Inhibition of steroid sulfatase with 4-substituted estrone and estradiol derivatives.

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Phan CM, Liu Y, Kim BM, Mostafa Y, Taylor SD

Inhibition of steroid sulfatase with 4-substituted estrone and estradiol derivatives.

Bioorg Med Chem. 2011 Oct 15;19(20):5999-6005. doi: 10.1016/j.bmc.2011.08.046. Epub 2011 Aug 30.

PubMed ID

21925885 [ View in PubMed

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Abstract

Steroid sulfatase (STS) catalyzes the desulfation of biologically inactive sulfated steroids to yield biologically active desulfated steroids and is currently being examined as a target for therapeutic intervention for the treatment of breast cancer. We previously demonstrated that 4-formyl estrone is a time- and concentration-dependent inhibitor of STS. We have prepared a series of 4-formylated estrogens and examined them as irreversible STS inhibitors. Introducing a formyl, bromo or nitro group at the 2-position of 4-formylestrone resulted in loss of concentration and time-dependent inhibition and a considerable decrease in binding affinity. An estradiol derivative bearing a formyl group at the 4-position and a benzyl group at the 17beta-position yielded a potent concentration and time-dependent STS inhibitor with a K(I) of 85 nM and a k(inact) of 0.021 min(-1) (k(inact)/K(I) of 2.3 x 10(5)M(-1)min(-1)). Studies with estrone or estradiol substituted at the 4-position with groups other than a formyl group revealed that good reversible inhibitors can be obtained by introducing small electron withdrawing groups at this position. An estradiol derivative with fluorine at the 4-position and a benzyl group at the 17beta-position yielded a potent, reversible inhibitor of STS with an IC(50) of 40 nM. The introduction of relatively small electron withdrawing groups at the 4-position of estrogens and their derivatives may prove to be a general approach to enhancing the potency of estrogen-derived STS inhibitors.

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Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Irosustat	Steryl-sulfatase	IC 50 (nM)	350	N/A	N/A	Details