Design and validation of specific inhibitors of 17β-hydroxysteroid dehydrogenases for therapeutic application in breast and prostate cancer, and in endometriosis

Joanna M Day; Helena J Tutill; Atul Purohit; Michael J Reed

doi:10.1677/ERC-08-0042

Design and validation of specific inhibitors of 17β-hydroxysteroid dehydrogenases for therapeutic application in breast and prostate cancer, and in endometriosis

Department of Endocrinology and Metabolic Medicine and Sterix Ltd, Imperial College London, St Mary's Hospital, 2nd Floor, Mint Wing, Winsland Street, London W2 1NY, UK

(Correspondence should be addressed to M J Reed; Email: m.reed{at}imperial.ac.uk)

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Figure 1
Steroid structures. (a) 4-Androstene-3,17-dione (Adione; with carbon positions numbered), (b) oestrone (E₁; with ring positions labelled), (c) 17β-oestradiol (E₂), (d) testosterone, (e) 5α-dihydrotestosterone (DHT), (f) 5-androstene-3β,17β-diol (Adiol) and (g) dehydroepiandrosterone (DHEA).
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Figure 2
Activity of (a) 17β-HSD1, (b) 17β-HSD3 and (c) 17β-HSD5 (AKR1C3/PGFS/20α-HSD/3α-HSD2).
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Figure 3
17β-HSD1 inhibition. (a) 3-chloroacetylpyridine-adenine dinucleotide, (b) 16α-bromoacetoxy-E₂ 3-methyl ether, (c) 6β-bromoacetoxyprogesterone, (d) 16,17-pyrazole-/-isoxazole-E₁, (e) equilin, (f) apigenin, (g) 4-hydroxychalcone, (h) cinnamic acid, (i) EM139, (j) 6β-(thiaheptanamide)-E₂, (k) EM1745, (l) 16β-m-carbamoyl benzyl-E₂, (m) C5′-pyridylethylamide-16,17-pyrazole-E₁, (n) STX1040 (2-ethyl-16β-m-pyridyl methyl amido-methyl-E₁), (o) non-steroidal STX1040 mimic, (p) pyrimidinone core and (q) 3-benzyl-2-(2-bromo-3,4,5-trimethoxy-phenyl)-8-hydroxy-3H-benzo[4,5]thieno[2,3-d]pyrimidin-4-one.
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Figure 4
STX1040 docked in place of E₂ in the 17β-HSD1 crystal structure (reproduced with permission from: Day et al. 2008).
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Figure 5
17β-HSD3 inhibitors. (a) 4-estrene-3,17-dione, (b) 5-androstene-3,17-dione, (c) atamestane, (d) 1,4-androstadiene-3,6,17-trione, (e) androsterone (ADT), (f) 3β-phenylmethyl-ADT, (g) 3β-amidomethyl-ADT derivatives, (h) 3-carbamate-ADT derivatives, (i) 3R-spiro-{3′-[3″-N-morpholino-2″-(3‴-cyclopentylpropionyloxy) propyl]-2′-oxo-oxazolidin-5′-yl}-5α-androstan-17-one, (j) 3-O-benzyl-androsterone, (k) BMS-856, (l) 8/9-substituted tetrahydrodibenzazocine (THB), (m) diphenyl-p-benzoquinone, (n) umbelliferone, (o) 1-(4-hydroxyphenyl)-nonan-1-one, (p) tributyltin chloride (TBT) and triphenyltin chloride (TPT).
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Figure 6
17β-HSD5 inhibitors and substrate analogues. (a) 1-(4′-nitrophenyl)-2-propen-1-ol to 1-(4′-nitrophenyl)-2-propen-1-one that alkylates the enzyme, (b) zearalenone, (c) coumestrol, (d) quercetin, (e) biochanin A, (f) α-methylcinnamic acid, (g) J2404, (h) cloxazolam, (i) 3α-spiro-oxirane, (j) 17β-spiro-oxirane, (k) 20α-spiro-oxirane, (l) EM1404, (m) indomethacin, (n) flufenamic acid, (o) N-(4-chlorobenzoyl)-melatonin, (p) rutin, (q) bimatoprost, (r) Ex144 and (s) 9,10-phenanthrenequinone.
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Figure 7
Inhibitors of other 17β-HSDs. (a) 17β-HSD2: (i) 1-methyl-4-phenyl-pyrrolidin-2-ones and (ii) 17-(spiro-δ-lactone)-E₂. (b) 17β-HSD10: AG18051 (1-azepan-1-yl-2-phenyl-2-(4-thioxo-1,4-dihydropyrazolo-[3,4-d]pyrimidin-5-yl)-ethanone).