- Exemestane metabolites: Synthesis, stereochemical elucidation, biochemical activity and anti-proliferative effects in a hormone-dependent breast cancer cell line
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Exemestane is a third-generation steroidal aromatase inhibitor that has been used in clinic for hormone-dependent breast cancer treatment in post-menopausal women. It is known that exemestane undergoes a complex metabolization, giving rise to some already identified metabolites, the 17β-hydroxy-6-methylenandrosta-1,4-dien-3-one (17-βHE) and the 6-(hydroxymethyl)androsta-1,4,6-triene-3,17-dione (6-HME). In this study, four metabolites of exemestane have been analyzed, three of them were synthesized (6β-spirooxiranandrosta-1,4-diene-3,17-dione (2), 1α,2α-epoxy-6-methylenandrost-4-ene-3,17-dione (3) and 17-βHE (4)) while one was acquired, the 6-HME (6). The stereochemistry of the epoxide group of 2 and 3 has been unequivocally elucidated for the first time on the basis of NOESY experiments. New structure-activity relationships (SAR) have been established through the observation that the substitution of the double bonds by epoxide groups led to less potent derivatives in microsomes. However, the reduction of the C-17 carbonyl group to a hydroxyl group originating 17-βHE (4) resulted in a significant increase in activity in MCF-7aro cells when compared to exemestane (IC500.25 μM vs 0.90 μM, respectively). All the studied metabolites reduced MCF-7aro cells viability in a dose and time-dependent manner, and metabolite 3 was the most potent one. Altogether our results showed that not only exemestane but also its main metabolites are potent aromatase inhibitors and reduce breast cancer cells viability. This suggests that exemestane efficacy may also be due to the active metabolites that result from its metabolic transformation. Our results emphasize the importance of performing further studies to expand our understanding of exemestane actions in breast cancer cells.
- Varela, Carla L.,Amaral, Cristina,Tavares Da Silva, Elisiário,Lopes, Andreia,Correia-Da-Silva, Georgina,Carvalho, Rui A.,Costa, Saul C.P.,Roleira, Fernanda M.F.,Teixeira, Natércia
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- 1,2-Dehydrogenation of steroidal 6-methylen derivatives. Synthesis of exemestane
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The development of an efficient dehydration method of steroidal 4-en-3-ones by using chloranil and BSTFA in the presence of triflic acid in refluxing toluene allowed us, starting from testosterone, to set a large-scale procedure for the synthesis of the anti-cancer drug exemestane in 70% overall yield.
- Marcos-Escribano, Andrés,Bermejo, Francisco A.,Bonde-Larsen, Antonio Lorente,Retuerto, Jesús Iglesias,Sierra, Ignacio Herráiz
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experimental part
p. 7587 - 7590
(2009/12/04)
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- Process for obtaining 6-Alkylidenandrost-1,4-diene-3one
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6-alkylidenandrost-1,4-dien-3-ones of general formula (I), wherein R is H o alkyl; R1 y R2, independently of one another, represent H, OR3, OC(=O) R4 or O-(GPH), wherein R3 is H; C1-C6 alkyl or aryl; R4 is H or C1-C6 alkyl,; and GPH is a hydroxyl protecting group; or R1 and R2, together with the carbon atom to which they are bonded, form a carbonyl group or equivalent or a cyclic ketal; can be obtained by a process comprising subjecting the corresponding 6-alkyliden-4-androsten-3-one to a dehydrogenation reaction in the 1,2 position in the presence of a quinine, a silylating agent and a strong acid.
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Page/Page column 11-12
(2009/07/10)
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- Synthesis and aromatase inhibition by potential metabolites of exemestane (6-methylenandrosta-1,4-diene-3,17-dione)
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Exemestane (6-methylenandrosta-1,4-diene-3,17-dione; FCE 24304) is an orally active irreversible aromatase inhibitor which is in phase II clinical evaluation for the potential therapy of postmenopausal breast cancer. A series of exemestane analogs, with modifications at the 6-methylene group and with additional reduction at the 17-keto group, were synthesized as potential metabolites and tested in vitro for their effect on human placental aromatase. All these new analogs were found to be less potent in inhibiting aromatase than exemestane. The most effective compound was the 17β-hydroxy- derivative (compound 2), which is 2.6-fold less potent than exemestane [50% inhibitory concentration (IC50) 69 and 27 nM, respectively]. The various C- 6 modified derivatives of the 17-oxo series were found to inhibit the aromatase enzyme in the following descending order: 6-methylene (exemestane) > 6-spirooxirane (6) > 6β-hydroxymethyl (11) > 6-hydroxymethyl (7) > 6β- carboxy (13), showing IC50 values of 27, 206, 295, 2,300, and 7,200 nM, respectively. The 17β-hydroxy analogs of some of the above mentioned compounds were also synthesized (3, 4, 12) and found to be 3-8-fold less potent than the corresponding 17-keto analogs.
- Buzzetti,Di Salle,Longo,Briatico
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p. 527 - 532
(2007/10/02)
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- 17-SUBSTITUTED ANDROSTA-1,4-DIEN-3-0NE DERIVATIVES
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The invention relates to new 17-hydroxy androsta-1,4-diene-3-one derivatives of the following formula STR1 wherein each of R and R. sub. 3, independently, is hydrogen or C 1-C 6 alkyl; R 1 is hydrogen, halogen or C 1-C 6 alkyl; R 2 is hydrogen or C 1-C 6 alkyl;R. sub.4 is hydrogen or fluorine;R 5 is (a) hydrogen or C. sub. 1-C 6 alkyl; (b) phenyl unsubstituted or substituted by one or two substituents independently chosen from C 1-C 6 alkyl, halogen and amino; (c) an acyl group; or (d) a hydroxy protecting group; and the pharmaceutically acceptable salts thereof,which are useful in therapy, in particular as anti-cancer agents.
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