Catalytic Castagnoli–Cushman reaction-based synthesis of tetrahydroisoquinolone–glutarimide dyads and their evaluation as potential cereblon ligands

A series of imines derived from α-aminoglutarimide and alhehydes RCHO was introduced into the In(OTf)₃-catalyzed Castagnoli–Cushman reaction with homophthalic anhydrides thus yielding novel glutarimide–tetrahydroisoquinolone dyads with moderate yields. Carrying out the reaction at room temperature affords isomers with cis-orientation of the R substituent and carboxy group whereas heating to 80 °C promotes conversion into more stable trans-isomers. Some selected compounds were evaluated in vitro, revealing mild or no antiproliferative effects, and tested for cereblon-binding, with the bestperforming compound showing an affinity in the range of canonical cereblon ligands.