Electron deficient, bivalent sulfur atoms have two areas of positive electrostatic potential, a consequence of the low-lying σ* orbitals of the C-S bond that are available for interaction with electron donors including oxygen and nitrogen atoms and, possibly, π-systems. Intramolecular interactions are by far the most common manifestation of this effect, which offers a means of modulating the conformational preferences of a molecule. Although a well-documented phenomenon, a priori applications in drug design are relatively sparse and this interaction, which is often isosteric with an intramolecular hydrogen-bonding interaction, appears to be underappreciated by the medicinal chemistry community. In this Perspective, we discuss the theoretical basis for sulfur σ* orbital interactions and illustrate their importance in the context of drug design and organic synthesis. The role of sulfur interactions in protein structure and function is discussed and although relatively rare, intermolecular interactions between ligand C-S σ* orbitals and proteins are illustrated.

The basis for unprecedented noncovalent bonding between anions and the aryl centroid of electron-deficient aromatic rings has been demonstrated by an ab initio study of the interaction between 1,3,5-triazine and the fluoride, chloride, and azide ion at the MP2 level of theory. Minima are also located corresponding to C[bond]H...X(-) hydrogen bonding, reactive complexes for nucleophilic attack on the triazine ring, and pi-stacking interactions (with azide). Trifluoro-1,3,5-triazine also participates in aryl centroid complexation and forms nucleophilic reactive complexes with anions. This novel mode of bonding suggests the development of new cyclophane-type receptors for the recognition of anions.

The redox siblings nitroxyl (HNO) and nitric oxide (NO) have often been assumed to undergo casual redox reactions in biological systems. However, several recent studies have demonstrated distinct pharmacological effects for donors of these two species. Here, infusion of the HNO donor Angeli's salt into normal dogs resulted in elevated plasma levels of calcitonin gene-related peptide, whereas neither the NO donor diethylamine͞NONOate nor the nitrovasodilator nitroglycerin had an appreciable effect on basal levels. Conversely, plasma cGMP was increased by infusion of diethylamine͞NONOate or nitroglycerin but was unaffected by Angeli's salt. These results suggest the existence of two mutually exclusive response pathways that involve stimulated release of discrete signaling agents from HNO and NO. In light of both the observed dichotomy of HNO and NO and the recent determination that, in contrast to the O2͞O 2 ؊ couple, HNO is a weak reductant, the relative reactivity of HNO with common biomolecules was determined. This analysis suggests that under biological conditions, the lifetime of HNO with respect to oxidation to NO, dimerization, or reaction with O2 is much longer than previously assumed. Rather, HNO is predicted to principally undergo addition reactions with thiols and ferric proteins. Calcitonin gene-related peptide release is suggested to occur via altered calcium channel function through binding of HNO to a ferric or thiol site. The orthogonality of HNO and NO may be due to differential reactivity toward metals and thiols and in the cardiovascular system, may ultimately be driven by respective alteration of cAMP and cGMP levels.Angeli's salt ͉ superoxide dismutase ͉ heme protein ͉ cGMP ͉ calcitonin gene-related peptide D uring the last two decades, discussion of the chemistry of nitric oxide (NO) in biological systems has primarily focused on the nitrosylation of heme proteins such as soluble guanylyl cyclase and the production of reactive nitrogen oxide species (RNOS) (1-3). The RNOS literature has largely been concerned with nitrogen dioxide (NO 2 ), dinitrogen trioxide (N 2 O 3 ), and peroxynitrite (ONOO Ϫ ), which are formed through reaction with molecular oxygen or superoxide (O 2 Ϫ ) (4-6). Recently, however, there has been increased interest in the one-electron reduction product of NO, nitroxyl (HNO͞NO Ϫ ; nitrosyl hydride͞nitroxyl anion). Of particular note are studies suggesting that oxidation of L-arginine by NO synthase (NOS) leads to production of nitroxyl rather than NO under certain conditions (7-10). In this light, elucidation of the chemical biology of nitroxyl has acquired new importance.Comparisons of the toxicological and pharmacological properties of nitrogen oxide donor compounds have revealed that NO and HNO in general elicit distinct responses under a variety of biological conditions. In vitro, HNO reacts with O 2 to generate potent oxidizing species capable of cleaving DNA, thereby augmenting oxidative damage (3, 11). The RNOS formed by NO autoxidation do not cause these cellular a...