(22) Our starting point, as exemplified by 1 (hARG1 IC 50 = 311 nM), has a moderate enzymatic activity. (23) Based on careful analysis of the binding site, in particular, the underexplored space not effectively occupied by 1, we envisioned that (1) a judicious cyclization of the α-amino group to the carbon backbone might be tolerated and fit better into the narrow pocket and (2) the resulting N-heterocyclic core could be leveraged as a template to better engage in direct or water-mediated H-bonds with residues Asp183 and/or Asp181, as observed by Van Zandt and co-workers ( 2, Figure 1B) (20) and ourselves previously. (21) In an attempt to identify the most appropriate cyclization approach, we employed a modular synthetic strategy by investigating a broad scope of N-heterocyclic cores with a variety of linker sizes ( Scheme 1).
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