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1.
ACS Med Chem Lett ; 7(4): 403-7, 2016 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-27096049

RESUMO

New securinine analogues have been prepared by semisynthesis. Two series were developed using either Suzuki or Sonogashira cross coupling reactions. The in vitro cytotoxicity of the compounds was assayed against HCT-116 colon cancer cells. The most potent derivatives showed promising growth inhibition on four tumoral cell lines giving a valuable insight on the structure-activity relationship (SAR) of securinine. Moreover, high antiproliferative effect against A-375 (melanoma) was observed with IC50 up to 60 nM.

2.
Eur J Med Chem ; 109: 287-93, 2016 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-26793989

RESUMO

A series of new securinine analogues was prepared by Heck reaction from readily accessible securinine and commercially available iodoarenes. The in vitro cytotoxicity of the prepared compounds was assayed against a panel of four cancer cell lines: A375, A549, HCT-116 and HL-60 showing promising growth inhibition with excellent IC50 values in the nanomolar range. The plasmatic stability of the most potent analogue was also investigated demonstrating that they might serve as valuable leads for the development of anticancer drugs.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Azepinas/química , Azepinas/farmacologia , Compostos Heterocíclicos de Anel em Ponte/química , Compostos Heterocíclicos de Anel em Ponte/farmacologia , Lactonas/química , Lactonas/farmacologia , Piperidinas/química , Piperidinas/farmacologia , Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Azepinas/síntese química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Euphorbiaceae/química , Compostos Heterocíclicos de Anel em Ponte/síntese química , Humanos , Lactonas/síntese química , Neoplasias/tratamento farmacológico , Piperidinas/síntese química
3.
PLoS One ; 9(5): e96941, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24810902

RESUMO

Chemical manipulations performed on the histone H3 lysine 9 methyltransferases (G9a/GLP) inhibitor BIX-01294 afforded novel desmethoxyquinazolines able to inhibit the DNA methyltransferase DNMT3A at low micromolar levels without any significant inhibition of DNMT1 and G9a. In KG-1 cells such compounds, when tested at sub-toxic doses, induced the luciferase re-expression in a stable construct controlled by a cytomegalovirus (CMV) promoter silenced by methylation (CMV-luc assay). Finally, in human lymphoma U-937 and RAJI cells, the N-(1-benzylpiperidin-4-yl)-2-(4-phenylpiperazin-1-yl)quinazolin-4-amine induced the highest proliferation arrest and cell death induction starting from 10 µM, in agreement with its DNMT3A inhibitory potency.


Assuntos
Azepinas/química , Azepinas/farmacologia , DNA (Citosina-5-)-Metiltransferases/antagonistas & inibidores , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Histona-Lisina N-Metiltransferase/antagonistas & inibidores , Quinazolinas/química , Quinazolinas/farmacologia , Azepinas/metabolismo , Domínio Catalítico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , DNA (Citosina-5-)-Metiltransferases/química , DNA (Citosina-5-)-Metiltransferases/metabolismo , DNA Metiltransferase 3A , Inibidores Enzimáticos/metabolismo , Antígenos de Histocompatibilidade/química , Antígenos de Histocompatibilidade/metabolismo , Histona-Lisina N-Metiltransferase/química , Histona-Lisina N-Metiltransferase/metabolismo , Humanos , Simulação de Acoplamento Molecular , Quinazolinas/metabolismo , Relação Estrutura-Atividade
4.
Phytochemistry ; 94: 184-91, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23618620

RESUMO

Six dichapetalins named dichapetalins N-S were isolated from Dichapetalum mombuttense, Dichapetalum zenkeri and Dichapetalum leucosia. They were accompanied in the same plants by the known dichapetalins A, B, C, I, L and M. The structures of the compounds were elucidated by 1D and 2D NMR experiments and mass spectrometry. They all possessed the dammarane skeleton substituted at position C-3 by a C6-C2 unit forming a 2-phenylpyran moiety. All contained a lactone ring in the side chain except dichapetalins O, Q and R, in which this ring was replaced by a lactol. Dichapetalin Q and R were also the first dichapetalins bearing a tertiary methyl and a double bond instead of the cyclopropane of the dammaranes. All these compounds were assayed against cancer cell lines HCT116 and WM 266-4 and displayed cytotoxic and anti-proliferative activities in the 10(-6) to 10(-8)M range.


Assuntos
Antineoplásicos Fitogênicos/química , Magnoliopsida/química , Extratos Vegetais/química , Raízes de Plantas/química , Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Células HCT116 , Células HL-60 , Compostos Heterocíclicos de 4 ou mais Anéis/química , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Humanos , Espectroscopia de Ressonância Magnética/métodos , Magnoliopsida/classificação , Estrutura Molecular , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia , Especificidade da Espécie , Compostos de Espiro/química , Compostos de Espiro/farmacologia , Relação Estrutura-Atividade
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