Solid-phase chemistry, organic synthesis, and an apparatus for multiple, simultaneous synthesis have been combined to generate libraries of organic compounds ("diversomers"). Arrays of compounds were synthesized over two to three steps incorporating chemically diverse building blocks on a polystyrene-based solid support in a multiple, simultaneous manner. The generality of this approach is illustrated by the syntheses of dipeptides, hydantoins, and benzodiazepines.

Therapeutics developed and sold as racemates can exhibit a limited therapeutic index because of side effects resulting from the undesired enantiomer (distomer) and/or its metabolites, which at times, forces researchers to abandon valuable scaffolds. Therefore, most chiral drugs are developed as single enantiomers. Unfortunately, the development of some chirally pure drug molecules is hampered by rapid in vivo racemization. The class of compounds known as immunomodulatory drugs derived from thalidomide is developed and sold as racemates because of racemization at the chiral center of the 3-aminoglutarimide moiety. Herein, we show that replacement of the exchangeable hydrogen at the chiral center with deuterium allows the stabilization and testing of individual enantiomers for two thalidomide analogs, including CC-122, a compound currently in human clinical trials for hematological cancers and solid tumors. Using “deuterium-enabled chiral switching” (DECS), in vitro antiinflammatory differences of up to 20-fold are observed between the deuterium-stabilized enantiomers. In vivo, the exposure is dramatically increased for each enantiomer while they retain similar pharmacokinetics. Furthermore, the single deuterated enantiomers related to CC-122 exhibit profoundly different in vivo responses in an NCI-H929 myeloma xenograft model. The (−)-deuterated enantiomer is antitumorigenic, whereas the (+)-deuterated enantiomer has little to no effect on tumor growth. The ability to stabilize and differentiate enantiomers by DECS opens up a vast window of opportunity to characterize the class effects of thalidomide analogs and improve on the therapeutic promise of other racemic compounds, including the development of safer therapeutics and the discovery of new mechanisms and clinical applications for existing therapeutics.

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The drug discovery process depends upon the synthesis and testing of thousands of compounds to bring a new drug through discovery, clinical testing, development, and FDA approval. Recent advances in high throughput screening have created the need for the accelerated synthesis of small organic molecules. By combining solid phase chemistry, organic synthesis, and automation with a unique apparatus capable of'performing techniques common to organic synthesis, "libraries" of organic compounds ( D I V E R S O M E R S~~) are efficiently generated. This was demonstrated by the multiple simultaneous synthesis of 40 hydantoins and 40 benrodiazepines, related to Dilantina and ValiurnB, respectively.

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