In and out, without a trace

The sulfonamide… I have always been fascinated by this functional group. Tonight I will discuss its relationship to regular amides. If you look at the inset below, you will find a peculiar difference in behavior of cyclic and acyclic sulfonamides/amides. We all know that acyclic sulfonamides are substantially more stable than regular amides towards hydrolysis (boiling HBr has been prescribed many a time, especially in the older literature). However, if you consider 4-memberd ring sultams and their carbonyl “relatives” – beta-lactams, you will note that now the reactivity is reversed and the sulfur analogs are more reactive during hydrolysis.


There is a paper by Page that discusses this interesting property:

There are many outstanding features possessed by sultams, and one of them is their ability to inhibit serine proteases. Not long ago, Sieber and colleagues made an interesting observation in the course of figuring out the mode of action of sultam-containing inhibitors of ClpP. Covalent labeling of ClpP’s Ser98 resulted not only in irreversible labelling of the active site serine, but proceeded to give the product of elimination, which resulted in dehydroalanine formation. This is an interesting lesson for those of us who are interested in the design of irreversible enzyme inhibitors. I am not aware of similar cases where the active site residue participates in such an elimination, although there might be some. Notably, the Dha residue was characterized by the authors using X-ray crystallography.


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