[reaction: see text] Various radical species generated from either the corresponding iodo- or bromo- compounds and tri-n-butyltin hydride were added in an intermolecular fashion to the activated acceptor pentafluorophenyl vinylsulfonate. The products of each reaction were then subjected to aminolysis with a variety of different amines.

[reaction: see text] An efficient intermolecular 1,3-dipolar cycloaddition of a variety of nitrones to pentafluorophenyl (PFP) vinylsulfonate is described. The transformation produces stable "reversed" cycloadducts of unprecedented stereo- and regioselectivity. Subsequent amine displacement of the PFP moiety furnished functionalized sulfonamide products in good yields.

A range of pentafluorophenyl (PFP) sulfonate esters derived from the reaction of PFP vinyl sulfonate and various nitrones are shown to have significant inhibitory activity against the bacterial enzymes DDAH and ADI.Nitric oxide (NO) is an important mediator of intracellular signaling and has attracted interest as a target for therapeutic intervention, as it is widely acknowledged that there are a variety of disease states for which NO is implicated. 1 One of the most significant problems associated with the design of inhibitors, is to target the pathological excess NO production without disrupting essential NO-mediated processes, often by seeking selectivity for a particular NOS isoform. One method for potentially circumventing these problems is the indirect modulation of NO levels by inhibition of the enzyme DDAH which is responsible for controlling levels of N G -methyl-L-arginine (MMA) and N G , N G , dimethyl-L-arginine (ADMA) which are endogeneous inhibitors of NOS. 2,3 Inhibition of bacterial DDAH 4 is also of interest as it offers opportunities for the development of new anti-bacterial agents. The structurally related enzyme arginine deiminase (ADI) is also a possible antibacterial/antiprotozoal target, as various pathogenic organisms utilize ADI to generate ATP under anaerobic conditions. 5aRecently high-resolution structures of a bacterial DDAH 6 and ADI 5 have been disclosed and it has been shown in both enzymes that the active site comprises a catalytic triad containing an acidic residue (Glu / Asp), a basic residue (His) and a cysteine residue (Cys) (Figure 1). Both enzymes are known to catalyze the conversion of the substrate(s) MMA and ADMA to citrulline as shown in figure 1. In a recent communication Knipp et al. described the cysteine modification of DDAH by HcyNO and proposed this as a lead for the possible development of covalent inhibitors of DDAH and ADI. 7 In that work it was proposed that it should be possible to rationally design covalent inhibitors of DDAH based on those findings. That work has prompted us to disclose our own studies, which identify novel small molecule inhibitors of DDAH and ADI. Whilst the development of small molecule inhibitors of both DDAH and ADI is appealing, it is notable that there is only one known inhibitor of bacterial DDAH, which has modest affinity and is an arginine homologue, 8 and there are no known inhibitors of ADI. Herein we disclose our preliminary studies on the use of pentafluorophenyl (PFP) sulfonates as an unprecedented new class of enzyme inhibitors. The biological activity of the PFP-sulfonate group is completely unexplored and is highlighted here by the development of inhibitors of DDAH and ADI As had previously been noted by one of us in the disclosure of the crystal structure of DDAH, the active site resembles that of a cysteine protease with a catalytic triad (Fig 1). 5 The work of Roush et al. on the use of sulfonates and sulfonamides as inhibitors of cysteine proteases, 9 stimulated us to speculate that it may be possible to generate inh...

A range of pentafluorophenyl (PFP) sulfonate esters derived from the reaction of PFP vinyl sulfonate and various nitrones are shown to have significant inhibitory activity against the bacterial enzymes DDAH and ADI.Nitric oxide (NO) is an important mediator of intracellular signaling and has attracted interest as a target for therapeutic intervention, as it is widely acknowledged that there are a variety of disease states for which NO is implicated. 1 One of the most significant problems associated with the design of inhibitors, is to target the pathological excess NO production without disrupting essential NO-mediated processes, often by seeking selectivity for a particular NOS isoform. One method for potentially circumventing these problems is the indirect modulation of NO levels by inhibition of the enzyme DDAH which is responsible for controlling levels of N G -methyl-L-arginine (MMA) and N G , N G , dimethyl-L-arginine (ADMA) which are endogeneous inhibitors of NOS. 2,3 Inhibition of bacterial DDAH 4 is also of interest as it offers opportunities for the development of new anti-bacterial agents. The structurally related enzyme arginine deiminase (ADI) is also a possible antibacterial/antiprotozoal target, as various pathogenic organisms utilize ADI to generate ATP under anaerobic conditions. 5aRecently high-resolution structures of a bacterial DDAH 6 and ADI 5 have been disclosed and it has been shown in both enzymes that the active site comprises a catalytic triad containing an acidic residue (Glu / Asp), a basic residue (His) and a cysteine residue (Cys) (Figure 1). Both enzymes are known to catalyze the conversion of the substrate(s) MMA and ADMA to citrulline as shown in figure 1. In a recent communication Knipp et al. described the cysteine modification of DDAH by HcyNO and proposed this as a lead for the possible development of covalent inhibitors of DDAH and ADI. 7 In that work it was proposed that it should be possible to rationally design covalent inhibitors of DDAH based on those findings. That work has prompted us to disclose our own studies, which identify novel small molecule inhibitors of DDAH and ADI. Whilst the development of small molecule inhibitors of both DDAH and ADI is appealing, it is notable that there is only one known inhibitor of bacterial DDAH, which has modest affinity and is an arginine homologue, 8 and there are no known inhibitors of ADI. Herein we disclose our preliminary studies on the use of pentafluorophenyl (PFP) sulfonates as an unprecedented new class of enzyme inhibitors. The biological activity of the PFP-sulfonate group is completely unexplored and is highlighted here by the development of inhibitors of DDAH and ADI As had previously been noted by one of us in the disclosure of the crystal structure of DDAH, the active site resembles that of a cysteine protease with a catalytic triad (Fig 1). 5 The work of Roush et al. on the use of sulfonates and sulfonamides as inhibitors of cysteine proteases, 9 stimulated us to speculate that it may be possible to generate inh...

A convenient microwave assisted synthesis of sulfonamides from PFP‐sulfonates is described. Reaction of various commercially available amines with pentafluorophenyl (PFP) sulfonate esters under microwave irradiation led to the corresponding sulfonamide products in good yields and without the requirement for chromatographic purification. The data shows that a number of functional groups are tolerated in both the amine and sulfonate ester and that the method can be extended to heterocyclic sulfonamides of potential biological interest.