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.
Li
Lian-Sheng
LS
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.
Babendure
Jennie L
JL
Sinha
Subhash C
SC
Olefsky
Jerrold M
JM
Lerner
Richard A
RA
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