- New metabolites from fungal biotransformation of an oral contraceptive agent: Methyloestrenolone
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Fungal cell cultures were used for the first time for the biotransformation of methyloestrenolone (1), an oral contraceptive. Fermentation of 1 with Macrophomina phaseolina, Aspergillus niger, Gibberella fujikuroi, and Cunninghamella echinulata produced eleven metabolites 2-12, six of which 2-5, 11 and 12 were found to be new. These metabolites were resulted from the hydroxylation at C-1, C-2, C-6, C-10, C-11, and C-17α-CH3, as well as aromatization of ring A of the steroidal skeleton of substrate 1. The transformed products were identified as 17α-methyl-6β,17β- dihydroxyestr-4-en-3-one (2), 17α-(hydroxymethyl)-11β,17β- dihydroxyestr-4-en-3-one (3), 17α-methyl-2α,11β,17β- trihydroxyestr-4-en-3-one (4), 17α-methyl-1β,17β-dihydroxyestr- 4-en-3-one (5), 17α-methyl-11α,17β-dihydroxyestr-4-en-3-one (6), 17α-methyl-11β,17β-dihydroxyestr-4-en-3-one (7), 17α-methyl-10β,17β-dihydroxyestr-4-en-3-one (8), 17α-(hydroxymethyl)-17β-hydroxyestr-4-en-3-one (9), 17α-methylestr-1,3,5(10)-trien-3,17β-diol (10), 17α-methyl-3, 17β-dihydroxyestr-1,3,5(10)-trien-6-one (11), and 17α-methyl-6β, 10β,17β-trihydroxyestr-4-en-3-one (12).
- Zafar, Salman,Bibi, Marium,Yousuf, Sammer,Choudhary, M. Iqbal
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p. 418 - 425
(2013/05/08)
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- Fungal transformation of methyltestosterone by the soil ascomycete Acremonium strictum to some hydroxy derivatives of 17-methylsteroid
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The ascomycete Acremonium strictum was used for the biotransformation of methyltestosterone (1), a pharmaceutical steroid substance, into some steroid derivatives (6β-hydroxy-17α-methyltestosterone (2), 6β,12β-dihydroxy-17α-methyltestosterone (3), 7β-hydroxy-17α-methyltestosterone (4), 6β,17β-dihydroxy- 17α-methylandrosta-1,4-dien-3-one (5), and 3,17β-dihydroxy-17α- methylestra-1,3,5(10)-triene (6). The fermentation was carried out in Sabouraud-dextrose broth (SDB) supplemented with 1 mM of the substrate, and the temperature and aeration rate were adjusted to 30 C and 150 rpm, respectively. The biotransformation characteristics observed were hydoxylations at C-6β, C-7β, and C-12β, 1,2-dehydrogenation, and ring A aromatization. The best fermentation conditions, such as temperature, substrate concentration, pH, incubation period, and aeration, were found to be 25 C, 1 mM, pH 6.5, 6 days, and 150 rpm, respectively, for maximum biotransformation of 1.
- Nassiri-Koopaei,Mogharabi,Amini,Shafiee,Faramarzi
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p. 665 - 670
(2013/11/06)
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- Effects of altering the electronics of 2-methoxyestradiol on cell proliferation, on cytotoxicity in human cancer cell cultures, and on tubulin polymerization
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A series of new analogues of 2-methoxyestradiol (1) were synthesized to further elucidate the relationships between structure and activity. The compounds were designed to diminish the potential for metabolic deactivation at positions 2 and 17 and were analyzed as inhibitors of tubulin polymerization and for cytotoxicity. 17α-Methyl-β-estradiol (30), 2-propynyl-17α- methylestradiol (39), 2-ethoxy-17-(1′-methylene)estra-1,3,5(10)-triene-3- ol (50) and 2-ethoxy-17α-methylestradiol (51) showed similar or greater tubulin polymerization inhibition than 2-methoxyestradiol (1) and contained moieties that are expected to inhibit deactivating metabolic processes. All of the compounds tested were cytotoxic in the panel of 55 human cancer cell cultures, and generally, the derivatives that displayed the most activity against tubulin were also the most cytotoxic.
- Edsall, Allison B.,Mohanakrishnan, Arasambattu K.,Yang, Donglai,Fanwick, Philip E.,Hamel, Ernest,Hanson, Arthur D.,Agoston, Gregory E.,Cushman, Mark
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p. 5126 - 5139
(2007/10/03)
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- Structure-activity relationships of 17α-derivatives of estradiol as inhibitors of steroid sulfatase
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The steroid sulfatase or steryl sulfatase is a microsomal enzyme widely distributed in human tissues that catalyzes the hydrolysis of sulfated 3-hydroxy steroids to the corresponding free active 3-hydroxy steroids. Since androgens and estrogens may be synthesized inside the cancerous cells starting from dehydroepiandrosterone sulfate (DHEAS) and estrone sulfate (E1S) available in blood circulation, the use of therapeutic agents that inhibit steroid sulfatase activity may be a rewarding approach to the treatment of androgeno-sensitive and estrogeno-sensitive diseases. In the present study, we report the chemical synthesis and biological evaluation of a new family of steroid sulfatase inhibitors. The inhibitors were designed by adding an alkyl, a phenyl, a benzyl, or a benzyl substituted at position 17α of estradiol (E2), a C18-steroid, and enzymatic assays were performed using the steroid sulfatase of homogenized JEG-3 cells or transfected in HEK-293 cells. We observed that a hydrophobic substituent induces powerful inhibition of steroid sulfatase while a hydrophilic one was weak. Although a hydrophobic group at the 17α-position increased the inhibitory activity, the steric factors contribute to the opposite effect. As exemplified by 17α-decyl-E2 and 17α-dodecyl-E2, a long flexible side chain prevents adequate fitting into the enzyme catalytic site, thus decreasing capacity to inhibit the steroid sulfatase activity. In the alkyl series, the best compromise between hydrophobicity and steric hindrance was obtained with the octyl group (IC50 = 440 nM), but judicious branching of side chain could improve this further. Benzyl substituted derivatives of estradiol were better inhibitors than alkyl analogues. Among the series of 17α-(benzyl substituted)-E2 derivatives studied, the 3′-bromobenzyl, 4′-tert-butylbenzyl, 4′-butylbenzyl, and 4′-benzyloxybenzyl groups provided the most potent inhibition of steroid sulfatase transformation of E1S into E1 (IC50 = 24, 28, 25, and 22 nM, respectively). As an example, the tert-butylbenzyl group increases the ability of the E2 nucleus to inhibit the steroid sulfatase by 3000-fold, and it also inhibits similarly the steroid sulfatase transformations of both natural substrates, E1S and DHEAS. Interestingly, the newly reported family of steroid sulfatase inhibitors acts by a reversible mechanism of action that is different from the irreversible mechanism of the known inhibitor estrone sulfamate (EMATE).
- Boivin,Luu-The,Lachance,Labrie,Poirier
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p. 4465 - 4478
(2007/10/03)
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- 11β-Substituted estradiol derivatives, potential high-affinity carbon- 11-labeled probes for the estrogen receptor: A structure-affinity relationship study
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In view of their possible development as carbon-11-labeled receptor-based radiotracers for imaging estrogen-responsive breast tumors, we have synthesized a series of estradiols (1), estriols (2), 11β-ethylestradiols (3), 11β-ethylestriols (4), 11β-methoxyestradiols (5), and 11β- methoxyestriols (6), differing in the type of substituent R present at the 17α-position (a, -H; b, -CH3; c, -C≡CH; d, -C≡CCH3; e, -Ph; f, -CH=CHMe cis), and measured their binding affinity for the estrogen receptor relative to estradiol (RBA). As expected, all the derivatives having an 11β-ethyl substituent have good binding properties (3a-d, 4a-d, RBA (25 °C): 109- 3000%), and among them there are several promising candidates for carbon-11 labeling. Moxestrol (RBA (25 °C) = 185%) and its corresponding estriol derivative (4c, RBA (25 °C) = 20%) were the analogs having the highest affinity in the 11β-methoxyestradiol (5a-f) and 11β-methoxyestriol (6a-e) series, respectively; other analogs (R = Me, C≡CMe, Ph, or cis-CH=CHMe) had uniformly lower RBA values.
- Napolitano,Fiaschi,Carlson,Katzenellenbogen
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p. 429 - 434
(2007/10/02)
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