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1.
Cell ; 181(2): 293-305.e11, 2020 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-32142653

RESUMO

Pulmonary tuberculosis, a disease caused by Mycobacterium tuberculosis (Mtb), manifests with a persistent cough as both a primary symptom and mechanism of transmission. The cough reflex can be triggered by nociceptive neurons innervating the lungs, and some bacteria produce neuron-targeting molecules. However, how pulmonary Mtb infection causes cough remains undefined, and whether Mtb produces a neuron-activating, cough-inducing molecule is unknown. Here, we show that an Mtb organic extract activates nociceptive neurons in vitro and identify the Mtb glycolipid sulfolipid-1 (SL-1) as the nociceptive molecule. Mtb organic extracts from mutants lacking SL-1 synthesis cannot activate neurons in vitro or induce cough in a guinea pig model. Finally, Mtb-infected guinea pigs cough in a manner dependent on SL-1 synthesis. Thus, we demonstrate a heretofore unknown molecular mechanism for cough induction by a virulent human pathogen via its production of a complex lipid.


Assuntos
Tosse/fisiopatologia , Glicolipídeos/metabolismo , Nociceptores/fisiologia , Fatores de Virulência/metabolismo , Adulto , Animais , Linhagem Celular , Tosse/etiologia , Tosse/microbiologia , Feminino , Glicolipídeos/fisiologia , Cobaias , Interações Hospedeiro-Patógeno , Humanos , Lipídeos/fisiologia , Pulmão/microbiologia , Macrófagos/microbiologia , Masculino , Camundongos , Mycobacterium tuberculosis/metabolismo , Mycobacterium tuberculosis/patogenicidade , Cultura Primária de Células , Tuberculose/microbiologia , Tuberculose Pulmonar/microbiologia , Tuberculose Pulmonar/fisiopatologia , Fatores de Virulência/fisiologia
2.
J Am Chem Soc ; 144(35): 16118-16130, 2022 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-36036508

RESUMO

Iridium(phosphoramidite) complexes catalyze an enantio- and diastereoselective three-component coupling reaction of alkenyl boronic esters, organolithium reagents, and secondary allylic carbonates. The reaction proceeds through an allylation-induced 1,2-metalate shift of the alkenyl boronate to form non-adjacent stereocenters. Mechanistic investigations outline the overall catalytic cycle and reveal trends in reactivity and selectivity. Analysis of relative stereochemistry in products derived from a variety of 1,1-disubtituted alkenyl boronates provides insight into the transition state of the addition and indicates a concerted pathway. Kinetic analysis of the reaction revealed the kinetic order dependence in boronate, the catalyst, and both the slow- and fast-reacting enantiomer of allylic carbonate as well as the turnover-limiting step of the reaction. Determination of nucleophile-specific parameters N and sN for alkenyl boronate complexes enabled comparison to other classes of nucleophiles. DFT calculations indicate the addition of the alkenyl boronate to the cationic Ir(π-allyl) intermediate and the 1,2-metalate shift occur in a concerted mechanism. The stereoselectivity is determined by ligand-substrate steric repulsions and dispersion interactions in the syn addition transition state. Hammett studies supported the computational results with regard to electronic trends observed with both aryl-derived alkenyl boronates and aryl carbonates.


Assuntos
Carbonatos , Irídio , Catálise , Irídio/química , Cinética , Estereoisomerismo
3.
J Am Chem Soc ; 143(13): 4921-4927, 2021 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-33755457

RESUMO

Alkenyl boronates add to Ir(π-allyl) intermediates with high enantioselectivity. A 1,2-metalate shift forms a second C-C bond and sets a 1,3-stereochemical relationship. The three-component coupling provides tertiary boronic esters that can undergo multiple additional functionalizations. An extension to trisubstituted olefins sets three contiguous stereocenters.


Assuntos
Compostos Alílicos/química , Ácidos Borônicos/química , Metais/química , Catálise , Estereoisomerismo
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