Crystallographic and molecular modeling studies on 3-ethyl-3-(4-pyridyl)piperidine-2,6-dione and its butyl analogue, inhibitors of mammalian aromatase. Comparison with natural substrates: prediction of enantioselectivity for N-alkyl derivatives.
Inhibitors of the cytochrome P450 enzyme aromatase, which is involved in the biosynthesis of estrogens from androgens, are of proven utility in the treatment of hormone-dependent breast cancer. The determination of the crystal structure of one such inhibitor, 3-ethyl-3-(4-pyridyl)piperidine-2,6-dione (2) and its 3-butyl analogue (3) is described. In the absence of three-dimensional structural information for the enzyme, conformational analysis and comparison with natural substrates has been performed in order to define possible "active" conformations. The enhanced inhibitory activity of 3 may be linked to hydrophobic interactions between the side chain and that portion of the enzyme that normally interacts with the B and C rings of a steroid substrate. Information gained from this study and previous studies by other workers has been combined in order to produce a hypothesis to explain the pattern of activity of N(1)-alkyl derivatives of 2. The successful application of this hypothesis to the prediction of the relative aromatase inhibitory activities of the two enantiomers of the N-octyl derivative (4) is described.
Laughton
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CA
Cancer Research Campaign Biomolecular Structure Unit, Institute of Cancer Research, Sutton, Surrey, U.K.
McKenna
R
R
Neidle
S
S
Jarman
M
M
McCague
R
R
Rowlands
M G
MG
D000616:Aminoglutethimide / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D000735:Androstenedione; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D047072:Aromatase Inhibitors; D055598:Chemical Phenomena; D002621:Chemistry; D003461:Crystallography; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D047072:Aromatase Inhibitors; D000616:Aminoglutethimide; C065552:3-butyl-3-(4-pyridyl)piperidine-2,6-dione; C049837:rogletimide; D000735:Androstenedione