RESUMO
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
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
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.