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Synthesis and evaluation of macrocyclic transition state analogue inhibitors for alpha-chymotrypsin. 2003

Kristina K Hansen, and Benjamin Grosch, and Sorana Greiveldinger-Poenaru, and Paul A Bartlett
Center for New Directions in Organic Synthesis, Department of Chemistry, University of California, Berkeley, California 94720-1460, USA.

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.

UI MeSH Term Description Entries
D007659 Ketones Organic compounds containing a carbonyl group Ketone
D007769 Lactams Cyclic AMIDES formed from aminocarboxylic acids by the elimination of water. Lactims are the enol forms of lactams. Lactam,Lactim,Lactims
D008956 Models, Chemical Theoretical representations that simulate the behavior or activity of chemical processes or phenomena; includes the use of mathematical equations, computers, and other electronic equipment. Chemical Models,Chemical Model,Model, Chemical
D010456 Peptides, Cyclic Peptides whose amino acid residues are linked together forming a circular chain. Some of them are ANTI-INFECTIVE AGENTS; some are biosynthesized non-ribosomally (PEPTIDE BIOSYNTHESIS, NON-RIBOSOMAL). Circular Peptide,Cyclic Peptide,Cyclic Peptides,Cyclopeptide,Orbitide,Circular Peptides,Cyclopeptides,Orbitides,Peptide, Circular,Peptide, Cyclic,Peptides, Circular
D001897 Boronic Acids Inorganic or organic compounds that contain the basic structure RB(OH)2. Boronic Acid,Acid, Boronic,Acids, Boronic
D002918 Chymotrypsin A serine endopeptidase secreted by the pancreas as its zymogen, CHYMOTRYPSINOGEN and carried in the pancreatic juice to the duodenum where it is activated by TRYPSIN. It selectively cleaves aromatic amino acids on the carboxyl side. Alpha-Chymotrypsin Choay,Alphacutanée,Avazyme
D000144 Acids, Acyclic Carboxylic acids that have open-chain molecular structures as opposed to ring-shaped structures. Acyclic Acids
D013379 Substrate Specificity A characteristic feature of enzyme activity in relation to the kind of substrate on which the enzyme or catalytic molecule reacts. Specificities, Substrate,Specificity, Substrate,Substrate Specificities
D014357 Trypsin A serine endopeptidase that is formed from TRYPSINOGEN in the pancreas. It is converted into its active form by ENTEROPEPTIDASE in the small intestine. It catalyzes hydrolysis of the carboxyl group of either arginine or lysine. EC 3.4.21.4. Tripcellim,Trypure,beta-Trypsin,beta Trypsin
D015842 Serine Proteinase Inhibitors Exogenous or endogenous compounds which inhibit SERINE ENDOPEPTIDASES. Serine Endopeptidase Inhibitor,Serine Endopeptidase Inhibitors,Serine Protease Inhibitor,Serine Protease Inhibitors,Serine Proteinase Antagonist,Serine Proteinase Antagonists,Serine Proteinase Inhibitor,Serine Proteinase Inhibitors, Endogenous,Serine Proteinase Inhibitors, Exogenous,Serine Protease Inhibitors, Endogenous,Serine Protease Inhibitors, Exogenous,Antagonist, Serine Proteinase,Endopeptidase Inhibitor, Serine,Inhibitor, Serine Endopeptidase,Inhibitor, Serine Protease,Inhibitor, Serine Proteinase,Protease Inhibitor, Serine,Proteinase Antagonist, Serine,Proteinase Inhibitor, Serine

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