Most of submitted designs uses acrylamides as warheads, sometimes with dialkylaminomethylene pendant, but there is another possibility: N-sulfonylaziridines, the main point being that it allows somewheat more fine-tuning than acrylamide. There are seemingly mild conditions under which (substituted) N-tosylaziridines are opened by thiols (https://doi.org/10.1016/j.tetlet.2006.01.086) so that moiety looks like it may be reactive enough. Sterically, these would be reasonably similar to vinylsulfones, and someone already suggested vinylsulfones as warheads. Among many options, these can be made in Mitsunobu reaction (for example https://doi.org/10.1080/00397919608004589) from appropriate ethanolamines, while using serine as starting material would provide a simple way to introduce dialkylaminomethylene pendant as either of enantiomers.
I don’t know if it’s a good idea - synthesis is definitely longer than with acrylamides - but I’ve found Chinese patent (CN107501270) that uses warhead like this in order to create analogue of ibrutinib, so maybe it’s worth giving a shot at some later stage. I can’t right now, but I’d try to upload some molecules with this motif sometime later
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Thanks, @miko_a. That is definitely something to look into. We plan on doing a “warhead scan” on some of the more promising molecules, so this may be very useful.
Reversibility is a key design consideration and these notes may be helpful (I have posted elsewhere on the forum so apologies if you’ve seen them already):
This study of warheads may be of interest (I’ve also posted it elsewhere on the forum so, once again, apologies if you’ve already seen it):
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