NITRIC OXIDE: Biology and Chemistry Vol. 1, No. 3, June, pp. 211–217 (1997) Article No. NO970125 An Examination of Some Derivatives of S -Nitroso-1-thiosugars as Vasodilators Anthony R. Butler,* ,1 Robert A. Field,* Iain R. Greig,* Frederick W. Flitney,† Stuart K. Bisland,† Faisel Khan,‡ and Jill J. F. Belch‡ *School of Chemistry and Centre for Biomolecular Sciences and †School of Biology and Preclinical Medicine, University of St Andrews, Fife, Scotland KY 16 9TS, United Kingdom; and ‡Department of Medicine, Ninewells Hospital, Dundee, Scotland DD1 9SY, United Kingdom Received January 2, 1997, and in revised form March 28, 1997 of NO and may also be the means by which NO is A number of S-nitrosated compounds derived transported around the body (7). from 1-thiosugars (glucose, galactose, xylose, malt- Most S-nitrosothiols are too unstable to be synthe- ose, and lactose) have been prepared and character- sized and isolated in vitro but there are two notable ized. Most of the compounds obtained were unstable exceptions to this generalization, viz. S-nitroso-D,L- either as solids or in solution. However, S-nitroso-1- penicillamine (SNAP) (8) and GSNO (9). These com- thio-2,3,4,6-tetra-O-acetylglucopyranose was stable pounds have been used for most of the biological enough to examine as a vasodilator using an iso- testing of S-nitrosothiols and two effects have been lated rat tail artery model. It also proved effective studied in some detail. S-Nitrosothiols act as vasodi- in human cutaneous vascular smooth muscle relax- lators (10, 11) in ex vivo testing and are also effective ation when delivered transdermally.  1997 Academic in whole animals (12). In addition, they prevent Press platelet adhesion and aggregation (13, 14) and have been used clinically for this purpose during percuta- neous transluminal coronary angioplasty (15). In vitro many S-nitrosothiols (RSNOs) 2 decompose The possibilities for structural variation in S-ni- with release of nitric oxide and formation of a disul- trosated amino acids are limited. In order to obtain fide (1): an NO-donor drug which can be delivered transder- mally we turned to other thiol-containing com- 2RSNO r RS-SR / 2NO. pounds. An important structural feature for this This reaction occurs thermally (2), photochemically mode of delivery is the presence of hydrophobic and hydrophilic groups in the molecule and so we consid- (3), and in solution in a process strongly catalyzed ered some derivatives of S-nitroso-1-thiosugars. by copper ions (4). Some S-nitrosothiols are formed Glyceryl trinitrate, an NO-producing drug used in endogenously, principally S-nitrosated human se- the treatment of a number of cardiovascular dys- rum albumin (5) and S-nitrosoglutathione (GSNO) functions, can be delivered transdermally and the (6) and, in vivo, other decomposition pathways may similarity between glycerol and a sugar prompted operate. S-Nitrosothiols may act as stores or pools our interest. There is, however, a significant differ- ence between glyceryl trinitrate and an S-nitrosoth- 1 To whom correspondence should be addressed. iol in terms of NO production. The former requires 2 Abbreviations used: RSNOs, S-nitrosothiols; GSNO, S-nitro- extensive metabolism, probably catalyzed by en- soglutathione; SNAP, S-nitroso-D,L-penicillamine; SNAG, S-ni- trosoacetylglucose; PU, perfusion units. zymes, before NO release can occur (16) while the 211 1089-8603/97 $25.00 Copyright  1997 by Academic Press All rights of reproduction in any form reserved.