Inhibition of human leukocyte elastase. 3. Synthesis and activity of 3'-substituted cephalosporins

Several 3'-substituted cephalosporin sulfones were synthesized from 3-(hydroxymethyl)cephalosporin, which was prepared by Ti(OiPr)4 hydrolysis of the corresponding acetate. A method was also developed to prepare a 3-vinylcephalosporin. Some of these compound were found to be potent time-depende...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1990-09, Vol.33 (9), p.2529-2535
Main Authors: Shah, Shrenik K, Brause, Karen A, Chandler, Gilbert O, Finke, Paul E, Ashe, Bonnie M, Weston, Hazel, Knight, Wilson B, Maycock, Alan L, Doherty, James B
Format: Article
Language:English
Subjects:
Cephalosporins - chemical synthesis
Cephalosporins - pharmacology
Chemical Phenomena
Chemistry
Humans
Leukocyte Elastase
Pancreatic Elastase - antagonists & inhibitors
Structure-Activity Relationship
Sulfones - chemical synthesis
Sulfones - pharmacology
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Summary:Several 3'-substituted cephalosporin sulfones were synthesized from 3-(hydroxymethyl)cephalosporin, which was prepared by Ti(OiPr)4 hydrolysis of the corresponding acetate. A method was also developed to prepare a 3-vinylcephalosporin. Some of these compound were found to be potent time-dependent inhibitors of human leukocyte elastase (HLE). The HLE inhibitory activity was correlated with sigma 1 and it was concluded that the potency was determined by the electron-withdrawing ability as well as the size of the substituent. A mechanism for inhibition of HLE by cephalosporin sulfones is proposed.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00171a030