Synthesis and evaluation of macrocyclic transition state analogue inhibitors for alpha-chymotrypsin.
Lactams 1 and 2 are readily formed from acyclic precursors in the presence of trypsin and chymotrypsin, respectively, identifying the macrocyclic ring system as a potential motif for constrained transition state analogue inhibitors of the serine peptidases. Ketone 3 was synthesized and shown to be a modest inhibitor of chymotrypsin (Ki = 220 microM), albeit 4-fold more potent than the acyclic hydroxy acid 25 (Ki = 1.5 mM as a mixture of epimers). A precursor (31) to the amino boronic acid 4 was also prepared; although this derivative was a potent inhibitor of chymotrypsin (Ki = 130 nM) by virtue of the boronic acid moiety, it showed no advantage over the des-amino analogue 32 (Ki = 120 nM), which is not capable of cyclizing.
Center for New Directions in Organic Synthesis, Department of Chemistry, University of California, Berkeley, California 94720-1460, USA.
Kristina K
KK
Hansen
Benjamin
B
Grosch
Sorana
S
Greiveldinger-Poenaru
Paul A
PA
Bartlett
D000144:Acids, Acyclic / Q000737:chemistry; D001897:Boronic Acids / Q000737:chemistry; D002918:Chymotrypsin / Q000737:chemistry*; D007659:Ketones / Q000737:chemistry; D007769:Lactams / Q000737:chemistry; D008956:Models, Chemical; D010456:Peptides, Cyclic / Q000737:chemistry*; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis*; D013379:Substrate Specificity; D014357:Trypsin / Q000737:chemistry
D000144:Acids, Acyclic; D001897:Boronic Acids; D007659:Ketones; D007769:Lactams; D010456:Peptides, Cyclic; D015842:Serine Proteinase Inhibitors; D002918:Chymotrypsin; C117608:alpha-chymotrypsin; D014357:Trypsin