RESUMEN
The first total synthesis of (±)-naupliolide has been achieved. The synthetic method includes a Simmons-Smith cyclopropanation of an allyl alcohol, diastereoselective cleavage of a benzylidene acetal group, radical cyclization of an aldehyde with a cyclopropane ring, and construction of an eight-membered ring by ring-closing metathesis.
RESUMEN
Inhibition of protein-protein interactions (PPIs) represents a major challenge in chemical biology and drug discovery. α-Helix mediated PPIs may be amenable to modulation using generic chemotypes, termed "proteomimetics", which can be assembled in a modular manner to reproduce the vectoral presentation of key side chains found on a helical motif from one partner within the PPI. In this work, it is demonstrated that by using a library of N-alkylated aromatic oligoamide helix mimetics, potent helix mimetics which reproduce their biophysical binding selectivity in a cellular context can be identified.
Asunto(s)
Imitación Molecular , Proteínas/química , Línea Celular Tumoral , HumanosRESUMEN
Inhibition of protein-protein interactions (PPIs) represents a major challenge in chemical biology and drug discovery. α-Helix mediated PPIs may be amenable to modulation using generic chemotypes, termed "proteomimetics", which can be assembled in a modular manner to reproduce the vectoral presentation of key side chains found on a helical motif from one partner within the PPI. In this work, it is demonstrated that by using a library of N-alkylated aromatic oligoamide helix mimetics, potent helix mimetics which reproduce their biophysical binding selectivity in a cellular context can be identified.
RESUMEN
α-Helix mediated protein-protein interactions are of major therapeutic importance. As such, the design of inhibitors of this class of interaction is of significant interest. We present methodology to modify N-alkylated aromatic oligoamide α-helix mimetics using 'click' chemistry. The effect is shown to modulate the binding properties of a series of selective p53/hDM2 inhibitors.
Asunto(s)
Proteínas Proto-Oncogénicas c-mdm2/química , Proteína p53 Supresora de Tumor/química , Amidas/química , Biomimética , Química Clic , Humanos , Concentración 50 Inhibidora , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/química , Unión Proteica , Mapeo de Interacción de Proteínas , Estructura Secundaria de Proteína , Proteómica/métodos , Proteínas Proto-Oncogénicas c-mdm2/antagonistas & inhibidores , Solventes/química , Propiedades de Superficie , Proteína p53 Supresora de Tumor/antagonistas & inhibidores , Proteína bcl-X/químicaRESUMEN
Inhibition of protein-protein interactions (PPIs) represents a significant challenge because it is unclear how they can be effectively and selectively targeted using small molecules. Achieving this goal is critical given the defining role of these interactions in biological processes. A rational approach to inhibitor design based on the secondary structure at the interface is the focus of much research, and different classes of designed ligands have emerged, some of which effectively and selectively disrupt targeted PPIs. This Review discusses the relevance of PPIs and, in particular, the importance of α-helix-mediated PPIs to chemical biology and drug discovery with a focus on designing inhibitors, including constrained peptides, foldamers and proteomimetic-derived ligands. In doing so, key challenges and major advances in developing generic approaches for the elaboration of PPI inhibitors are highlighted. The challenges faced in developing such ligands as drug leads--and how criteria applied to these may differ from conventional small-molecule drugs--are summarized.
Asunto(s)
Antineoplásicos/farmacología , Inhibidores Enzimáticos/farmacología , Mapas de Interacción de Proteínas/efectos de los fármacos , Proteínas/antagonistas & inhibidores , Proteínas/metabolismo , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Diseño de Fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Unión Proteica/efectos de los fármacos , Estructura Secundaria de Proteína , Proteínas/química , Transducción de Señal/efectos de los fármacosRESUMEN
Protein-protein interactions (PPIs) mediate cellular pathways and are implicated in numerous aberrant conditions. α-Helix mimetics-small molecules that reproduce the spatial projection of key residues from an α-helix involved in a PPI-are attractive generic templates for development of screening libraries, however library syntheses of α-helix mimetics with diverse functionality are less established. This manuscript describes the automated, microwave assisted solid phase synthesis based on one such scaffold; an N-alkylated oligobenzamide.