Novel 6-O-acylated vitamin C derivatives as hyaluronidase inhibitors with selectivity for bacterial lyases.
Previously, we identified ascorbic acid 6-O-hexadecanoate as an up to 1500 times more potent inhibitor of bacterial and bovine hyaluronidases than the parent compound, vitamin C, and determined a crystal structure of hyaluronidase from Streptococcus pneumoniae in complex with the inhibitor. As the alkanoyl chain interacts with a hydrophobic patch of the enzyme we synthesized other 6-O-acylated vitamin C derivatives bearing various lipophilic residues and investigated the inhibition of Streptococcus agalactiae strain 4755 hyaluronidase (SagHyal(4755)) and of bovine testicular hyaluronidases (BTH) in a turbidimetric assay. All compounds showed selectivity for the bacterial enzyme. Whereas vitamin C 6-O-hexanoate only weakly inhibited SagHyal(4755), the inhibition of both enzymes increased with the length of the aliphatic chain. In the case of the 6-O-octadecanoate, IC(50) values of 0.9 and 39microM for SagHyal(4755) and BTH, respectively, were determined. Partial replacement of the aliphatic chain with a phenyl, p-phenylene or p-biphenylyl group resulted in inhibitors with activity in the lower micromolar range, too. The title compounds are among the most potent inhibitors of both enzymes known to date.
Spickenreither
Martin
M
Institute of Pharmacy, Pharmaceutical/Medicinal Chemistry II, University of Regensburg, Universitätsstr. 31, D-93040 Regensburg, Germany.
Braun
Stephan
S
Bernhardt
Günther
G
Dove
Stefan
S
Buschauer
Armin
A
D000818:Animals; D001205:Ascorbic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D002417:Cattle; D003460:Crystallization; D018360:Crystallography, X-Ray; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006821:Hyaluronoglucosaminidase / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D008968:Molecular Conformation; D013237:Stereoisomerism; D013292:Streptococcus agalactiae / Q000201:enzymology*; D013296:Streptococcus pneumoniae / Q000201:enzymology*; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D006821:Hyaluronoglucosaminidase; D001205:Ascorbic Acid