethers, and kinetic anomeric effect-dependent stereoselective glycosidations have been developed.


Assuntos
ADP-Ribose Cíclica/química , Ciclopropanos/química , Desenho de Fármacos , Desenvolvimento de Medicamentos , Inositol 1,4,5-Trifosfato/química , Cálcio/metabolismo , Ciclopropanos/síntese química , Inibidores Enzimáticos , Glucose/química , Ligantes , Conformação Molecular , Fenômenos de Química Orgânica , Peptídeos Cíclicos/química , Peptidomiméticos , Estereoisomerismo
8.
Org Lett ; 22(2): 714-717, 2020 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-31908171

RESUMO

A convergent sequence to access the indole alkaloid (±)-melokhanine E in 12-steps (8-step longest linear sequence) and an 11% overall yield is reported. The approach utilizes two cyclopropane moieties as reactive precursors to a 1,3-dipole and imine species to enable stereoselective construction of the core scaffold through a formal [3 + 2] cycloaddition. The natural product was evaluated for its antimicrobial activity based on isolation reports; however, no activity was observed. The reported efforts serve as a synthetic platform to prepare an array of alkaloids bearing this core structural motif.


Assuntos
Ciclopropanos/química , Iminas/química , Alcaloides de Triptamina e Secologanina/síntese química , Reação de Cicloadição , Estrutura Molecular , Alcaloides de Triptamina e Secologanina/química , Estereoisomerismo
9.
Org Biomol Chem ; 18(5): 830-844, 2020 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-31956877

RESUMO

Avibactam is a non ß-lactam ß-lactamase inhibitor that has recently been approved in association with a ß-lactam antibiotic for the treatment of severe infections caused by otherwise resistant bacteria. Its therapeutic success encouraged the development of many congeners based on its particular diazabicyclooctane scaffold. This review presents a detailed overview of the synthetic strategies that have been implemented to acces these complex bicyclic compounds with a particular focus on those that are currently on the market or in clinical trials.


Assuntos
Compostos Aza/síntese química , Compostos Azabicíclicos/síntese química , Ciclo-Octanos/síntese química , Inibidores de beta-Lactamases/síntese química , Compostos Aza/química , Compostos Aza/farmacologia , Compostos Azabicíclicos/química , Compostos Azabicíclicos/farmacologia , Ciclo-Octanos/química , Ciclo-Octanos/farmacologia , Ciclopropanos/química , Inibidores de beta-Lactamases/química , Inibidores de beta-Lactamases/farmacologia
10.
Chem Soc Rev ; 49(3): 908-950, 2020 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-31958107

RESUMO

Donor and donor-donor carbenes are two important kinds of carbenes, which have experienced tremendous growth in the past two decades. This review provides a comprehensive overview of the recent development of donor and donor-donor carbene chemistry. The development of this chemistry offers efficient protocols to construct a wide variety of C-C and C-X bonds in organic synthesis. This review is organized based on the different types of carbene precursors, including diazo compounds, hydrazones, enynones, cycloheptatrienes and cyclopropenes. The typical transformations, the reaction mechanisms, as well as their subsequent applications in the synthesis of complex natural products and bioactive molecules are discussed. Due to the rapidly increasing interest in this area, we believe that this review will provide a timely and comprehensive discussion of recent progress in donor and donor-donor carbene chemistry.


Assuntos
Metano/análogos & derivados , Compostos Azo/química , Catálise , Ciclopropanos/química , Hidrazonas/química , Metais/química , Metano/síntese química , Estrutura Molecular , Estereoisomerismo
11.
Molecules ; 25(2)2020 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-31936532

RESUMO

A traceless approach to quinolin-4(1H)-one scaffolds through Rh(III)-catalyzed redox-neutral [3+3] cyclization of N-nitrosoanilines with cyclopropenones has been achieved. This protocol features short reaction time and atom-economical combination without extra additives, which can be further applied in the construction of privileged heterocyclic compounds in pharmaceutical chemistry.


Assuntos
Aporfinas/química , Ciclopropanos/química , Compostos Heterocíclicos/química , Ródio/química , Catálise , Ciclização , Hidroxiquinolinas/química , Indóis/química , Estrutura Molecular , Oxirredução
12.
J Med Chem ; 63(5): 2263-2281, 2020 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-31589043

RESUMO

ß-Site amyloid precursor protein cleaving enzyme 1 (BACE1) is an aspartyl protease that plays a key role in the production of amyloid ß (Aß) in the brain and has been extensively pursued as a target for the treatment of Alzheimer's disease (AD). BACE2, an aspartyl protease that is structurally related to BACE1, has been recently reported to be involved in melanosome maturation and pigmentation. Herein, we describe the development of a series of cyclopropylthiazines as potent and orally efficacious BACE1 inhibitors. Lead optimization led to the identification of 20, a molecule with biochemical IC50 BACE2/BACE1 ratio of 47. Administration of 20 resulted in no skin/fur color change in a 13-day mouse hypopigmentation study and demonstrated robust and sustained reduction of CSF and brain Aß40 levels in rat and monkey pharmacodynamic models. On the basis of a compelling data package, 20 (AM-6494) was advanced to preclinical development.


Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Ciclopropanos/farmacologia , Inibidores Enzimáticos/farmacologia , Tiazinas/farmacologia , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Peptídeos beta-Amiloides/metabolismo , Animais , Ácido Aspártico Endopeptidases/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Ciclopropanos/química , Ciclopropanos/farmacocinética , Ciclopropanos/uso terapêutico , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/uso terapêutico , Humanos , Masculino , Camundongos , Modelos Moleculares , Fragmentos de Peptídeos/líquido cefalorraquidiano , Fragmentos de Peptídeos/metabolismo , Ratos Sprague-Dawley , Tiazinas/química , Tiazinas/farmacocinética , Tiazinas/uso terapêutico
13.
Org Lett ; 21(20): 8473-8478, 2019 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-31596600

RESUMO

A unified step-economical strategy for accessing histone deacetylase inhibitory peptides is proposed, based on the late-stage installation of multiple zinc-binding functionalities via the cleavage of the strained cyclopropane ring in the common pluripotent cyclopropanol precursor. The efficacy of the proposed diversity-oriented approach has been validated by short stereoselective synthesis of natural product chlamydocin, containing a challenging-to-install fragment of (2S,9S)-2-amino-8-oxo-9,10-epoxydecanoic acid (Aoe) and a range of its analogues, derivatives of 2-amino-8-oxodecanoic and 2-aminosuberic acids.


Assuntos
Ciclopropanos/farmacologia , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Ciclopropanos/química , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Estrutura Molecular , Peptídeos Cíclicos/síntese química , Peptídeos Cíclicos/química , Peptídeos Cíclicos/farmacologia , Estereoisomerismo
14.
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
15.
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
16.
J Agric Food Chem ; 67(42): 11591-11597, 2019 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-31557017

RESUMO

A simple and eco-friendly dispersive solid-phase extraction method coupled with ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was developed for the determination of the chiral pesticide tefluthrin in food and environmental samples. The response surface methodology was applied to optimize separation conditions. The elution order of tefluthrin enantiomers was Z-cis-(1S,3S)-(-)-tefluthrin and Z-cis-(1R,3R)-(+)-tefluthrin on a Lux Cellulose-1 chiral column was identified via a polarimeter and vibrating circular dichroism. The average recoveries in five matrices ranged from 76.9 to 107.6%, with intraday relative standard deviations (RSDs) less than 15.6% and interday RSDs less than 12.5% for two enantiomers. The enantioselective degradation was investigated via laboratory incubation experiments. Slightly enantioselective degradation was observed under aerobic conditions; (1S,3S)-tefluthrin degraded preferentially with the enantiomer fraction value of 0.57 at 120 days of incubation. No remarkable enantioselective degradation was observed under anaerobic and sterile conditions. It was the first time that pyrethroid pesticides were determined at the enantiomer levels via UPLC-MS/MS. This novel method was successfully applied for the enantioselective analysis of tefluthrin enantiomers in authentic samples, indicating its efficacy in investigating the environmental stereochemistry of tefluthrin in the food web and environment. It is of crucial importance to improve risk assessment and regulation of chiral pesticides in an agricultural system.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Ciclopropanos/química , Hidrocarbonetos Fluorados/química , Praguicidas/química , Poluentes do Solo/química , Solo/química , Espectrometria de Massas em Tandem/métodos , Estereoisomerismo
17.
Molecules ; 24(17)2019 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-31480796

RESUMO

Diazo compounds have proven to be a useful class of carbenes or metal carbenoids sources under thermal, photochemical, or metal-catalyzed conditions, which can subsequently undergo a wide range of synthetically important transformations. Recently, asymmetric photocatalysis has provoked increasing research interests, and great advances have been made in this discipline towards the synthesis of optically enriched compounds. In this context, the past two decades have been the most productive period in the developments of enantioselective photochemical reactions of diazo compounds due to a better understanding of the reactivities of diazo compounds and the emergence of new catalytic modes, as well as easier access to and treatment of stabilized diazo compounds. This review highlights these impressive achievements according to the reaction type, and the general mechanisms and stereochemical inductions are briefly discussed as well.


Assuntos
Compostos Azo/química , Processos Fotoquímicos , Catálise , Reação de Cicloadição , Ciclopropanos/síntese química , Ciclopropanos/química , Estereoisomerismo
18.
Eur J Med Chem ; 182: 111626, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31445232

RESUMO

A new series of fluorinated 5-HT2C agonists were designed and synthesized on the basis of our previous work on 2-phenylcyclopropylmethylamines as a potential approach for the treatment of central nervous system disorders. Key fluorinated cyclopropane moieties were constructed through transition metal catalyzed [2 + 1]-cycloaddition of aromatic vinyl fluorides, and the absolute stereochemistry of the representative compound (-)-21a was established. Functional activity measuring calcium flux at 5-HT2 receptors reveals high potency for compounds (+)-21a-d. In particular, (+)-21b had no detectable 5-HT2B agonism and displayed reasonable selectivity against 5-HT2A. Molecular docking studies were further performed to explain the compounds' possible binding poses to the 5-HT2C receptor.


Assuntos
Ciclopropanos/farmacologia , Desenho de Fármacos , Metilaminas/farmacologia , Receptor 5-HT2C de Serotonina/metabolismo , Ciclopropanos/síntese química , Ciclopropanos/química , Relação Dose-Resposta a Droga , Halogenação , Humanos , Metilaminas/síntese química , Metilaminas/química , Simulação de Acoplamento Molecular , Estrutura Molecular , Receptor 5-HT2B de Serotonina/metabolismo , Relação Estrutura-Atividade
19.
Org Lett ; 21(18): 7380-7385, 2019 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-31465235

RESUMO

We report the catalytic enantio- and diastereoselective preparation of aminocyclopropanes by the cyclopropanation of terminal and (Z)-internal 2-azadienes with donor/acceptor carbenes derived from α-diazoesters. The resulting cyclopropanes bear quaternary carbon stereogenic centers vicinal to the amino-substituted carbon and are formed as a single diastereomer in up to 99:1 er and 97% yield with 0.5 mol % of Rh2(DOSP)4 and only 1.5 equiv of the diazo reagent. Transformations with internal azadienes afford cyclopropanes with three contiguous stereogenic centers.


Assuntos
Alcadienos/química , Compostos Aza/química , Carbono/química , Ciclopropanos/síntese química , Compostos Organometálicos/química , Catálise , Ciclopropanos/química , Estrutura Molecular , Estereoisomerismo
20.
Org Lett ; 21(17): 6966-6971, 2019 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-31433193

RESUMO

The Simmons-Smith-Furukawa reaction was used to generate 4'/5'-spirocyclopropanated uridine analogs from electron-rich exocyclic enol esters. During synthesis, the native hydroxylation pattern of the nucleoside is preserved and offers the possibility for a late stage 5'-phosphorylation at the spirocyclopropanol moiety. All synthesized spirocyclopropanated uridine derivatives, including the corresponding 5'-monophosphate (cpUMP), were evaluated with respect to their antiviral activity in an HRSV assay showing moderate, but promising activity.


Assuntos
Antivirais/farmacologia , Ciclopropanos/farmacologia , Vírus Sincicial Respiratório Humano/efeitos dos fármacos , Compostos de Espiro/farmacologia , Uridina/farmacologia , Antivirais/síntese química , Antivirais/química , Cristalografia por Raios X , Ciclopropanos/síntese química , Ciclopropanos/química , Testes de Sensibilidade Microbiana , Modelos Moleculares , Conformação Molecular , Compostos de Espiro/síntese química , Compostos de Espiro/química , Uridina/análogos & derivados , Uridina/síntese química
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