122370-91-6Relevant articles and documents
Exemestane metabolites: Synthesis, stereochemical elucidation, biochemical activity and anti-proliferative effects in a hormone-dependent breast cancer cell line
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
, p. 336 - 345 (2014)
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.
1,2-Dehydrogenation of steroidal 6-methylen derivatives. Synthesis of exemestane
Marcos-Escribano, Andrés,Bermejo, Francisco A.,Bonde-Larsen, Antonio Lorente,Retuerto, Jesús Iglesias,Sierra, Ignacio Herráiz
experimental part, p. 7587 - 7590 (2009/12/04)
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.
17-SUBSTITUTED ANDROSTA-1,4-DIEN-3-0NE DERIVATIVES
-
, (2008/06/13)
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.