1H NMR studies on the reductively triggered release of heterocyclic and steroid drugs from 4,7-dioxoindole-3-methyl prodrugs

Hypoxia is a feature of several disease states, including cancer and rheumatoid arthritis. Prodrug systems which, after bioreduction, selectively release active drugs in these tissues may be important in therapy. An improved preparation of 1,2-dimethyl-3-hydroxymethyl-5-methoxyindole-4,7-dione was developed. Mitsunobu coupling with (5-substituted) isoquinolin-1-ones (potent inhibitors of poly(ADP-ribose)polymerase) gave 1-(1,2-dimethyl-4,7-dioxo-5-methoxyindol-3-ylmethoxy)isoquinolines and N-(1,2-dimethyl-4,7-dioxo-5-methoxyindol-3-ylmethyl)isoquinolin-1-ones. Similar coupling with the anticancer drug pentamethylmelamine gave its potential prodrug 1,2-dimethyl-3-(N-(4,6-bis(dimethylamino)-1,3,5-triazin-2-yl)-N-methylaminomethyl)-5-methoxyindole-4,7-dione. Treatment of sodium prednisolone hemisuccinate with 3-chloromethyl-1,2-dimethyl-5-methoxyindole-4,7-dione gave an analogous candidate prodrug of the anti-inflammatory drug prednisolone. In a chemical model system for bioreduction, SnCl2 in CDCl3/CD3OD triggered rapid stoichiometric release of isoquinolin-1-ones from the O-linked prodrugs but not from the N-linked analogues. Use of this system allowed the release process to be monitored in situ by 1H NMR spectroscopy. Diethyl hydrazine-1,2-dicarboxylate was found to reduce SnIV to SnII, making the overall reductive release catalytic in tin. The reduced (hydroquinone) prodrug may have a short lifetime under these reductive conditions, meaning that only good leaving groups are expelled. Thus 1-(1,2-dimethyl-4,7-dioxo-5-methoxyindol-3-ylmethoxy)isoquinolines and analogues may be useful as reductively triggered prodrugs.