- Structure-activity relationships of new A,D-ring modified steroids as aromatase inhibitors: Design, synthesis, and biological activity evaluation
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Inhibition of aromatase is an efficient approach for the prevention and treatment of breast cancer. New A,D-ring modified steroid analogues of formestane and testolactone were designed and synthesized and their biochemical activity was investigated in vitro in an attempt to find new aromatase inhibitors and to gain insight into their structure-activity relationships (SAR). All compounds tested were less active than formestane. However, the 3-deoxy steroidal olefin 3a and its epoxide derivative 4a proved to be strong competitive aromatase inhibitors (Ki = 50 and 38 nM and IC 50 = 225 and 145 nM, respectively). According to our findings, the C-3 carbonyl group is not essential for anti-aromatase activity, but 5α-stereochemistry and some planarity in the steroidal framework is required. Furthermore, modification of the steroidal cyclopentanone D-ring, by construction of a δ-lactone six-membered ring, decreases the inhibitory potency. From the results obtained, it may be concluded that the binding pocket of the active site of aromatase requires planarity in the region of the steroid A,B-rings and the D-ring structure is critical for the binding.
- Cepa, Margarida M. D. S.,Tavares Da Silva, Elisiário J.,Correia-Da-Silva, Georgina,Roleira, Fernanda M. F.,Teixeira, Natércia A. A.
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- Synthesis and bioconversions of formestane
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In an effort to generate new steroidal aromatase inhibitors, formestane (4-hydroxyandrost-4-ene-3,17-dione) (1) was biotransformed by Rhizopus oryzae to yield the known 4β,5α-dihydroxyandrostane-3,17-dione as the major product (5) and bioconverted by Beauveria bassiana to afford the known reduced 4,17β-dihydroxyandrost-4-en-3-one (6) and 3α,17β-dihydroxy- 5β-androstan-4-one (7) and the new 4,11α,17β-trihydroxyandrost- 4-en-3-one (8). All the metabolites showed more potent activities than their parent congener in the aromatase and MCF-7 breast cancer assays. The bioactivities and structural elucidation of these metabolites as well as the semisynthesis of formestane (1) from testosterone (2) are reported herein.
- Martin, Glenroy D. A.,Narvaez, Javier,Marti, Anne
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- An improved preparation of aromatase inhibitor 4-hydroxyandrost-4-ene-3,17-dione
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The title compound has been prepared in 47% overall yield from androst-4-ene-3,17-dione (1) by a two-step sequence comprising hydroxylation of 1 with OsO4/H2O2, followed by dehydration of the resultant diols 3 in alkaline medium.
- Ciattini,Morera,Ortar
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- Practical preparation of diosphenols by ring opening of α,β-epoxyketones catalyzed by silica gel supported acids
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The mixed acid (H2SO4-HOAc) catalyzed ring opening of α,β-epoxyketone was the most used method for the preparation of diosphenols, but it seriously suffered from poor yields and tedious workup operations. By using silica gel supported mixed acid (H2SO 4-HOAc), a variety of α,β-epoxyketones were converted into the corresponding diosphenols in unprecedented high yields within a few minutes. Georg Thieme Verlag Stuttgart.
- Zhu, Rui,Xing, Lixin,Wang, Xinyan,Cheng, Chuanjie,Liu, Bo,Hu, Yuefei
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p. 2267 - 2271
(2008/02/09)
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- X-ray and deuterium labeling studies on the abnormal ring cleavages of a 5β-epoxide precursor of formestane
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A new convergent synthesis of the antitumor steroid formestane (4-OHA) 5 has been performed from the easily available epimeric mixture of 5α- and 5β-androst-3-en-17-one 1a and 1b in order to attempt a yield improvement. A two-step oxidative route followed by base-catalyzed isomerization was applied to the 5α- and 5β-epimers 1a and 1b, either as a mixture or separately, leading to the title compound 5. From epimer 1a an efficient process was attained to prepare the desired aromatase inhibitor formestane. Epimer 1b led to the formation of the same compound 5. Additionally, 1b have also been converted in 5β-hydroxyandrostane-3,17-dione 12 and androst-4-ene-3,17-dione 13, revealing an unexpected reactivity of the 3β,4β-epoxy-5β-androstan-17-one intermediate 6 formed from 1b during the first oxidative step with performic acid. Cleavage of the epoxide 6 led to the trans-diaxial and the trans-diequatorial vic-diols 7 and 8 and to the 1,3-diol 9. The formation of the abnormal products 8 and 9 were investigated through X-ray and deuterium labeling studies. Diol 8 was formed through a trans-diequatorial epoxide ring opening and the 1,3-diol 9 was formed through an intramolecular rearrangement involving a 1,2-hydride shift. All the vic-diols 3, 7 and 8 formed, proved to be good precursors for the synthesis of the target compound 5. Copyright
- Tavares Da Silva, Elisiario J,Roleira, Fernanda M.F,Sa E Melo, M.Luisa,Campos Neves, Andre S,Paixao, Jose A,De Almeida, Maria J,Silva, Manuela R,Andrade, Lourdes C.R
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p. 311 - 319
(2007/10/03)
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- Improved syntheses of aromatase inhibitors and neuroactive steroids efficient oxidations and reductions at key positions for bioactivity
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An Henbest reduction, followed by the preparation of a silyl enol ether and oxidation in situ with m-CPBA has led to the neurosteroids 3α-hydroxy- and 3α,21-dihydroxy-5α-pregnanolones. Using testosterone as starting material, a new short synthesis of an aromatase inhibitor, 4-OHA, has been achieved through hydroboration/oxidation followed by a Swern type oxidation and epimerization. Another aromatase inhibitor, androst-4-ene-3,6,17-trione, has been efficiently prepared using PCC on montmorillonite K10, under ultrasonic irradiation.
- Campos Neves, Andre S.,Sa E Melo, Maria Luisa,Moreno, Maria Jose S. M.,Tavares Da Silva, Elisiario J.,Salvador, Jorge A. R.,Da Costa, Saul P.,Martins, Rosa Maria L. M.
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p. 3255 - 3264
(2007/10/03)
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- Novel approach to the synthesis of the aromatase inhibitor 4-hydroxyandrost-4-ene-3,17-dione (4-OHA)
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A straightforward synthesis of the title compound is achieved through a novel approach, comprising the oxidation of the easily available 5α-androst-3-en-17-one 1 in two sequential steps to yield the kinetic diosphenol 4, which gives the desired 4-OHA 5 by base-catalysed isomerization.
- Tavares Da Silva, Elisiario J.,Sa E Melo, Maria L.,Campos Neves, Andre S.
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p. 1649 - 1650
(2007/10/03)
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- Synthesis and Evaluation of a New Series of Mechanism-Based Aromatase Inhibitors
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A series of new 4-(alkylthio)-substituted androstenedione analogues was designed as potential suicide inhibitors of aromatase on the basis of mechanistic considerations on the mode of action of the enzyme.Their synthesis and biological evaluation are described.Among the most interesting are the 4--, 4-androstenediones 12, 13, and 14 with respective IC50's of 2.7, 0.8, and 0.94 μM.Compound 12 was a reversible inhibitor of aromatase while compounds 13 and 14 displayed time-dependent kinetics of inhibition with respective KI's and half-times of inactivation of 30 nM and 3.75 min for 13 and 30 nM and 3 min for 14.The inhibition of aromatase by 14 was NADPH-dependent, and was protected by the presence of substrate (0.5-1 μM), while β-mercaptoethanol (0.5 mM) failed to protect the enzyme from inactivation.Dialysis failed to reactivate aromatase previously inactivated by 14.The mechanistic implications of these findings are discussed.
- Lesuisse, D.,Gourvest, J. F.,Hartmann, C.,Tric, B.,Benslimane, O.,et al.
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p. 1588 - 1597
(2007/10/02)
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- 5α-Androstanobisfuroxan
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Synthesis of a potential vasodilator 5α-androstanobisfuroxan (2) is described.
- Jindal, Dharam Paul,Yadav, Mange Ram
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p. 515 - 516
(2007/10/02)
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- Participation of the 19-Substituent in the Conversion of 19-Hydroxyandrost-4-ene-3,17-dione into the Corresponding 4,5-Diosphenol
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The synthesis of 4,19-dihydroxyandrost-4-ene-3,17-dione from 19-hydroxy-4β,5-epoxy-5β-androstane-3,17-dione and from 4β,5,19-trihydroxy-5β-androstane-3,17-dione is described.Under various reaction conditions other products are obtained as a result of participation of the 19-hydroxy group to form cyclic ethers.The formation of two of these products, 4α,5-isopropylidene-3α-hydroxy-3β,19-epoxy-5α-androstan-17-one and 4α-hydroxy-4β,19-epoxy-5α-androstane-3,17-dione, can be avoided by treatment of the aforementioned trihydroxy dione with acetic acid in the presence of HCl.
- Hrycko, Sophia,Morand, Peter
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p. 2899 - 2904
(2007/10/02)
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- Interactions of Thiol-Containing Androgens with Human Placental Aromatase
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A series of thiol androgens were synthesized and investigated to characterize structural features important for the inhibition of aromatase.Analogues of androstenedione with thiol groups in either the 2α-, 10β-, or 19-positions caused time-dependent inhibition of human placental aromatase.When their KI and kcat values were compared with those of 4-hydroxyandrost-4-ene-3,17-dione (4-OHa) and 10-β-propargylestr-4-ene-3,17-dione (PED), the thiol androgen 10β-mercaptoestr-4-ene-3,17-dione (10β-SHnorA) proved to be the most potent suicide substrate.However, 19-merc aptoandrost-4-ene-3,17-dione (19-SHA) was the best all-around inhibitor.All compounds except 19-SHA exhibited normal type I P-450 difference spectra with partially purified/solubilized, human placental aromatase.The KS values for the series of compounds compared qualitatively to the KI values determined from the time and concentration-dependent inhibition experiments. 19-SHA induced split Soret peaks at 380 and 474 nm, which suggested binding of the 19-thiolate directly to the ferric iron of aromatase.This binding could be displaced by aminoglutethimide but not by androstenedione.The inhibitory activity of 19-SHA may be explained by two independent mechanisms: (1) suicide inactivation of aromatase in the ferrous state; and (2) a direct "hyper-type II" binding to the remaining portion of the cytochrome in the ferric state.A free thiol group was necessary for the suicide inhibitory activity of 19-SHA; time-dependent inactivation of aromatase by 19-(acetylthio)androst-4-ene-3,17-dione (19-SAcA) and 19-xanthogenylandrost-4-ene-3,17-dione (19-XanA) could be prevented if the microsomes were preincubated with a carboxyesterase inhibitor.Aromatase previously inactivated by either thiol androgens, 4-OHA, or PED could not be reactivated after incubation with the disulfide reducing agent dithiothreitol, which suggests that a disulfide bond may not be involved in aromatase inactivation by these inhibitors.
- Bednarski, Patrick J.,Nelson, Sidney D.
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p. 203 - 213
(2007/10/02)
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- The Synthesis of 4-Hydroxyandrost-4-ene-3,17-dione and other Potential Aromatase Inhibitors
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We describe novel syntheses of 4-hydroxyandrost-4-ene-3,17-dione (Ia) and related compounds, some containing fluorine.In addition we provide further evidence of the general tendency of 2- and 6-substituted androst-4-ene-3,17-diones to undergo rearrangement reactions, and thus provide new routes to 6-fluoro- and 2,6-difluoro-derivatives.Several of these compounds are potent aromatase inhibitors.
- Mann, John,Pietrzak, Barbara
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p. 2681 - 2685
(2007/10/02)
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