Design and Synthesis of Transition State Analogs for Induction of Hydride Transfer Catalytic Antibodies

Alcohol dehydrogenases and related aldehyde reductase enzymes catalyze the oxidation of alcohols to aldehydes and the simultaneous reduction of a nicotinamide derivative (NAD(+) or NADP(+)) to the corresponding 1,4-dihydronicotinamide. Herein we report the design and synthesis of a stable transition state analog for this hydride transfer process. Compound 1 is a rigid [3.2.2] bicyclic structure containing 3-piperidone oxime as a mimic for 1,4-dihydronicotinamide. The piperidone is held in the boat conformation corresponding to the transition state by a three-atom lactam bridge between N(1) and C(4). The oxime function mimics the carboxamide group in nicotinamide. The lactam nitrogen serves as an attachment point for the alkyl group of the alcohol substrate, and the amide oxygen atom mimics its hydroxyl group. Compound 1 was prepared in 10 steps from N-benzylpiperidone, functionalized with substrate and cofactor recognition elements into transition state analogs 2 and 3 and conjugated to carrier proteins for immunization. These novel analogs open the way for the exploration of the dehydrogenase reaction using catalytic antibodies.