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1.
Bioorg Med Chem Lett ; 109: 129848, 2024 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-38876176

RESUMO

We explored novel immunosuppressive agents with immune tolerance using a phenotypic drug discovery strategy, focusing on costimulatory molecules in T cells, and obtained triazolothienodiazepine derivatives. Their mechanism of action is to inhibit the bromodomain and extra-terminal domain (BET) family, as we have previously reported. Selective inhibition of the first bromodomain (BD1) of the BET family is expected to exert antitumor and immunosuppressive effects, similar to BET inhibitors. This study identified furopyridine derivatives 7 and 8 with high BD1 inhibitory activity and high selectivity over BD2. Compound 7 was found to be orally bioavailable and exhibited anti-inflammatory activity in a lipopolysaccharide-induced model.


Assuntos
Piridinas , Piridinas/química , Piridinas/farmacologia , Piridinas/síntese química , Animais , Humanos , Administração Oral , Relação Estrutura-Atividade , Camundongos , Descoberta de Drogas , Lipopolissacarídeos/farmacologia , Lipopolissacarídeos/antagonistas & inibidores , Estrutura Molecular , Ratos , Domínios Proteicos
2.
Bioorg Med Chem Lett ; 109: 129849, 2024 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-38876177

RESUMO

Clinical studies have shown that inhibitors of bromodomain and extra-terminal domain (BET) proteins, particularly BRD4, have antitumor activity and efficacy. The BET protein has two domains, BD1 and BD2, and we previously focused on BD1 and reported orally bioavailable BD1-selective inhibitors. In this study, we obtained a BD1 inhibitor, a more potent and highly selective pyrazolopyridone derivative 13a, and confirmed its in vivo efficacy.


Assuntos
Piridonas , Humanos , Administração Oral , Relação Estrutura-Atividade , Animais , Piridonas/química , Piridonas/farmacologia , Piridonas/síntese química , Piridonas/farmacocinética , Pirazóis/química , Pirazóis/farmacologia , Pirazóis/síntese química , Descoberta de Drogas , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/metabolismo , Estrutura Molecular , Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas de Ciclo Celular/metabolismo , Camundongos , Domínios Proteicos , Relação Dose-Resposta a Droga , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Ratos , Proteínas que Contêm Bromodomínio
3.
J Org Chem ; 84(17): 10615-10628, 2019 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-31379168

RESUMO

Copper(I)-catalyzed stereodivergent nucleophilic propargylation at the anomeric carbon of unprotected N-acetyl mannosamine was developed using 3-substituted allenylboronates as a nucleophile. The homopropargylic alcohol products contained two contiguous stereocenters, and two stereoisomers out of the four possible isomers were selectively obtained in a catalyst-controlled manner by applying either basic conditions: a MesCu/(R,R,R)-Ph-SKP catalyst with a B(OiPr)3 additive or acidic conditions: a CuBF4/(S,S,S)-Ph-SKP catalyst with an MeB(OiPr)2 additive. Mechanistic studies suggested the presence of distinct active nucleophilic species depending on the conditions: an allenylcopper species under the basic conditions or an allenylboronate activated by the Lewis acidic copper catalyst under the acidic conditions. The propargylation products were concisely transformed into C3-substituted sialic acids in two steps without the use of protecting groups.

4.
Chem Pharm Bull (Tokyo) ; 66(3): 231-234, 2018 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-28824027

RESUMO

A catalytic carboxylic acid-selective aldol reaction with trifluoromethyl ketones was developed. Reversible and selective covalent bond formation between a boron catalyst and a carboxylic acid is key to realizing the unprecedented catalytic aldol reaction of simple carboxylic acids. The reaction proceeded chemoselectively at the α-position of carboxylic acid even in the presence of ketone, ester, or amide functional groups in the donor substrates. The chemoselectivity is beneficial for late-stage derivatizations of biologically relevant compounds, as demonstrated by the conversion of indomethacin and triacetylcholic acid.


Assuntos
Aldeídos/síntese química , Boro/química , Ácidos Carboxílicos/química , Cetonas/química , Catálise , Ésteres/química , Estrutura Molecular , Relação Estrutura-Atividade
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