Joe
These designs have three unspecified stereo centers. What is the stereoselectivity of the synthesis startegy you propose?
These designs have three unspecified stereo centers. What is the stereoselectivity of the synthesis startegy you propose?
I think the idea of merging these structures is good. Nevertheless, I would recommend holding off until we’ve got a better idea of the binding mode for BEN-DND-93268d01-8 and have established that inhibitory activity of ADA-UCB-6c2cb422-1 is maintained when it is annulated to PET-UNK-c9c1e0d8-3 .
I’d expect BEN-DND-93268d01-8 to be predominantly neutral at pH = 7 (the pKa for values for 1,4-dimethylpiperazine and glycine amide are each ~8). I found a couple of relevant crystal structures (HODQUP and UWUJAZ ) in the Cambridge Structural Database and these point to a conformation in which the amide NH of BEN-DND-93268d01-8 eclipses the lone pair of the piperazine nitrogen.
On the second thought i think that this design is wrong, because most probably the dominant isomer would be trans- and so it would be flat. If BEN-DND-93268d01-8 docks the way I think it does piperidine would overlap with, say, p-phenylenediamine from ALP-POS-c59291d4-2, that would mean that N-acetylpiperidine part of that trans-azadecalin would be perpendicular to preferred conformation of piperidine. Either way, conformation of bound BEN-DND-93268d01-8 will be needed to say anything about this molecule
Cis- isomer, on the other hand, won’t be flat so maybe it could bind in right conformation. But I’m not sure.