SYNTHESIS AND STRUCTURAL CHARACTERIZATION OF THE TRIMERIC FUROXAN (EQUALS FURAZAN 2-OXIDE) SYSTEM, A NEW POTENT VASODILATING MOIETY

The synthesis, structural characterization, and NO donor properties of a series of terfuroxan (= terfurazan trioxide) derivatives la-h and 2 a-j are reported (Schemes I and 2). Structural assignments were confir med principally by mass and C-13- and H-1-NMR spectroscopy. The extent and the initial rate of NO release in the presence of thiol cofactor was evaluated for each derivative. Vasodilator effects of all the terf uroxan derivatives were evaluated on endothelium-denuded strips of rat aorta precontracted with noradrenaline. Concentration-response curves were also evaluated in the presence of 10 mu M oxyhemoglobin (HbO(2)) , a well known NO scavenger. The whole series displays high vasodilati ng potency; the most active terfuroxans (la, b,g and 2i) are 5-10 time s as potent as glyceryl trinitrate taken as reference (see Table 3). T he potency decrease observed in the presence of HbO(2) agrees with the involvement of NO in the vasorelaxing action. The 4,3':4',4 '' connec tion (series 1; furoxan numbering) gives rise to the most potent compo unds. The conformational factors seem to play important roles in the a ctivity. No clear relationship between physico-chemical properties of the substituents and potencies of derivatives emerges.