Biochemical aromatization of 2-methyleneandrostenedione: stereochemistry of hydrogen removal at the C-1 position.
To explore a stereochemistry of hydrogen removal at C-1 of the powerful aromatase inhibitor 2-methyleneandrostenedione (1), of which the A-ring conformation is markedly different from that of the natural substrate androstenedione (AD), in the course of the aromatase-catalyzed A-ring aromatization producing 2-methylestrone (2), we synthesized [1alpha-2H]labeled steroid 1 and its [1beta-2H]stereoisomer, and the metabolic fate of the C-1 deuterium in aromatization was analyzed by gas chromatography-mass spectrometry (GC-MS) in each. Parallel experiments with the natural substrates [1alpha-2H] and [1beta-2H]ADs were also carried out. The GC-MS analysis indicated that 2-methyl estrogen 2 produced from [1alpha-2H]labeled substrate 1 retained completely the 1alpha-deuterium (1beta-H elimination), while product 2 obtained from [1beta-2H]isomer 1 lost completely the 1beta-deuterium. Stereospecific 1beta-hydrogen elimination was also observed in the parallel experiments with the labeled ADs as established previously. The results indicate that biochemical aromatization of the 2-methylene steroid 1 proceeds through the 1beta-hydrogen removal concomitant with cleavage of the C(10)-C(19) bond, yielding 1(10),4-dienone 9, in a similar manner to that involved in AD aromatization. This would give additional evidence for the stereomechanisms for the last step of aromatization of AD, requiring the stereospecific 1beta-hydrogen abstraction and cleavage of the C(10)-C(19) bond, and for the enolization of a carbonyl group at C-3 in the A-ring aromatization.
Numazawa
Mitsuteru
M
Tohoku Pharmaceutical University, 4-1 Komatsushima-4-chome, Sendai 981-8558, Japan. numazawa@tohoku-pharm.ac.jp
Handa
Wakako
W
Matsuzaki
Hisao
H
D000735:Androstenedione / Q000031:analogs & derivatives* / Q000378:metabolism; D047072:Aromatase Inhibitors / Q000378:metabolism*; D003903:Deuterium / Q000737:chemistry; D006859:Hydrogen / Q000737:chemistry*; D007536:Isomerism; D008968:Molecular Conformation; D015394:Molecular Structure
C516041:2-methyleneandrostenedione; D047072:Aromatase Inhibitors; D000735:Androstenedione; D006859:Hydrogen; D003903:Deuterium