Synthesis and biochemical properties of 6-bromoandrostenedione derivatives with a 2,2-dimethyl or 2-methyl group as aromatase inhibitors.

doi:10.1248/BPB.27.1878

Paper

Synthesis and biochemical properties of 6-bromoandrostenedione derivatives with a 2,2-dimethyl or 2-methyl group as aromatase inhibitors.

Published Nov 1, 2004 · M. Numazawa, Wakako Handa, Keiko Yamada

Biological & pharmaceutical bulletin

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Abstract

To gain insight into the mechanism for irreversible inactivation of aromatase by 6beta-bromoandrostenedione (1), one of the earliest discovered suicide substrates, in relation to the catalytic function of the enzyme, the 2,2-dimethyl derivative of compound 1, steroid 4, and its 6alpha-isomer 5, as well as 2-methyl-1,4-diene steroid 8 and its 6alpha-bromide 10, were synthesized. All of the steroids inhibited aromatase activity in human placental microsomes with apparent K(i)'s ranging between 10 and 81 nM. The 2,2-dimethyl-6beta- and 6alpha-bromo steroids 4 and 5 were extremely powerful inhibitors (K(i): 14 and 10 nM, respectively), but these two did not cause a time-dependent inactivation of aromatase in the presence of NADPH; in contrast, the 2-methyl-1,4-diene steroids 8 and 10 caused time-dependent inactivation with apparent k(inact) of 0.035 and 0.071 min(-1), respectively, in a suicide manner. These results indicate that the 2,2-dimethyl function of the 6beta-bromide 4 would prevent the inactivation of aromatase caused by inhibitor 1 in a suicide manner, probably through steric activity, whereas the 2-methyl group of steroid 8 did not significantly affect the suicidal inactivation by the parent 1,4-diene steroid, a typical suicide substrate.

In Vitro Study

Study Snapshot

The 2,2-dimethyl function of 6-bromoandrostenedione derivatives prevents suicide-induced aromatase inactivation, while the 2-methyl group of steroid 8 does not significantly affect this process.

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

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Paper

Synthesis and biochemical properties of 6-bromoandrostenedione derivatives with a 2,2-dimethyl or 2-methyl group as aromatase inhibitors.

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References

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The 4,5-epoxy-19-oxo compound 6 is a reactive electrophile that irreversibly binds to the active site of aromatase, inhibiting its enzyme activity in a competitive manner.

Citations

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Smaller, less bulky aromatase inhibitors with less steric effect and greater hydrophobicity are more effective in combating estrogen-mediated breast cancer.

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Microbial biotransformation of drostanolone enanthate into new metabolites led to compounds with varying cytotoxic potential against various cancer cell lines.

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