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1.
J Med Chem ; 66(16): 11216-11236, 2023 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-37535857

RESUMO

Mixed Lineage Kinase domain-Like pseudokinase (MLKL) is implicated in a broad range of diseases due to its role as the ultimate effector of necroptosis and has therefore emerged as an attractive drug target. Here, we describe the development of PROteolysis TArgeting Chimeras (PROTACs) as a novel approach to knock down MLKL through chemical means. A series of candidate degraders were synthesized from a high-affinity pyrazole carboxamide-based MLKL ligand leading to the identification of a PROTAC molecule that effectively degraded MLKL and completely abrogated cell death in a TSZ model of necroptosis. By leveraging the innate ability of these PROTACs to degrade MLKL in a dose-dependent manner, the quantitative relationship between MLKL levels and necroptosis was interrogated. This work demonstrates the feasibility of targeting MLKL using a PROTAC approach and provides a powerful tool to further our understanding of the role of MLKL within the necroptotic pathway.


Assuntos
Necroptose , Proteínas Quinases , Quimera de Direcionamento de Proteólise , Apoptose , Morte Celular , Necroptose/efeitos dos fármacos , Proteínas Quinases/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Quimera de Direcionamento de Proteólise/química , Quimera de Direcionamento de Proteólise/farmacologia
2.
Bioorg Med Chem Lett ; 15(21): 4867-71, 2005 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-16143522

RESUMO

Starting from the potent and selective but poorly brain penetrant 5-HT6 receptor antagonist SB-271046, a successful strategy for improving brain penetration was adopted involving conformational constraint with concomitant reduction in hydrogen bond count. This provided a series of bicyclic heteroarylpiperazines with high 5-HT6 receptor affinity. 5-Chloroindole 699929 combined high 5-HT6 receptor affinity with excellent brain penetration and also had good oral bioavailability in both rat and dog.


Assuntos
Encéfalo/metabolismo , Piperazinas/síntese química , Receptores de Serotonina/efeitos dos fármacos , Antagonistas da Serotonina/síntese química , Antagonistas da Serotonina/farmacocinética , Administração Oral , Animais , Disponibilidade Biológica , Barreira Hematoencefálica , Cães , Conformação Molecular , Permeabilidade , Piperazinas/farmacocinética , Piperazinas/farmacologia , Ratos , Antagonistas da Serotonina/farmacologia , Relação Estrutura-Atividade
3.
Bioorg Med Chem Lett ; 14(15): 3937-41, 2004 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-15225702

RESUMO

Potent inhibitors of bacterial methionyl tRNA synthetase (MRS) have previously been reported. Through SAR of the quinolone moiety, the right hand side pharmacophore for MRS inhibition has now been defined as an NH-C-NH functionality in the context of a bicyclic heteroaromatic system. Potent antibacterial fused-pyrimidone and fused-imidazole analogues have been obtained and enantioselective activity demonstrated. Compound 46 demonstrated very good antibacterial activity against panels of antibiotic-resistant staphylococci and enterococci.


Assuntos
Antibacterianos/síntese química , Inibidores Enzimáticos/síntese química , Metionina tRNA Ligase/antagonistas & inibidores , Antibacterianos/farmacologia , Enterococcus faecalis/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Cinética , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Quinolonas , Staphylococcus/efeitos dos fármacos , Relação Estrutura-Atividade
4.
J Org Chem ; 68(2): 387-401, 2003 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-12530864

RESUMO

Titanium(IV) benzylidenes bearing a masked oxygen or nitrogen nucleophile in the ortho position were generated from thioacetals, using low-valent titanocene complex, Cp2Ti[P(OEt)3]2. Methylene acetal, alkyl ether, silyl ether, fluoro, tertiary amino, and N-alkyl, N-benzyl, N-prenyl, and N-silyl tert-butyl carbamate groups were tolerated in the titanium alkylidene reagents (Schrock carbenes). Aryl-chlorine bonds were stable to the titanium benzylidene functionality, but there was poor chemoselectivity for the reduction of the thioacetal in the presence of an aryl chloride. The titanium benzylidenes converted Merrifield and Wang resin-bound esters into enol ethers. The oxygen nucleophile was masked as a TMS ether, and when the resin-bound enol ethers bearing this ortho substituent were treated with 1% TFA in dichloromethane, benzofurans were released from resin in high yields. The chameleon catch strategy ensured excellent purity. In a similar way, N-alkylated and N-silylated tert-butyl carbamates were used for the synthesis of N-alkyl and N-Boc indoles, respectively. These traceless solid-phase syntheses of heterocycles are believed to involve postcleavage modification rather than cyclative termination.

5.
Bioorg Med Chem Lett ; 12(21): 3171-4, 2002 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-12372526

RESUMO

The antimicrobial natural product chuangxinmycin has been found to be a potent and selective inhibitor of bacterial tryptophanyl tRNA synthetase (WRS). A number of analogues have been synthesised. The interaction with WRS appears to be highly constrained, as only sterically smaller analogues afforded significant inhibition. The only analogue to show inhibition comparable to chuangxinmycin also had antibacterial activity. WRS inhibition may contribute to the antibacterial action of chuangxinmycin.


Assuntos
Antibacterianos/farmacologia , Inibidores Enzimáticos/farmacologia , Indóis/farmacologia , Staphylococcus aureus/enzimologia , Triptofano-tRNA Ligase/antagonistas & inibidores , Antibacterianos/síntese química , Bactérias/efeitos dos fármacos , Inibidores Enzimáticos/síntese química , Hidrólise , Indicadores e Reagentes , Indóis/síntese química , Testes de Sensibilidade Microbiana , Staphylococcus aureus/efeitos dos fármacos , Estereoisomerismo , Relação Estrutura-Atividade
6.
Org Lett ; 4(1): 75-8, 2002 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-11772094

RESUMO

[reaction: see text] Titanium(IV) benzylidenes bearing a masked nitrogen nucleophile in the ortho position converted Merrifield resin-bound esters into enol ethers. An unusual nitrogen protecting group, N-silylated tert-butyl carbamate, was employed. One percent TFA released N-Boc indoles in high yield and purity. N-Methyl indoles were also prepared. Cyclative termination was not required to release the chameleon catch. The first example of a carbonyl group within a titanium alkylidene reagent is reported.

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