title: Novel anthraquinone inhibitors of human leukocyte elastase and cathepsin G.
abstract: A large series of variously substituted anthraquinones has been synthesized and assayed for inhibitory capacity against human leukocyte elastase (HLE) and cathepsin G (CatG), two serine proteinases implicated in diseases characterized by the abnormal degradation of connective tissue, such as pulmonary emphysema and rheumatoid arthritis. It was found that 2-alkyl-1,8-dihydroxyanthraquinone analogues are competitive inhibitors of HLE with IC50 values ranging from 4 to 10 microM, and also inhibit CatG with IC50 values ranging from 25 to 55 microM. Consequently, analogues containing the 2-alkyl-1-hydroxy-8-methoxyanthraquinone substitution pattern inhibit HLE to the same magnitude as for the compounds above, but show very little inhibition of CatG. Anthraquinones containing long, hydrophobic n-butyl carbonate moieties in the 1- and 8-positions in conjunction with a third hydrophobic substituent in the 2- or 3-position are highly selective for HLE, with Ki values in the range of 10(-7) M. All of the inhibitors described are completely reversible, with no evidence of acyl-enzyme formation detected.
authors.affiliation: School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta 30332.
authors.forename: D E
authors.initials: DE
authors.lastname: Zembower
authors.forename: C M
authors.initials: CM
authors.lastname: Kam
authors.forename: J C
authors.initials: JC
authors.lastname: Powers
authors.forename: L H
authors.initials: LH
authors.lastname: Zalkow
mesh_terms: D000880:Anthraquinones / Q000138:chemical synthesis / Q000494:pharmacology*; D056649:Cathepsin G; D002403:Cathepsins / Q000037:antagonists & inhibitors*; D006801:Humans; D019272:Leukocyte Elastase; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors*; D012697:Serine Endopeptidases; D013329:Structure-Activity Relationship
chemical_list: D000880:Anthraquinones; D002403:Cathepsins; D012697:Serine Endopeptidases; C534094:CTSG protein, human; D056649:Cathepsin G; D010196:Pancreatic Elastase; D019272:Leukocyte Elastase