Synthesis and evaluation of photolabile insulin prodrugs

We have developed two photolabile insulin prodrugs, insulin-2P and insulin-3P. These prodrugs were synthesized by protecting GlyA1 (NαA1), and one or both of the PheB1 (NαB1) and LysB29 (NεB29) amino groups in insulin using 5′-(α-methyl-nitro-piperonyl)oxy-carbonyl as the protecting group. These insulin prodrugs were efficiently activated by exposure to longwave UV light to produce insulin quantitatively. Using 2-deoxyglucose uptake assays, both di- and tri-protected compounds were less active than native insulin in the protected state, and showed comparable activity to native insulin upon photoactivation.