RESUMO
A high throughput screen allowed the identification of N-hydroxyimide inhibitors of ERCC1-XPF endonuclease activity with micromolar potency, but they showed undesirable selectivity profiles against FEN-1. A scaffold hop to a hydroxypyrimidinone template gave compounds with similar potency but allowed selectivity to be switched in favour of ERCC1-XPF over FEN-1. Further exploration of the structure-activity relationships around this chemotype gave sub-micromolar inhibitors with >10-fold selectivity for ERCC1-XPF over FEN-1.
Assuntos
Proteínas de Ligação a DNA/antagonistas & inibidores , Endonucleases/antagonistas & inibidores , Imidas/farmacologia , Pirimidinonas/farmacologia , Reparo do DNA , Relação Dose-Resposta a Droga , Endonucleases Flap/antagonistas & inibidores , Células Hep G2 , Humanos , Imidas/química , Estrutura Molecular , Pirimidinonas/química , Relação Estrutura-AtividadeRESUMO
Catechol-based inhibitors of ERCC1-XPF endonuclease activity were identified from a high-throughput screen. Exploration of the structure-activity relationships within this series yielded compound 13, which displayed an ERCC1-XPF IC50 of 0.6 µM, high selectivity against FEN-1 and DNase I and activity in nucleotide excision repair, cisplatin enhancement and γH2AX assays in A375 melanoma cells. Screening of fragments as potential alternatives to the catechol group revealed that 3-hydroxypyridones are able to inhibit ERCC1-XPF with high ligand efficiency, and elaboration of the hit gave compounds 36 and 37 which showed promising ERCC1-XPF IC50 values of <10 µM.
Assuntos
Catecóis/farmacologia , Reparo do DNA/efeitos dos fármacos , Proteínas de Ligação a DNA/antagonistas & inibidores , Endonucleases/antagonistas & inibidores , Piridonas/farmacologia , Catecóis/química , Linhagem Celular Tumoral , Desoxirribonuclease I/antagonistas & inibidores , Desoxirribonuclease I/metabolismo , Relação Dose-Resposta a Droga , Endonucleases Flap/antagonistas & inibidores , Humanos , Estrutura Molecular , Piridonas/química , Relação Estrutura-AtividadeRESUMO
The generation of carbon radicals by halogen-atom and group transfer reactions is generally achieved using tin and silicon reagents that maximize the interplay of enthalpic (thermodynamic) and polar (kinetic) effects. In this work, we demonstrate a distinct reactivity mode enabled by quantum mechanical tunneling that uses the cyclohexadiene derivative γ-terpinene as the abstractor under mild photochemical conditions. This protocol activates alkyl and aryl halides as well as several alcohol and thiol derivatives. Experimental and computational studies unveiled a noncanonical pathway whereby a cyclohexadienyl radical undergoes concerted aromatization and halogen-atom or group abstraction through the reactivity of an effective H atom. This activation mechanism is seemingly thermodynamically and kinetically unfavorable but is rendered feasible through quantum tunneling.
RESUMO
Starting from compound 1, we utilized biostructural data to successfully evolve an existing series into a new chemotype with a promising overall profile, exemplified by 19.
Assuntos
Desenho de Fármacos , Indanos/química , Indanos/farmacologia , Receptores de AMPA/metabolismo , Sulfonamidas/química , Sulfonamidas/farmacologia , Regulação Alostérica , Animais , Linhagem Celular , Cristalografia por Raios X , Humanos , Indanos/metabolismo , Indanos/farmacocinética , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Doenças do Sistema Nervoso/tratamento farmacológico , Doenças do Sistema Nervoso/metabolismo , Pirazóis/química , Pirazóis/metabolismo , Pirazóis/farmacocinética , Pirazóis/farmacologia , Ratos , Ratos Wistar , Relação Estrutura-Atividade , Sulfonamidas/metabolismo , Sulfonamidas/farmacocinéticaRESUMO
Starting from an HTS derived hit 1, application of biostructural data facilitated rapid optimization to lead 22, a novel AMPA receptor modulator. This is the first demonstration of how structure based drug design can be exploited in an optimization program for a glutamate receptor.
Assuntos
Indazóis/química , Receptores de AMPA/química , Tiofenos/química , Regulação Alostérica , Animais , Sítios de Ligação , Cristalografia por Raios X , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Ensaios de Triagem em Larga Escala , Humanos , Indazóis/síntese química , Indazóis/farmacologia , Microssomos/metabolismo , Estrutura Terciária de Proteína , Ratos , Receptores de AMPA/metabolismo , Tiofenos/síntese química , Tiofenos/farmacologiaRESUMO
Starting from lead compound 1, we demonstrate how X-ray structural data can be used to understand SAR and expediently optimize bioavailability in a novel series of AMPA receptor modulators, furnishing 5 with improved bioavailability and robust in vivo activity.