NITRIC-OXIDE CHELETROPIC TRAPS (NOCTS) WITH IMPROVED THERMAL-STABILITY AND WATER SOLUBILITY

The search for nitric oxide cheletropic traps (NOCTs) of the 7,7,8,8-t etraalkyl-o-quinodimethane type which would have properties appropriat e for monitoring the formation of nitric oxide in cell cultures and in vivo by magnetic resonance techniques is described. In addition to th e necessary condition that a NOCT reacts rapidly with NO to yield a pe rsistent nitroxide radical, two additional properties were sought: (i) thermal stability at the temperature of interest (37 degrees C) and ( ii) water solubility. To these ends, a number of 1,1,3,3-tetraalkyl-2- indanones (and a related naphthalene derivative) were synthesized and subjected to UV photolysis in solution, a procedure which generally (t hough not in all cases) caused the elimination of carbon monoxide and formation of the corresponding o-quinodimethane. The thermal instabili ty of many of these compounds is due to a 1,5-sigmatropic hydrogen ato m transfer which, for example, converts 7,7,8,8-tetramethyl-o-quinodim ethane (1) to o-isopropyll-alpha-methylstyrene(1P) with a half-life of only ca. 140 s at 37 degrees C. Several o-quinodimethanes were discov ered which were, for all practical purposes, completely stable at 37 d egrees C. The most suitable lipid-soluble NOCT discovered was 7-(2-ind enyl)-7,8,8-trimethyl-o-quinodimethane (5), which is stable and reacts very rapidly with NO to form a persistent nitroxide. Various derivati ves of 5 were also examined and found to be equally, or almost equally , effective NOCTs. Water solubility was explored by addition of water- solubilizing groups to the ring of 1. The carboxylic acid group, 13, w as found to be particularly suitable, since the carboxylate anion 14 c onferred excellent water solubility without,interfering with either th e nitric oxide trapping reaction or the necessary photoelimination of carbon monoxide from the starting indanone. Of even greater importance , the carboxylate group had no apparent effect on the rate of the ther mal 1,5-sigmatropic rearrangement; i.e., the rates of decay of 14 and 1 were equal within experimental error. It is concluded that NOCTs of the o-quinodimethane class having long lifetimes and a high reactivity toward NO can now be prepared with appropriate lipophilic, hydrophili c, or amphiphilic properties. These NOCTs should prove suitable for ex ploratory use in biological systems.