Nitric Oxide Cheletropic Traps (NOCTs) with Improved Thermal Stability and Water Solubility

Abstract

The search for nitric oxide cheletropic traps (NOCTs) of the 7,7,8,8-tetraalkyl-o-quinodimethane type which would have properties appropriate for monitoring the formation of nitric oride in cell cultures and in vivo by magnetic resonance techniques is described. In addition to the necessary condition that a NOCT reacts rapidly with NO to yield a persistent nitroxide radical, two additional properties were sought: (i) thermal stability at the temperature of interest (37 "C) and (ii) water solubility. To these ends, a number of 1 ,1,3,3-tetraailcyIyl-2-indanones (and a related naphthalene derivative) were synthesized and subjected to UV photolysis in solution, a procedure which generally (though not in all cases) caused the elimination of carbon monoxide and formation of the corresponding o-quinodimethane. The thermal instability of many of these compounds is due to a 1,S-sigmatropic hydrogen atom transfer which, for example, converts 7,7,8,8-tetramethyl-o-quinodimethane (1) to o-isopropyl-a-methylstyrene ( 1 4 with a half-life of only ca. 140 s at 37 "C. Several o-quinodimethanes were discovered which were, for all practical purposes, completely stable at 37 OC. The most suitable lipid-soluble NOCT discovered was 7-(2-indenyl)-7,8,8-trimethyl-o-quinodimethane (5),which is stable and reacts very rapidly with NO to form a persistent nitroxide. Various derivatives 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, was found to be particularly suitable, since the carboxylate anion 14 conferred excellent water solubility without interfering with either the nitric oxide trapping reaction or the necessary photoelimination of carbon monoxide frpjn the starting indanone. Of even greater importance, the carboxylate group had no apparent effect on the rate of the thermal 1,s-sigmatropic rearrangement; Le., 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, hydrophilic, or amphiphilic properties. These NOCTs should prove suitable for exploratory use in biological systems.

Changes of plasma l-arginine levels in spontaneously hypertensive rats under induced hypotension

“…Although a number of methods are capable of measuring the continuous release of NO (Palmer et al, 1987;Kikuchi et al, 1993;Korth et al, 1994), they are not suitable for our purpose because of the short half-life (`5 sec) of NO in vivo (30). Measuring the final NO metabolite, nitrate ion, in plasma (Thienpont et al, 1995;Takahashi et al, 1992;Zeballos et al, 1995) as an indicative of NO release seems to be more appropriate, and will have to be the method of choice in a further study.…”

Synthesis and Properties of a pH‐Insensitive Fluorescent Nitric Oxide Cheletropic Trap (FNOCT)

“…5) [15]. Thereby, the excitation wavelength for the hydroxylamine product 9 (from 7) is shifted from 315 (8) to 380 nm (9), which is advantageous for applications in cellular systems because shortwavelength excitation may damage living cells and hampers also the application due to interference with fluorescence of typical cell constituents, especially NAD(P)H.…”

NMR solvent effect study of pyrroline‐N‐oxide spin traps: Microenvironments in sodium dodecyl sulfate micelles

“…nitrone 5) inside the SDS micelle (fmb) is 0.77. Further, the nitronyl 13C NMR chemical shift for 5 completely inside the micelle (amb) may be calculated via the use of Eqn (6) and is found to be 143.56 ppm. This value is ca.…”

“…'~ This paper describes the complete 13C NMR assignments of ten cyclic nitrone spin traps 1-10 in chloroform. With nitrones 4-10 the possibility of correlating the nitronyl I3C NMR chemical shift (6) with the substituent constant (a)'5 was explored. It is noteworthy that nitrone spin adducts may be correlated by s t r~c t u r e '~.…”