RESUMEN
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.
RESUMEN
Antibody-drug conjugates (ADCs) are a growing class of therapeutics that harness the specificity of antibodies and the cell-killing potency of small-molecule drugs. Beyond cytotoxics, there are few examples of the application of an ADC approach to difficult drug discovery targets. Here, we present the initial development of a non-internalising ADC, with a view to selectively inhibiting an extracellular protein. Employing the wellinvestigated matrix metalloproteinase-9 (MMP-9) as our model, we adapted a broad-spectrum, nonselective MMP inhibitor for conjugation and linked this to a MMP-9-targeting antibody. The resulting ADC fully inhibits MMP-9, and ELISA results suggest antibody targeting can direct a nonselective inhibitor.
Asunto(s)
Anticuerpos Monoclonales de Origen Murino/inmunología , Ácidos Hidroxámicos/química , Inmunoconjugados/inmunología , Metaloproteinasa 9 de la Matriz/inmunología , Inhibidores de Proteasas/química , Pirazinas/química , Animales , Anticuerpos Monoclonales de Origen Murino/química , Anticuerpos Monoclonales de Origen Murino/metabolismo , Línea Celular , Pruebas de Enzimas , Fluorometría , Humanos , Ácidos Hidroxámicos/metabolismo , Inmunoconjugados/química , Inmunoconjugados/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Ratones , Inhibidores de Proteasas/metabolismo , Unión Proteica , Pirazinas/metabolismo , Sulfonamidas/química , Sulfonamidas/metabolismoRESUMEN
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.
Asunto(s)
Proteínas de Unión al ADN/antagonistas & inhibidores , Endonucleasas/antagonistas & inhibidores , Imidas/farmacología , Pirimidinonas/farmacología , Reparación del ADN , Relación Dosis-Respuesta a Droga , Endonucleasas de ADN Solapado/antagonistas & inhibidores , Células Hep G2 , Humanos , Imidas/química , Estructura Molecular , Pirimidinonas/química , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Catecoles/farmacología , Reparación del ADN/efectos de los fármacos , Proteínas de Unión al ADN/antagonistas & inhibidores , Endonucleasas/antagonistas & inhibidores , Piridonas/farmacología , Catecoles/química , Línea Celular Tumoral , Desoxirribonucleasa I/antagonistas & inhibidores , Desoxirribonucleasa I/metabolismo , Relación Dosis-Respuesta a Droga , Endonucleasas de ADN Solapado/antagonistas & inhibidores , Humanos , Estructura Molecular , Piridonas/química , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Diseño de Fármacos , Indanos/química , Indanos/farmacología , Receptores AMPA/metabolismo , Sulfonamidas/química , Sulfonamidas/farmacología , Regulación Alostérica , Animales , Línea Celular , Cristalografía por Rayos X , Humanos , Indanos/metabolismo , Indanos/farmacocinética , Microsomas Hepáticos/metabolismo , Modelos Moleculares , Enfermedades del Sistema Nervioso/tratamiento farmacológico , Enfermedades del Sistema Nervioso/metabolismo , Pirazoles/química , Pirazoles/metabolismo , Pirazoles/farmacocinética , Pirazoles/farmacología , Ratas , Ratas Wistar , Relación Estructura-Actividad , Sulfonamidas/metabolismo , Sulfonamidas/farmacocinéticaRESUMEN
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.
Asunto(s)
Indazoles/química , Receptores AMPA/química , Tiofenos/química , Regulación Alostérica , Animales , Sitios de Unión , Cristalografía por Rayos X , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Ensayos Analíticos de Alto Rendimiento , Humanos , Indazoles/síntesis química , Indazoles/farmacología , Microsomas/metabolismo , Estructura Terciaria de Proteína , Ratas , Receptores AMPA/metabolismo , Tiofenos/síntesis química , Tiofenos/farmacologíaRESUMEN
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.