Samarium Diiodide Catalysis for Novel Bioiosteres

Descripción del proyecto

Fotoactivación para mejorar la eficacia catalítica de Sml2

La sustitución bioisostérica de los farmacóforos aromáticos es una estrategia en el desarrollo de fármacos para reducir la formación de metabolitos tóxicos. La sustitución de los núcleos aromáticos por andamiajes rígidos ricos en carbono mejoraría tanto la estabilidad metabólica como la potencia. Sin embargo, muchos análogos permanecen inexplorados debido a la falta de métodos sintéticos eficaces. Con trabajos recientes se han logrado avances significativos en este campo utilizando SmI2 en catálisis de relevo radical para permitir la síntesis de andamiajes bioisostéricos. Con el apoyo de las Acciones Marie Skłodowska-Curie, el equipo del proyecto Sam-4-Bio se basará en estos avances integrando un método novedoso con descubrimientos recientes sobre la mejora de la eficiencia catalítica de SmI2. En el proyecto se intenta desarrollar una plataforma versátil para generar bioisóteres de ortoarenos, como los 1,2-BCHeps.

Objetivo

The concept of bioisosteric replacement of arene pharmacophores in drug candidates has garnered increasing attention as a powerful tool to circumvent the production of toxic metabolites through detrimental metabolic modifications of the arene backbone. Replacement of the arene core in drug candidates with rigid, C(sp3)-rich bioisosteric scaffold improves their metabolic stability, potency, lipophilicity, and solubility. Crucially, cage-like structures with defined exit vectors renders them bioisosteres with superior ability to dock in the chiral binding pocket of the target receptor. Therefore, the demand for C(sp3)-rich bioisosteric replacements is skyrocketing and recent endeavors have provided a variety of decorated saturated systems mimicking substituted arenes. While initial studies were mostly directed towards bioisosteres of mono- and para-substituted arenes, recent efforts have focussed more on bioisosteres for ortho- and meta-substituted aromatic rings. Despite the significant development of synthetic strategies for preparing already proven bioisosteres, the lack of synthetic methods to access many unexplored analogues, such as bicyclo[2.2.1]heptanes (BCHeps), renders their potential undetermined to date. Consequently, developing general, catalytic, sustainable methods for rapidly accessing 1,2-BCHeps is an urgent necessity. Recent breakthroughs from the Procter group have set a new benchmark by applying radical relay catalysis using SmI2 for accessing bioisosteric scaffolds. Sam-4-Bio will integrate this novel concept with the group’s recent finding of enhancing catalytic efficiency of SmI2 by photoactivation, to develop a catalytic platform for accessing unexplored bioisosteres of ortho-arenes like 1,2-BCHeps. Challenging insertion of alkene into the bridgehead bond of strained housane ketones under SmI2-catalysis will deliver key intermediates for downstream manipulation en route to new saturated analogues of validated drugs with superior bioactivity.