Beyond Born-Oppenheimer pharmaceutical quantum chemistry of thalidomide analogs and deuterium substituents

Thalidomide and its analogs, designed as sedatives or sleep medications, have been diverted as effective immuno- modulatory imide drugs, although their teratogenicity led by racemization had been a problem. Reducing the racemization initiated by proton dissociation from the chiral center is essential to reduce the side effect. This study applied density functional theory calculations considering nuclear quantum effects to understand the differences in the racemization among them in aqueous conditions. It was clarified that the kinetic isotope effect of Lenalidomide is over three times larger than the others by carbonyl group lack in the phthalimide ring, leading to structural differences upon hydration. This supports previous reports that deuteration of Lenalidomide stabilizes the enantiomers, i.e., significantly reducing racemization.