Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 11 de 11
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
J Org Chem ; 89(5): 3194-3201, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38349765

RESUMO

The X-H insertion reaction constitutes a powerful tool to create diversity through the diazo decomposition of diazocarbonyl compounds. However, until now, X-H insertion on α-diazo-ß-aryl-ß-hydroxyester scaffolds, readily prepared by aldol-type addition, remained a challenge for the organic chemist. We report herein the first O-H insertions on O-protected α-diazo-ß-aryl-ß-hydroxyesters, providing straightforward access to a wide range of α,ß-dioxygenated esters through modulation of the alcohol and of the aryl substituent. The key feature to achieving this transformation is the use of Rh(I) catalysts, which proved to be crucial to favor the targeted O-H insertion product over the competing 1,2-H and 1,2-Ar migration products. Overall, 32 O-H insertion products have been prepared, in moderate to good yields, with a diastereoisomeric ratio up to 7.5:1 in favor of the syn diastereoisomer.

2.
J Org Chem ; 87(21): 14264-14273, 2022 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-36200939

RESUMO

Acid-catalyzed decomposition of diazocarbonyl compounds triggers a wide range of transformations leading to synthetically useful building blocks with high diversity. In this field, the chemistry of α-diazo-ß-hydroxy ester substrates is largely dominated by migration processes. We describe herein a new approach to original mixed monosilyl acetals from O-protected α-diazo-ß-hydroxy-ß-aryl esters and alcohols, catalyzed by trimethylsilyl trifluoromethanesulfonate (TMSOTf). The ratio between these original mixed acetals, the symmetric acetals, and the migration products fluctuates depending on the catalyst, the nature of the alcohols, and the substituent on the aromatic ring. Fifty-six examples are reported herein with yields up to 71% and diastereoselectivity up to 6:1. Such mixed monosilyl acetals constitute a synthetic equivalent of α-substituted ß-oxoesters with high potential for further transformations.

3.
Org Lett ; 21(9): 2988-2992, 2019 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-30859834

RESUMO

A convergent and rapid synthesis of original C2,C3-unsaturated, C11,C13-keto-enol macrocycles with a peloruside A skeleton has been developed. These original unsaturated macrocycles constitute valuable platforms to access peloruside A analogues with high diversity. The four-fragment strategy implemented features two aldol-type couplings with the central C12-C14 building block TES-diazoacetone and a late-stage ring-closing metathesis. Enantiopure analogue 18ab showed antiproliferative activity in the low micromolar range on NCI and MCF7 tumor cell lines.

4.
Chimia (Aarau) ; 71(12): 836-840, 2017 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-29289244

RESUMO

Buruli ulcer, classified as a neglected tropical disease by the World Health Organization, is caused by a mycobacterium which secretes a macrolidic exotoxin called mycolactone A/B. In this article, several synthetic strategies for the preparation of this toxin are discussed, highlighting the importance of total synthesis for the exploration of biological mechanism underpinning relevant human diseases.


Assuntos
Úlcera de Buruli/etiologia , Macrolídeos/síntese química , Humanos
5.
Org Biomol Chem ; 13(35): 9190-3, 2015 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-26269088

RESUMO

We have recently developed methodology based on oxidative radical reactions for the synthesis of [3.3.0]-bicyclic lactones containing both cyclopentanes and γ-lactams along with application of this methodology to the synthesis of natural products and complex molecular architectures. Herein we report an extension of this methodology to the synthesis of oxygen heterocycles including bicyclic bis-lactones.


Assuntos
Acetatos/química , Furanos/química , Furanos/síntese química , Compostos Organometálicos/química , Técnicas de Química Sintética , Ciclização , Lactonas/síntese química , Lactonas/química , Oxigênio/química
6.
Sci Transl Med ; 7(289): 289ra85, 2015 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-26019221

RESUMO

Inflammation adversely affects the health of millions of people worldwide, and there is an unmet medical need for better anti-inflammatory drugs. We evaluated the therapeutic interest of mycolactone, a polyketide-derived macrolide produced by Mycobacterium ulcerans. Bacterial production of mycolactone in human skin causes a combination of ulcerative, analgesic, and anti-inflammatory effects. Whereas ulcer formation is mediated by the proapoptotic activity of mycolactone on skin cells via hyperactivation of Wiskott-Aldrich syndrome proteins, analgesia results from neuronal hyperpolarization via signaling through angiotensin II type 2 receptors. Mycolactone also blunts the capacity of immune cells to produce inflammatory mediators by an independent mechanism of protein synthesis blockade. In an attempt to isolate the structural determinants of mycolactone's immunosuppressive activity, we screened a library of synthetic subunits of mycolactone for inhibition of cytokine production by activated T cells. The minimal structure retaining immunosuppressive activity was a truncated version of mycolactone, missing one of the two core-branched polyketide chains. This compound inhibited the inflammatory cytokine responses of human primary cells at noncytotoxic doses and bound to angiotensin II type 2 receptors comparably to mycolactone in vitro. Notably, it was considerably less toxic than mycolactone in human primary dermal fibroblasts modeling ulcerative activity. In mouse models of human diseases, it conferred systemic protection against chronic skin inflammation and inflammatory pain, with no apparent side effects. In addition to establishing the anti-inflammatory potency of mycolactone in vivo, our study therefore highlights the translational potential of mycolactone core-derived structures as prospective immunosuppressants.


Assuntos
Inflamação/tratamento farmacológico , Macrolídeos/uso terapêutico , Animais , Doença Crônica , Células HeLa , Humanos , Imunomodulação , Inflamação/patologia , Células Jurkat , Macrolídeos/química , Camundongos , Mycobacterium ulcerans/fisiologia , Dor/complicações , Dor/tratamento farmacológico , Substâncias Protetoras/uso terapêutico , Acetato de Tetradecanoilforbol/farmacologia
7.
J Med Chem ; 57(17): 7382-95, 2014 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-25158122

RESUMO

Mycolactone is a complex macrolide toxin produced by Mycobacterium ulcerans, the causative agent of skin lesions called Buruli ulcers. Mycolactone-mediated activation of neural (N) Wiskott-Aldrich syndrome proteins (WASP) induces defects in cell adhesion underpinning cytotoxicity and disease pathogenesis. We describe the chemical synthesis of 23 novel mycolactone analogues that differ in structure and modular assembly of the lactone core with its northern and southern polyketide side chains. The lactone core linked to southern chain was the minimal structure binding N-WASP and hematopoietic homolog WASP, where the number and configuration of hydroxyl groups on the acyl side chain impacted the degree of binding. A fluorescent derivative of this compound showed time-dependent accumulation in target cells. Furthermore, a simplified version of mycolactone mimicked the natural toxin for activation of WASP in vitro and induced comparable alterations of epithelial cell adhesion. Therefore, it constitutes a structural and functional surrogate of mycolactone for WASP/N-WASP-dependent effects.


Assuntos
Toxinas Bacterianas/química , Macrolídeos/química , Proteína da Síndrome de Wiskott-Aldrich/química , Toxinas Bacterianas/metabolismo , Toxinas Bacterianas/farmacologia , Adesão Celular/efeitos dos fármacos , Células HeLa , Humanos , Cinética , Macrolídeos/metabolismo , Macrolídeos/farmacologia , Modelos Químicos , Estrutura Molecular , Mycobacterium ulcerans/química , Ligação Proteica , Proteína da Síndrome de Wiskott-Aldrich/metabolismo
8.
Chemistry ; 20(17): 5054-63, 2014 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-24623534

RESUMO

The synthesis and physical characterization of a new class of N-heterocycle-boryl radicals is presented, based on five membered ring ligands with a N(sp(2) ) complexation site. These pyrazole-boranes and pyrazaboles exhibit a low bond dissociation energy (BDE; BH) and accordingly excellent hydrogen transfer properties. Most importantly, a high modulation of the BDE(BH) by the fine tuning of the N-heterocyclic ligand was obtained in this series and could be correlated with the spin density on the boron atom of the corresponding radical. The reactivity of the latter for small molecule chemistry has been studied through the determination of several reaction rate constants corresponding to addition to alkenes and alkynes, addition to O2 , oxidation by iodonium salts and halogen abstraction from alkyl halides. Two selected applications of N-heterocycle-boryl radicals are also proposed herein, for radical polymerization and for radical dehalogenation reactions.

9.
Nat Prod Rep ; 30(12): 1527-67, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24178858

RESUMO

Mycobacterium ulcerans infections (Buruli ulcer disease) have a long history that can be traced back 150 years. The successive discoveries of the mycobacteria in 1948 and of mycolactone A/B in 1999, the toxin responsible for this dramatic necrotic skin disease, resulted in a paradigm shift concerning the disease itself and in a broader sense, delineated an entirely new role for bioactive polyketides as virulence factors. The fascinating history, biology and chemistry of M. ulcerans infections are discussed in this review.


Assuntos
Úlcera de Buruli , Macrolídeos/síntese química , Úlcera de Buruli/história , História do Século XX , Humanos , Macrolídeos/química , Estrutura Molecular
10.
Chemistry ; 17(51): 14413-9, 2011 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-22127975

RESUMO

Mycolactones are complex macrolides responsible for a severe necrotizing skin disease called Buruli ulcer. Deciphering their functional interactions is of fundamental importance for the understanding, and ultimately, the control of this devastating mycobacterial infection. We report herein a diverted total synthesis approach of mycolactones analogues and provide the first insights into their structure-activity relationship based on cytopathic assays on L929 fibroblasts. The lowest concentration inducing a cytopathic effect was determined for selected analogues, allowing a clear picture to emerge by comparison with the natural toxins.


Assuntos
Toxinas Bacterianas/síntese química , Úlcera de Buruli/induzido quimicamente , Macrolídeos/síntese química , Animais , Toxinas Bacterianas/química , Toxinas Bacterianas/farmacologia , Úlcera de Buruli/microbiologia , Úlcera de Buruli/patologia , Fibroblastos/efeitos dos fármacos , Macrolídeos/química , Macrolídeos/farmacologia , Camundongos , Estrutura Molecular , Infecções por Mycobacterium/patologia , Mycobacterium ulcerans/química , Relação Estrutura-Atividade
11.
Chemistry ; 16(43): 12920-7, 2010 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-20878804

RESUMO

Recently, boryl radicals have been the subject of revived interest. These structures were generated by hydrogen-abstraction reactions from the corresponding boranes (i.e., from amine or phosphine boranes). However, the classical issue remains their high B--H bond-dissociation energy (BDE), thereby preventing a very efficient hydrogen-abstraction process. In the present paper, new N-heteroaryl boranes that exhibiting low B--H BDE are presented; excellent hydrogen-transfer properties have been found. Both the generation and the reactivity of the associated boryl radicals have been investigated through their direct observation in laser flash photolysis. The boryl radical interactions with double bonds, oxygen, oxidizing agent, and alkyl halides have been studied. Some selected applications of N-heteroaryl boryl radicals as new polymerization-initiating structures are proposed to evidence their high intrinsic reactivity.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...