Prodrugs for targeting hypoxic tissues: regiospecific elimination of aspirin from reduced indolequinones.
A series of regioisomeric derivatives of a 1-methylindole-4,7-dione were synthesised, substituted with a 2-acetoxybenzoate leaving group linked through the (indol-2-yl)methyl or (indol-3-yl)methyl (or propenyl) positions. Reductive elimination of the leaving group occurred from the (indol-3-yl)methyl derivatives but not the 2-substituted regioisomers, indicating that only the C-3 position may be utilised in bioreductively-activated drug delivery, which was demonstrated with an aspirin prodrug.
Jaffar
M
M
School of Pharmacy, University of Manchester, UK.
Everett
S A
SA
Naylor
M A
MA
Moore
S G
SG
Ulhaq
S
S
Patel
K B
KB
Stratford
M R
MR
Nolan
J
J
Wardman
P
P
Stratford
I J
IJ
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001168:Arthritis / Q000378:metabolism; D001241:Aspirin / Q000737:chemistry* / Q000378:metabolism; D005609:Free Radicals / Q000378:metabolism; D006801:Humans; D000860:Hypoxia / Q000188:drug therapy / Q000378:metabolism; D007211:Indoles / Q000737:chemistry* / Q000378:metabolism; D009369:Neoplasms / Q000378:metabolism; D010084:Oxidation-Reduction; D011355:Prodrugs / Q000737:chemistry* / Q000378:metabolism; D011809:Quinones / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship