title: Synthesis and aromatase inhibition of 3-cycloalkyl-substituted 3-(4-aminophenyl)piperidine-2,6-diones.
abstract: The synthesis of 3-cycloalkyl-substituted 3-(4-aminophenyl)piperidine-2,6-diones is described [cyclopentyl (1), cyclohexyl (2)]. The enantiomers of 2 were separated either by using HPLC on optically active sorbent or by crystallization of the brucine salt of the phthalamic acid of 2. The absolute configuration of the (+)- and (-)-enantiomers of 2 were assigned as S and R, respectively, by comparing the CD spectra to those of the enantiomers of aminoglutethimide (AG, 3-(4-aminophenyl)-3-ethylpiperidine-2,6-dione). The compounds were tested in vitro for inhibition of human placental aromatase, the cytochrome P450-dependent enzyme which is responsible for the conversion of androgens to estrogens. Compounds 1 and 2 inhibited aromatase by 50% at 1.2 and 0.3 microM, respectively (IC50 AG = 37 microM). According to the findings with AG, the (+)-enantiomer of 2 was responsible for the inhibitory activity, being a 240-fold more potent aromatase inhibitor in vitro than racemic AG. On the other hand, (+)-2 displayed a strongly reduced inhibition of desmolase (cholesterol side-chain cleavage enzyme) compared to AG (relative activity = 0.3). Thus (+)-2 is of interest as a potential drug for the treatment of estrogen-dependent diseases, e.g. mammary tumors.
authors.affiliation: Fachrichtung 12.1 Pharmazeutische Chemie, Universität des Saarlandes, FRG.
authors.forename: R W
authors.initials: RW
authors.lastname: Hartmann
authors.forename: C
authors.initials: C
authors.lastname: Batzl
authors.forename: T M
authors.initials: TM
authors.lastname: Pongratz
authors.forename: A
authors.initials: A
authors.lastname: Mannschreck
mesh_terms: D000616:Aminoglutethimide / Q000494:pharmacology; D047072:Aromatase Inhibitors; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000037:antagonists & inhibitors; D002851:Chromatography, High Pressure Liquid; D002942:Circular Dichroism; D003460:Crystallization; D005260:Female; D006801:Humans; D008968:Molecular Conformation; D010881:Piperidones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010920:Placenta / Q000201:enzymology; D013237:Stereoisomerism
chemical_list: D047072:Aromatase Inhibitors; D010881:Piperidones; D000616:Aminoglutethimide; C075253:3-(4-aminophenyl)-3-cyclohexylpiperidine-2,6-dione; D002786:Cholesterol Side-Chain Cleavage Enzyme