Interesting question by @Van_DeventerJim: Which electrophiles are most suitable to be introduced into complex (bio)molecules by click chemistry, while keeping the reactive group intact? I have no direct experience, but I want to give my two cents, on what I think could work(1/29) https://twitter.com/Van_DeventerJim/status/1381432430696001536">https://twitter.com/Van_Deven...
I think the two strategies that are most promising would be to 1) use a low reactivity electrophile that will survive the click conditions as is or 2) use a masked electrophile that can be activated, e.g. by light, after the click chemistry. (2/29)
Which of these strategies I would chose, depends on several factors. These include: How reactive is the final probe supposed to be (very specific vs. broad profiling)? Which amino acids do you intent to target? How well would a possible activation step be tolerated? (3/29)
Full disclosure at this point. I am not aiming to give a comprehensive overview and if I miss your work on this, I apologize in advance and encourage you to add to this thread. These are just a few thoughts of mine on what could be promising and were I would start. (4/29)
For using low reactivity electrophiles, acryl amides would be an obvious choice, if targeting cysteines is suitable. @Keribackus probably has one of the most comprehensive experiences on this reactive group from her @nature paper ( http://doi.org/10.1038/nature18002).">https://doi.org/10.1038/n... (5/29)
As @nasufovic_v also pointed out as response to this tweet, even α-chloroacetamides seem to be feasible, if some more reactivity towards cysteines would be desired. This has e.g. been shown in this paper by the group of Yue Wang in J. Med. Chem. (7/29) http://doi.org/10.1021/acs.jmedchem.6b01237">https://doi.org/10.1021/a...
Furthermore, heteroaromatic sulfones could be feasible. Brent Martin @MichiganChem (sadly not on twitter as far as I know) would probably be one of the best persons to comment on this based on his group& #39;s paper in @J_A_C_S. (9/29) http://doi.org/10.1021/jacs.9b08831">https://doi.org/10.1021/j...
If you are not in the luxurious situation to have a suitable cysteine in the target, things are of course getting a little more complicated. There are some reactive groups that I think should be suitable here. (10/29)
For targeting lysines, activated esters, which are hydrolytically stable enough, might work. Polyfluorinated phenols seem most suitable as leaving group. @SpringGroupChem even studied their stability to click conditions in this @ChemCommun paper (11/29) http://doi.org/10.1039/C9CC04022F">https://doi.org/10.1039/C...
I could also imagine N-acyl-N-alkyl sulfonamides to work in this case, but I have not found click chemistry on them in the literature. The group of Itaru Hamachi @KyotoU_News just recently used them in complex molecules in this @J_A_C_S paper. (12/29) https://doi.org/10.1021/jacs.1c00703">https://doi.org/10.1021/j...
Depending on what you want to do, it might also be feasible to bring in the unreactive N-acyl sulfonamide into the molecule by click chemistry and activate it later on by alkylation (see below). (13/29)
Last but certainly not least, for targeting different amino acid residues, the SuFEx chemistry pioneered by K. Barry Sharpless @scrippsresearch should be feasible. The group of Hua‐Li Qin published on clicking these compounds in this @EurJOC paper. (15/29) http://doi.org/10.1002/ejoc.201801825">https://doi.org/10.1002/e...
A second strategy would be to use activatable electrophiles. These come in two flavors, as protected reactive group that are activated in a separate reaction or light-activatable electrophiles that are activated in situ. (17/29)
For protected reactive groups, I already hinted at the N-acyl-N-alkyl sulfonamides that could be introduced as N-acyl sulfonamides using click chemistry and then activated using alkylation. Another example of this is in this @NatureComms paper. (18/29) http://doi.org/10.1038/s41467-018-04343-0">https://doi.org/10.1038/s...
While these can also be used for activation in situ as discussed below, I can also imagine to use this as a protection group strategy to liberate this highly reactive group in a separate reaction and then have the electrophile available without requiring in situ activation(20/29)
Directly activating electrophiles in situ for me has additional advantages as the initial compound will be unreactive. In this way, it is highly likely that it will not cause trouble during the click chemistry and that it will also enable in cell studies more easily. (21/29)
The 2,5-disubstituted tetrazole is stable to click chemistry as e.g. shown by the group of @doc_jlmeier in this paper in @ChemBioChem. (26/29) http://doi.org/10.1002/cbic.201800651">https://doi.org/10.1002/c...
To wrap up, I will engage in some shameless self-promotion. If you want to learn more about the proteome-wide reactivity of most of these reactive groups and some more, also check out our @ChemRxiv with first author @patrick_zanon. (27/29) http://doi.org/10.26434/chemrxiv.14186561">https://doi.org/10.26434/...
These are my thoughts. I would be excited if others would add their thoughts or experimental experiences to this thread. As I mentioned, we have not tried this experimentally, so I would also be excited to hear if some of you disagree on some (hopefully not all) points. (28/29)
Thanks @Van_DeventerJim for bringing up this interesting question and making me do my homework on this topic that I wanted to look into for a while now (also for making me spent way too much time on it). I hope my thoughts are helpful and maybe even provoke some discussion(29/29)
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