Stereochemistry of the Functional Group Determines the Mechanism of Aromatase Inhibition by 6-Bromoandrostenedione*

Osawa, Yoshio; Coon, Minor J.

doi:10.1210/endo-121-3-1010

Cited by 22 publications

(9 citation statements)

References 31 publications

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“…C19H,,N02 requires M, 323.2460). 6J300 MHz; CDSOD) 0.76 (3 H, S, 18-H,), 1.17 (3 H, S , 19-H3), Androsta-4,6diene-3,17dione 16 This compound, prepared as reported,,, provided spectral and analytical data as described.,, Epoxidation of androsta-4,6-diene-3,17dione 16 with MCPBA 6a,7a-dihydrooxireno [ 6,7] androst4ene-3,17dione 17 and 4~,5pdihydrooxireno [4,5]androst-6-ene-3,17dione 18 A mixture of the dienone 16 (2.5 g, 8.8 mmol) and MCPBA (80-90% ex Janssen Chemica; 2.6 g) in freshly distilled CHCl, (120 cm3) was refluxed for 2 h. More MCPBA (600 mg) was added to the reaction mixture, which was refluxed for a further 1 h. After cooling of the mixture, excess of MCPBA was destroyed by the addition of saturated aq. sodium sulfite (50 cm3).…”

Section: (E)-6-(hydroxyimino)-5a-androstane-3~517p-triolllmentioning

confidence: 99%

“…The mixture was stirred for 2.5 h, after which excess of LAH was decomposed with water (2 cm3). Processing as described above for compounds 5 and 6 gave a solid (1 24 mg, crude 6~~,7~-dihydroazirino [6,7]androst-4-ene-3,17-dio13), which was oxidized without purification.…”

Section: P-azido-7a-hydroxyandrost4-ene-317dione 19mentioning

confidence: 99%

“…For example, 6pbromo-, 6P-ethyl-and 7a-(4'-aminophenyl)sulfanyl-androstenedione' have been found to be among the most potent inhibitors produced to date (KJK, = 0.35, 0.08 and 0.35 respectively). In addition, 3-deoxy-6a,7a-cyclopropa [6,7]AD has recently been shown to be a potent aromatase inhibitor (Ki/K,,, = 0.09). l o Consequently, we embarked on the synthesis of the hitherto undescribed 6,7-aziridino steroids 21 and 23 (see Scheme 5), thinking that they might also bind tightly to the enzyme.…”

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confidence: 99%

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Synthesis of 6α,7α- and 6β,7β-aziridinoandrost-4-ene-3,17-diones and related compounds: potential aromatase inhibitors

Njar¹,

Hartmann²,

Robinson³

1995

J. Chem. Soc., Perkin Trans. 1

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Section: (E)-6-(hydroxyimino)-5a-androstane-3~517p-triolllmentioning

confidence: 99%

Section: P-azido-7a-hydroxyandrost4-ene-317dione 19mentioning

confidence: 99%

mentioning

confidence: 99%

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Synthesis of 6α,7α- and 6β,7β-aziridinoandrost-4-ene-3,17-diones and related compounds: potential aromatase inhibitors

Njar¹,

Hartmann²,

Robinson³

1995

J. Chem. Soc., Perkin Trans. 1

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“…27, No. 11 whereas the same molecular modification of 6a-bromoAD (2) decreased the binding affinity (K i : 3.4 nM 28) vs. 10.0 nM for 2 vs. 5). The results suggest that the two 6-bromides 1 and 2 may bind to the active site in a different manner.…”

Section: ) Results and Discussionmentioning

confidence: 95%

Synthesis and Biochemical Properties of 6-Bromoandrostenedione Derivatives with a 2,2-Dimethyl or 2-Methyl Group as Aromatase Inhibitors

Numazawa

Handa

Yamada

2004

Biological & Pharmaceutical Bulletin

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Aromatase is a unique cytochrome P-450 enzyme that catalyzed the synthesis of estrone and estradiol from the 4-en-3-one androgens androstenedione (AD) and testosterone. [1][2][3] The aromatization process appears to proceed with three oxygenations at the C-19 position of the androgens, followed by the eventual loss of the C-19 angular methyl group and the elimination of the 1b,2b-hydrogens, resulting in aromatization of the A-ring of the androgen molecule to the estrogen. [4][5][6] Inhibitors of aromatase are useful in treating estrogen-dependent diseases such as a breast cancer. [7][8][9][10][11] For this reason, a number of aromatase inhibitors, analogs of the substrate AD, have been described. Among the inhibitors, suicide substrates are of interest due to their high selectivity. 12) 4-hydroxy-, 13) 6-oxo, 14) and 6b-bromo-ADs 15) are the earliest discovered suicide substrates. The three former steroids act by oxygenation of the 19-angular methyl moiety in the inactivation of human placental aromatase in a suicide manner, 12,[16][17][18] whereas the inactivation mechanism for the 6b-bromo inhibitor 1 (Fig. 1), which has a very high affinity to aromatase, is currently unknown.On the other hand, Furth et al. previously reported that the 2,2-dimethyl substrate analog 2,2-dimethylAD (3) is an excellent competitive inhibitor of aromatase. 19) In addition, it was also reported that the 2,2-dimethyl analogs of the suicide substrates 4-hydroxyAD 19) and 6-oxoAD 20) lost their enzyme-inactivating ability via a suicide mechanism without diminution of their competitive inhibitory potency. This, along with the previous findings 21) regarding the aromatase reaction of a series of 2-methylAD derivatives, indicates that the 2,2-dimethyl group prevents the aromatase-catalyzed 19-oxygenation of the two suicide substrates, producing a reactive electrophile that binds irreversibly to a nucleophilic residue of the active site of the enzyme.Taken together, to determine whether or not 19-oxygenation is involved in the suicidal inactivation of aromatase by 6b-bromoAD (1), we focused on the 2,2-dimethyl derivative. This paper describes the synthesis of 2,2-dimethyl-6a-and 6b-bromoADs (4, 5) and their aromatase inactivation ability. Steroids 4 and 5 did not deactivate aromatase in a suicide manner. MATERIALS AND METHODS General Methods and MaterialsMelting points were measured on a Yanagimoto melting point apparatus and are uncorrected. IR spectra were recorded on a Perkin-Elmer FT-IR 1725X spectrophotometer in KBr pellets. UV spectra were determined in 95% ethanol on a Hitachi 150-20 UV spectrophotometer. 1 H-NMR spectra were obtained in CDCl 3 solution with a JEOL EX 270 (270 MHz) using tetramethylsilane (dϭ0.00) as an internal standard, and mass spectra (MS; electron impact) were obtained with a JEOL JMS-DX 303 spectrometer. Thin-layer chromatography (TLC) was performed on E. Merck precoated silica gel plates (Darmstadt, Germany). Column chromatography was conducted with silica gel (E. Merck, 70-230 mesh).[ To gain insight into th...

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“…It is also studied to identify inhibitors for use in treating cancers. Aromatase inhibitors include androgens with different A-rings than A and T, e.g ., 1,4,6-androstatriene-3,17-dione (ATD), azoles, e.g ., fadrozole, and androgens α-halogenated at carbon 6 (C6), e.g ., 6α-bromoA (Osawa et al, 1987), 6α-fluoroA (Rowlands et al, 1987) and 6α-fluoroT (Kellis and Vickery, 1990). When A is in the aromatase catalytic cleft, C6 is near the access channel (Ghosh et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Two aromatase inhibitors inhibit the ability of a third to promote mating in male rats

Yahr

2015

Hormones and Behavior

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Aromatase, the enzyme that aromatizes androstenedione (A) to estrone and testosterone (T) to estradiol (E), affects androgen control of male sex behavior in many vertebrates. In male monkeys, rats and quail, E mimics the ability of T to promote mating, and aromatase inhibitors block mating induced by T but not E. Aromatase inhibitors include androgens with different A-rings than T and A, e.g., 1,4,6-androstatriene-3,17-dione (ATD), azoles, e.g., fadrozole, and androgens α-halogenated at carbon 6, e.g., 6α-bromoA, 6α-fluoroA and 6α-fluoroT. 6α-FluoroT is the only 6α-halogenated androgen studied in regard to mating. It promotes mating in male rats and quail and was studied, before it was known to inhibit aromatase, because it can not be aromatized yet has the same A-ring as T. 6α-FluoroT might promote mating by binding estrogen receptors (ER) directly, i.e., unassisted, or by metabolism to an androgen that binds ER. Since neither process would require aromatase, this study tested both hypotheses by determining how mating induced in castrated male rats by 6α-fluoroT is affected by ATD and fadrozole. Both aromatase inhibitors inhibited the effects of 6α-fluoroT on mating. Thus, 6α-fluoroT does not promote mating by direct ER binding or metabolism to another androgen. Since aromatase underlies a process in which 6α-fluoroT, unlike most nonaromatizable androgens, mimics T effects on male sex behavior, the process must involve a feature that 6α-fluoroT shares with T but not other nonaromatizable androgens. A-ring structure is a candidate. A hypothesis is also offered for how aromatase may participate without aromatizing the androgen.

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Stereochemistry of the Functional Group Determines the Mechanism of Aromatase Inhibition by 6-Bromoandrostenedione*

Cited by 22 publications

References 31 publications

Synthesis of 6α,7α- and 6β,7β-aziridinoandrost-4-ene-3,17-diones and related compounds: potential aromatase inhibitors

Synthesis of 6α,7α- and 6β,7β-aziridinoandrost-4-ene-3,17-diones and related compounds: potential aromatase inhibitors

Synthesis and Biochemical Properties of 6-Bromoandrostenedione Derivatives with a 2,2-Dimethyl or 2-Methyl Group as Aromatase Inhibitors

Two aromatase inhibitors inhibit the ability of a third to promote mating in male rats

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