Novel 21-amino steroids as potent inhibitors of iron-dependent lipid peroxidation

• Published in: The Journal of biological chemistry Vol. 262; no. 22; pp. 10438 - 10440
• Main Authors: Braughler, J M, Pregenzer, J F, Chase, R L, Duncan, L A, Jacobsen, E J, McCall, J M
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Elsevier Inc 05-08-1987; American Society for Biochemistry and Molecular Biology
• Subjects: Analytical, structural and metabolic biochemistry; Animals; Biological and medical sciences; brain; Brain - drug effects; Brain - metabolism; Butylated Hydroxytoluene - pharmacology; Cell Membrane - metabolism; Deferoxamine - pharmacology; Enzymes and enzyme inhibitors; Fundamental and applied biological sciences. Psychology; iron; Iron - pharmacology; lipid peroxidation; Lipid Peroxides - metabolism; Oxidoreductases; Pregnatrienes - pharmacology; Rats; steroids; Synaptosomes - drug effects; Synaptosomes - metabolism; Thiobarbiturates; Vitamin E - pharmacology; Brain; Rat; Homogenate; Rodentia; Lipids; Iron; Pyridine derivatives; Vertebrata; Mammalia; Chelating agent; Pyrimidine derivatives; Inhibitor; Peroxidation
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1016/S0021-9258(18)60979-2

Two representative compounds from a novel chemical series of potent inhibitors of lipid peroxidation are described. The compounds 21-[4-(2,6-di-1-pyrrolidinyl-4-pyrimidinyl)-1-piperazinyl]-16 alpha-methylpregna-1,4,9(11)-triene-3,20-dione monomethane sulfonate (U74006F) and 21-[4-(3,6-bis(diethylamino)-2-pyridinyl)-1-piperazinyl]-16 alpha-methylpregna-1,4,9(11)triene-3,20-dione hydrochloride (U74500A) inhibited lipid peroxidation in brain homogenates and purified brain synaptosomes under a variety of conditions involving iron. With IC50 values ranging from 2 to 60 microM, U74006F and U74500A were comparable in potency to alpha-tocopherol or butylated hydroxytoluene and were nearly 100 times as potent as desferrioxamine. Some specificity for intact phospholipid membranes is suggested since the ability of U74006F or U74500A to inhibit lipid peroxidation was greatly reduced in methanol solutions of arachidonic acid. Despite close similarities in their structures, their response to increasing concentrations of Fe2+ in lipid peroxidation assays differed qualitatively. One of the compounds, U74500A, may act as a membrane localized chelator of iron.