Isothiuronium

Abstract: Early in the investigation of the relation between molecular structure and radiation-protective activity in the mercaptoalkylamines (1), it was discovered that certain isothiuronium compounds afforded a greater degree of protection than the mercaptoalkylamines against doses of X-radiation that are ordinarily fatal to mice. In a preliminary report, Doherty and Burnett (2) presented evidence that two such compounds, S, 2-aminoethylisothiuronium Br HBr (AET) and S, 3-aminopropylisothiuronium Br HBr (APT), were more effective on a molar basis (especially at lower concentrations) than 2-mercaptoethylamine (MEA). The thiuronium compounds were also somewhat less toxic and possessed the further advantage of being chemically stable salts not susceptible to autoxidation. A tentative conclusion, based on the limited number of compounds tested up to that time, was that the structure essential for maximum protective activity would include a free amino group, placed in position 2 or 3 to the sulfhydryl or isothiuronium group. In view of the increased protective activity of the aminoalkylisothiuronium compounds, we thought it worth while to (1) determine the active form of AET and APT at physiological pH's and (2) prepare and examine a larger series of isothiuronium compounds to better correlate compound structure with protective activity. Such a study should yield information necessary for an understanding of the nature of the chemical protection against radiation damage offered by these compounds. In addition, clues to the nature of the biochemical systems affected might be furnished by the structure of the active compounds. Compounds with increased activity and selectivity would be especially useful for the discovery and study of such systems.

Abstract: 1. The preparation of a series of compounds derived from diamines by replacing one amino group by a dimethylsulphonium, isothiuronium, trimethylammonium, NN′-dimethylimidazolium or N-methylpyridinium species is described. 2. The behaviour of these compounds as substrates of pig kidney diamine oxidase is reported. All but the trimethylammonium compounds proved to be substrates. 3. Many of these compounds showed potent inhibition at high substrate concentration and this was studied. 4. On the basis of these and other observations a scheme for enzyme–substrate interaction is suggested.