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 (N(alphaA1)), and one or both of the PheB1 (N(alphaB1)) and LysB29 (N(epsilonB29)) amino groups in insulin using 5'-(alpha-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.
The Skaggs Institute for Chemical Biology and Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Lian-Sheng
LS
Li
Jennie L
JL
Babendure
Subhash C
SC
Sinha
Jerrold M
JM
Olefsky
Richard A
RA
Lerner
D041721:3T3-L1 Cells; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D003847:Deoxyglucose / Q000493:pharmacokinetics; D007328:Insulin / Q000031:analogs & derivatives* / Q000494:pharmacology; D051379:Mice; D010777:Photochemistry; D011355:Prodrugs / Q000138:chemical synthesis* / Q000494:pharmacology / Q000528:radiation effects; D013329:Structure-Activity Relationship; D014466:Ultraviolet Rays
D007328:Insulin; D011355:Prodrugs; D003847:Deoxyglucose