C6-(N,N-butyl-methyl-heptanamide) derivatives of estrone and estradiol as inhibitors of type 1 17β-hydroxysteroid dehydrogenase: Chemical synthesis and biological evaluation

17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1), an oxidoreductase which has a preferential reductive activity using NADPH as cofactor, converts estrone to estradiol and is expressed in many steroidogenic tissues including breast and in malignant breast cells. As estradiol stimulates the growth and development of hormone-dependent breast cancer, inhibition of the final step of its synthesis is an attractive target for the treatment of this disease. The parallel synthesis of novel focused libraries of 16-substituted estrone derivatives and modified E-ring pyrazole steroids as new potent 17beta-HSD1 inhibitors is described. Substituted 3-O-sulfamoylated estrone derivatives were used as templates and were immobilised on 2-chlorotrityl chloride resin to give resin-bound scaffolds with a multi-detachable linker. Novel focused libraries of 16-substituted estrone derivatives and new modified E-ring steroids were assembled from these immobilised templates using solid-phase organic synthesis and solution-phase methodologies. Among the derivatives synthesised, the most potent 17beta-HSD1 inhibitors were 25 and 26 with IC50 values in T-47D human breast cancer cells of 27 and 165 nm, respectively. Parallel synthesis resulting in a library of C5'-linked amides from the pyrazole E-ring led to the identification of 62 with an IC50 value of 700 nM. These potent inhibitors of 17beta-HSD1 have a 2-ethyl substituent which will decrease their estrogenic potential. Several novel 17beta-HSD1 inhibitors emerged from these libraries and these provide direction for further template exploration in this area. A new efficient diastereoselective synthesis of 25 has also been developed to facilitate supply for in vivo evaluation, and an X-ray crystal structure of this inhibitor is presented.

Hydroxysteroid Dehydrogenases

Pyrazole

Linker

10.1002/cmdc.200500087

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Citations (38)

17β-hydroxysteroid dehydrogenase activity in human thymus

Steroids (1967)

R A Jungmann Eva Kot John S. Schweppe

Hydroxysteroid Dehydrogenases

Isotope dilution

Specific activity

10.1016/0039-128x(67)90118-3

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Citations (6)

Modification of Estrone at the 6, 16, and 17 Positions: Novel Potent Inhibitors of 17β-Hydroxysteroid Dehydrogenase Type 1

Journal of Medicinal Chemistry (2006)

G.M. Allan Harshani R. Lawrence Joséphine Cornet Christian Bubert Delphine S. Fischer

The 17β-hydroxysteroid dehydrogenases (17β-HSDs) catalyze the interconversion between the oxidized and reduced forms of androgens and estrogens at the 17 position. The 17β-HSD type 1 enzyme (17β-HSD1) catalyzes the reduction of estrone to estradiol and is expressed in malignant breast cells. Inhibitors of this enzyme thus have potential as treatments for hormone dependent breast cancer. Here we report the syntheses and biological evaluation of novel inhibitors based on the estrone or estradiol template. These have been investigated by modification at the 6, 16 or 17 positions or combinations of these in order to gain information about structure−activity relationships by probing different areas in the enzyme active site. Activity data have been incorporated into a QSAR with predictive power, and the X-ray crystal structures of compounds 15 and 16c have been determined. Compound 15 has an IC50 of 320 nM for 17β-HSD1 and is selective for 17β-HSD1 over 17β-HSD2. Three libraries of amides are also reported that led to the identification of inhibitors 19e and 20a, which have IC50 values of 510 and 380 nM respectively, and 20h which, having an IC50 value of 37 nM, is the most potent inhibitor of 17β-HSD1 reported to date. These amides are also selective for 17β-HSD1 over 17β-HSD2.

Hydroxysteroid Dehydrogenases

IC50

Structure–activity relationship

10.1021/jm050830t

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Citations (74)

Structure–activity relationship of HIV-1 protease inhibitors containing AHPBA. Part III: modification of P2 site

Bioorganic & Medicinal Chemistry (1998)

Eiji Takashiro

IC50

Structure–activity relationship

Protease inhibitor (pharmacology)