Synthesis and evaluation of estradiol derivatives with 16α-(bromoalkylamide), 16α-(bromoalkyl) or 16α-(bromoalkynyl) side chain as inhibitors of 17β-hydroxysteroid dehydrogenase type 1 without estrogenic activity

The inhibitory effects of 13-epimeric estrones, D-secooxime and D-secoalcohol estrone compounds on human placental 17b-hydroxysteroid dehydrogenase type 1 isozyme (17b-HSD1) were investigated. The transformation of estrone to 17b-estradiol was studied by an in vitro radiosubstrate incubation method. 13a-Estrone inhibited the enzyme activity effectively with an IC 50 value of 1.2 mM, which indicates that enzyme affinity is similar to that of the natural estrone substrate. The 13b derivatives and the compounds bearing a 3-hydroxy group generally exerted stronger inhibition than the 13a and 3-ether counterparts. The 3-hydroxy13b-D-secoalcohol and the 3-hydroxy-13a-D-secooxime displayed an outstanding cofactor dependence, i.e. more efficient inhibition in the presence of NADH than NADPH. The 3-hydroxy13b-D-secooxime has an IC 50 value of 0.070 mM and is one of the most effective 17b-HSD1 inhibitors reported to date in the literature.

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“…These IC 50 results are similar to those of the earlier published results by other authors (for placental 17b-HSD1) 5,23,[35][36][37] .…”

Section: B-hsd1 Inhibitionsupporting

confidence: 82%

Comparative investigation of thein vitroinhibitory potencies of 13-epimeric estrones and D-secoestrones towards 17β-hydroxysteroid dehydrogenase type 1

Herman

Szabó

Bacsa

et al. 2016

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…Notably, a few earlier studies have suggested that the oxidative activity of 17h-HSD present in ZR-75-1 cells was due to the presence of the type II isozyme (25,(29)(30)(31), a 42.8 kDa enzyme (mRNA = 1.4 kb) consisting of 387 amino acid residues (21,32,33). Using RT-PCR, we determined the mRNA levels of various oxidative 17h-HSD isozymes (namely, types II, IV, and VIII) in all four cell lines used in this study.…”

Section: Discussionmentioning

confidence: 99%

Selective Insensitivity of ZR-75-1 Human Breast Cancer Cells to 2-Methoxyestradiol: Evidence for Type II 17β-Hydroxysteroid Dehydrogenase as the Underlying Cause

Liu

Lee²,

Zhu³

2005

Cancer Research

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2-Methoxyestradiol (2-MeO-E 2 ), a nonpolar endogenous metabolite of 17B-estradiol, has strong antiproliferative, apoptotic, and antiangiogenic actions. Among the four human breast cancer cell lines tested (MCF-7, T-47D, ZR-75-1, and MDA-MB-435s), the ZR-75-1 cells were selectively insensitive to the antiproliferative actions of 2-MeO-E 2 , although these cells had a similar sensitivity as other cell lines to several other anticancer agents (5-fluorouracil, mitomycin C, doxorubicin, colchicine, vinorelbine, and paclitaxel). Mechanistically, this insensitivity is largely attributable to the presence of high levels of a steroid-selective metabolizing enzyme, the type II 17B-hydroxysteroid dehydrogenase (17B-HSD), in the ZR-75-1 cells, which rapidly converts 2-MeO-E 2 to the inactive 2-methoxyestrone, but this enzyme does not metabolically inactivate other nonsteroidal anticancer agents. The type II 17B-HSD-mediated conversion of 2-MeO-E 2 to 2-methoxyestrone in ZR-75-1 cells followed the first-order kinetics, with a very short half-life (f2 hours). In comparison, the T-47D, MCF-7, and MDA-MB-435s human breast cancer cells, which were highly sensitive to 2-MeO-E 2 , had very low or undetectable catalytic activity for the conversion of 2-MeO-E 2 to 2-methoxyestrone. Reverse transcription-PCR analysis of the mRNA levels of three known oxidative 17B-HSD isozymes (types II, IV, and VIII) revealed that only the type II isozyme was selectively expressed in the ZR-75-1 cells, whereas the other two isozymes were expressed in all four cell lines. Taken together, our results showed, for the first time, that the high levels of type II 17B-HSD present in ZR-75-1 cells were largely responsible for the facile conversion of 2-MeO-E 2 to 2-methoxyestrone and also for the selective insensitivity to the antiproliferative actions of 2-MeO-E 2 . (Cancer Res 2005; 65(13): 5802-11)

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“…Disappointing results were however obtained when they were tested in homogenated HEK-293 cells overexpressing 17␤-HSD1 (IC 50 = 13 and 38 M, respectively for 22 and 23) [40]. Fortunately, compound 22 did not display estrogenic effects and did show 74% of antiestrogenic activity at 1 M when tested on ZR-75-1 cells [43]. In fact, it inhibited the E2 (0.1 nM)-induced cell proliferation close to the level reached by untreated (control) cells.…”

Section: C16-derivatives Of E2 Which Have Dual Action: 17ˇ-hsd1 Inactmentioning

confidence: 73%

“…In the second approach to eliminate the residual estrogenic activity of 18, new potential dual-action inhibitors were designed by substituting the 16␣-position of E2 with various bromoalkylamide side chains containing two pharmacophores within the same chain. After optimization [41][42][43][44], the inhibitory potency of compounds 22 and 23 was evaluated by measuring the reduction of E1 (1 nM) into E2 using both pure and transfected 17␤-HSD1. Disappointing results were however obtained when they were tested in homogenated HEK-293 cells overexpressing 17␤-HSD1 (IC 50 = 13 and 38 M, respectively for 22 and 23) [40].…”

Section: C16-derivatives Of E2 Which Have Dual Action: 17ˇ-hsd1 Inactmentioning

confidence: 99%

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

Synthesis and evaluation of estradiol derivatives with 16α-(bromoalkylamide), 16α-(bromoalkyl) or 16α-(bromoalkynyl) side chain as inhibitors of 17β-hydroxysteroid dehydrogenase type 1 without estrogenic activity

Cited by 23 publications

References 36 publications

Comparative investigation of thein vitroinhibitory potencies of 13-epimeric estrones and D-secoestrones towards 17β-hydroxysteroid dehydrogenase type 1

Comparative investigation of thein vitroinhibitory potencies of 13-epimeric estrones and D-secoestrones towards 17β-hydroxysteroid dehydrogenase type 1

Selective Insensitivity of ZR-75-1 Human Breast Cancer Cells to 2-Methoxyestradiol: Evidence for Type II 17β-Hydroxysteroid Dehydrogenase as the Underlying Cause

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

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