Novel structural features increase the antioxidant effect of estrogen analogues on low density lipoprotein

• A six-carbon d-ring increased the antioxidant activity of estrogen analogues.
• Estrogen analogues with a fluorine atom at C-2 were potent antioxidants.
• Unsaturated analogues with a substituted 3-OH group inhibited lipid peroxidation.

Many known estrogens, both natural and synthetic, may act as antioxidants. We designed and synthesized 22 novel estrogen analogues with different ring junctions or substitutions, such as fluorine. We studied the antioxidant capacity in vitro of 35 synthetic estrogen analogues in aqueous lipoprotein solution by monitoring the formation of conjugated dienes. In addition to a free C-3 hydroxyl group, the two most active antioxidants had either a methyl group at C-4 and a six-carbon D-ring, or a fluorine atom at C-2 and an unsaturated B-ring. Extension of the D-ring increased the antioxidant capacity of 6-oxa estrogens. Compounds with a fluorine atom at C-2 were similar or more potent antioxidants compared with the principal endogenous estrogen, 17β-estradiol. In compounds with a substituted C-3 hydroxyl group, the antioxidant capacity could be significantly increased by additional double bonds in the C- or D-rings. In conclusion, we show that the antioxidant capacity of estrogen analogues could be increased by structural changes.

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