Focused Libraries of 16‐Substituted Estrone Derivatives and Modified E‐Ring Steroids: Inhibitors of 17ß‐Hydroxysteroid Dehydrogenase Type 1

Abstract

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.

Contribution to the development of inhibitors of 17β-hydroxysteroid dehydrogenase types 1 and 7: Key tools for studying and treating estrogen-dependent diseases

“…Since this amide group can be found in the nicotinamide moiety of 17␤-HSD1 cofactor (NADPH or NADH), we hypothesized that it could generate key interaction with amino acid neighboring the catalytic site. In fact, our results and those from other researchers [12,20,33,[71][72][73] clearly demonstrated the importance of an alkylamide group for inhibiting some 17␤-HSDs. Among the synthesized compounds 55-62, 55 was the most potent inhibitor with an IC 50 value of 44 nM for the transformation of E1 (60 nM) into E2 by 17␤-HSD1 in intact T-47D cells [74].…”

“…Compounds 55 and 73 were used by Fournier and Poirier [92] to determine the involvement of reductive 17␤-HSD1 and 17␤-HSD7, respectively, in the formation of E2 in four cell lines of endometrial cancer and one cell line of cervical cancer. Having in mind a certain controversy regarding which reductive 17␤-HSD isoform(s) is(are) involved in breast cancer, types 1, 7 or/and 12, Laplante et al [89] used selective inhibitors of three 17␤-HSDs, type 1 (55), type 7 (73) and type 12, to investigate the relative importance of each isoform in the formation of E2 in ten human breast cancer cell lines. The results clearly showed a great variability between each cell line.…”

A New Nonestrogenic Steroidal Inhibitor of 17β-Hydroxysteroid Dehydrogenase Type I Blocks the Estrogen-Dependent Breast Cancer Tumor Growth Induced by Estrone

“…Expression of 17b-HSD1 is increased in breast tumors of postmenopausal women and the level of expression has prognostic significance (15,17,18). Inhibiting 17b-HSD1 activity could thus constitute a valuable way of reducing E2 level with the aim of shrinking breast tumors (19)(20)(21)(22)(23).…”

Synthesis of Libraries of 16β‐Aminopropyl Estradiol Derivatives for Targeting Two Key Steroidogenic Enzymes

“…Indeed, the sulfamate linker that we developed [27][28][29] was recently used in the synthesis of focused libraries of 16-substituted E 1 derivatives as inhibitors of type 1 17b-HSD. [53] In summary, the multidetachable sulfamate linker can be used profitably in the solid-phase combinatorial synthesis of E 2 and E 1 derivatives, sulfamoylated or not, to potentially accelerate the discovery of compounds with therapeutic action against hormone-sensitive diseases and eventually for the synthesis of other types of phenolic compounds with important biological applications.…”