Novel 6-hydroxychroman-2-carbonitrile inhibitors of membrane peroxidative injury.
Novel 6-hydroxychroman-2-carbonitrile compounds have been synthesized, and their antiperoxidant activity against superoxide-dependent, iron-promoted mycocardial phospholipid peroxidation has been evaluated quantitatively. With few exceptions, these compounds afforded significant, concentration-dependent antiperoxidant protection to myocardial-membrane phospholipid at sub- to low-micromolar concentrations. Structure-activity correlation demonstrated that R1-, R2-, and R3-methyl groups in the aromatic ring enhanced antiperoxidant activity, whereas hydrophobic groups at either R4 or R5 of the pyran ring compromised antiperoxidant efficacy. The most efficacious antiperoxidant synthesized contained a catechol moiety at R4 and was some 10-fold more potent than alpha-tocopherol. None of the 6-hydroxychroman-2-carbonitrile antiperoxidants scavenged superoxide or inhibited the enzymatic superoxide generator, xanthine oxidase, at effective antiperoxidant concentrations. The ability of these compounds to interrupt the propagatory phase of an on-going peroxidation reaction indicated that they acted as antiperoxidants by trapping chain-carrying lipid peroxyl radicals. Since a number of the 6-hydroxychroman-2-carbonitriles were most potent antiperoxidants than a variety of known chain-breaking compounds, this new class of phenolic antioxidants may represent a novel approach to the design of therapeutics against diseases in which lipid peroxidation is a causative factor or in which lipid peroxidases serve as mediators.
Janero
D A
DA
Department of Pharmacology and Chemotherapy, Hoffmann-La Roche Inc., Nutley, NJ 07110-1199.
Cohen
N
N
Burghardt
B
B
Schaer
B H
BH
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001578:Benzopyrans / Q000494:pharmacology*; D002462:Cell Membrane / Q000378:metabolism; D002839:Chromans / Q000494:pharmacology*; D005609:Free Radicals; D007501:Iron / Q000494:pharmacology; D015227:Lipid Peroxidation / Q000187:drug effects*; D008563:Membrane Lipids / Q000378:metabolism*; D015394:Molecular Structure; D009206:Myocardium / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology*; D010743:Phospholipids / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship; D013481:Superoxides / Q000378:metabolism / Q000494:pharmacology; D013858:Thiobarbiturates; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors
D000975:Antioxidants; D001578:Benzopyrans; D002839:Chromans; D005609:Free Radicals; D008563:Membrane Lipids; D009570:Nitriles; D010743:Phospholipids; D013858:Thiobarbiturates; D013481:Superoxides; D007501:Iron; D014969:Xanthine Oxidase; C029684:thiobarbituric acid