RESUMO
A virtual screening strategy, through molecular docking, for the elaboration of an electronic library of Pontin inhibitors has resulted in the identification of two original scaffolds. The chemical synthesis of four candidates allowed extensive biological evaluations for their anticancer activity. Two compounds displayed an effect on Pontin ATPase activity, and one of them also exhibited a noticeable effect on cell growth. Further biological studies revealed that the most active compound induced apoptotic cell death together with necrosis, this latter effect being likely related to the cellular balance of ATP regulation.
Assuntos
Antineoplásicos/farmacologia , Proteínas de Transporte/antagonistas & inibidores , DNA Helicases/antagonistas & inibidores , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , ATPases Associadas a Diversas Atividades Celulares , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Proteínas de Transporte/metabolismo , Proliferação de Células/efeitos dos fármacos , DNA Helicases/metabolismo , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Células HCT116 , Células HL-60 , Humanos , Células KB , Células MCF-7 , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Vitamin D receptor (VDR) antagonists have therapeutic potential in treatment of allergic conditions and hypercalcemia driven by granulomatous diseases. We have identified an o-aminoanilide analogue of the hormonal form of vitamin D with a dienyl side chain that functions as a strong VDR antagonist. Modeling studies indicate that antagonism arises from side chain rigidity, when compared to a more flexible saturated analogue, which interferes with H12 folding/alignment.
Assuntos
Anilidas/síntese química , Calcitriol/análogos & derivados , Calcitriol/síntese química , Receptores de Calcitriol/antagonistas & inibidores , Anilidas/farmacologia , Ligação Competitiva , Calcitriol/farmacologia , Linhagem Celular Tumoral , Citocinas/biossíntese , Polarização de Fluorescência , Humanos , Modelos Moleculares , Receptores de Calcitriol/agonistas , Estereoisomerismo , Esteroide Hidroxilases/biossíntese , Relação Estrutura-Atividade , Vitamina D3 24-Hidroxilase , Linfopoietina do Estroma do TimoRESUMO
Incorporation of zinc-binding groups into the side-chain of 1alpha,25-dihydroxyvitamin D(3) (1,25D) fully bifunctional hybrid molecules which act both as vitamin D receptor agonists and histone deacetylase inhibitors. These bifunctional hybrids display in vitro antiproliferative activity against the AT84 squamous carcinoma cell line while lacking the in vivo hypercalcemic effects of 1,25D.
Assuntos
Antineoplásicos/química , Inibidores de Histona Desacetilases/química , Receptores de Calcitriol/agonistas , Vitamina D/análogos & derivados , Zinco/química , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Vitamina D/químicaRESUMO
A concise and efficient total synthesis of alkaloid narceine imide is disclosed. The key steps are based upon the sequential construction of the isoindolinone template followed by metalation and coupling with an isoquinolinium salt. Subsequent E1cb elimination enables the creation of the arylmethylene unit with the concomitant formation of the dimethylaminoethyl chain and ultimate deprotection completes the synthesis of the natural product.
