Synthesis and aromatase inhibition by potential metabolites of exemestane (6-methylenandrosta-1,4-diene-3,17-dione)
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Cited by (44)
Anticancer activity of novel steroidal 6-substituted 4-en-3-one D-seco dinitriles
2018, SteroidsCitation Excerpt :This steroidal AI is a structural analogue of androstenedione, a natural substrate of aromatase, with a methylene group at C-6. A series of exemestane analogs, with modifications at the 6-methylene group and with additional reduction at the 17-keto group, were synthesized, but all of these analogs were less potent in inhibiting aromatase than exemestane [12]. Non-steroidal third-generation AIs used in the treatment of breast cancer include anastrozole (IV) and letrozole (V), azoles containing two nitrile groups.
Microbial-catalysed derivatization of anti-cancer drug exemestane and cytotoxicity of resulting metabolites against human breast adenocarcinoma cell line (MCF-7) in vitro
2016, SteroidsCitation Excerpt :Compound 6 (6β,17β-dihydroxyandrost-4-en-3-one, 6β-testosterone) was previously reported through the biotransformation of testosterone heptanoate with F. fujikuroi and Fusarium solani [24]. Metabolite 7 (17β-hydroxy-6α-spiroxirandrost-1,4-diene-3-one) was previously reported as a chemically transformed product of exemestane (1) [25]. Compound 8 was obtained as a white crystalline compound, and its structure was deduced by detailed spectroscopic analysis.
Exemestane metabolites suppress growth of estrogen receptor-positive breast cancer cells by inducing apoptosis and autophagy: A comparative study with Exemestane
2015, International Journal of Biochemistry and Cell BiologyCitation Excerpt :Buzzetti et al. (1993) was the first to describe the anti-aromatase activity of exemestane (1) versus 17-βHE (4), 6-HME (6) and other potential exemestane metabolites, as the 6β-spirooxiranandrosta-1,4-diene-3,17-dione (2), that presented modifications at the 6-methylene group and additional reduction at the 17-keto group (Buzzetti et al., 1993). He demonstrated, in placental microsomes, that metabolites were less potent in inhibiting aromatase than exemestane (1), though between the metabolites the 17-βHE (4) and 6β-spirooxiranandrosta-1,4-diene-3,17-dione (2), an intermediary metabolite of exemestane (de Albuquerque Cavalcanti et al., 2011; Cavalcanti Gde et al., 2011), were considered the most potent inhibitors (Buzzetti et al., 1993). Recently, our group showed that, in human placental microsomes and in ER+ breast cancer cells, the metabolites 17-βHE (4), 6-HME (6) and 6β-spirooxiranandrosta-1,4-diene-3,17-dione (2) are potent AIs (Varela et al., 2014), presenting metabolite 4 an anti-aromatase activity higher than exemestane (1).
Recent developments in steroidal and nonsteroidal aromatase inhibitors for the chemoprevention of estrogen-dependent breast cancer
2015, European Journal of Medicinal ChemistryCitation Excerpt :Its irreversible inhibition and lack of other endocrine effects makes it a promising drug for the treatment of estrogen-dependent disease states [20]. MDL-18,962 was a highly potent irreversible inhibitor of human placental aromatase [21]. Most of the potent steroidal AIs reported in the 1900s were A- and B-modified steroids; therefore, to explore the anti-aromatase activity of D-modified steroids, Gasi et al. (2001) synthesized several 17α-substituted-17β-hydroxy-16-oximino derivatives of 5-androstene and the corresponding D-seco derivatives.
Exemestane metabolites: Synthesis, stereochemical elucidation, biochemical activity and anti-proliferative effects in a hormone-dependent breast cancer cell line
2014, European Journal of Medicinal ChemistryCitation Excerpt :Efforts have been done to isolate its 6α-isomer (compound 2a) nevertheless, all attempts resulted unfruitful being 2a always obtained in mixture. Although compound 2 has already been described [13], the stereochemistry of its C-6 epoxide group had not been unequivocally established. Therefore, two-dimensional NOESY experiments were used to assign the C-6 epoxide stereochemistry of compound 2.