[Derivatives of exemestane--synthesis and evaluation of aromatase inhibition].
The irreversible aromatase inhibitor exemestane (6) reacts with nitromethane and sodium ethanolate to yield the Michael adduct 9. The aldehyde 10 is obtained by Nef reaction of the nitro compound 9 and affords the 1,4-dihydropyridine (DHP) 11 by Hantzsch reaction using methyl beta-aminocrotonate in acetic acid. The new compounds showed a reduced inhibitory potency towards aromatase (IC50 values: 9, 0.91 microM; 10, 2.5 microM; 11, 10 microM) compared to 6 (IC50 = 0.23 microM). The 1,4-DHP 11 was dehydrogenated with CAN or electrochemically (E1/2 =1.18 V) to yield the corresponding pyridine 12.
Görlitzer
K
K
Institut für Pharmazeutische Chemie' Analytische Chemie der Technischen Universität Braunschweig, Germany. k.goerlitzer@tu-bs.de
Bonnekessel
Ch
Ch
Jones
P G
PG
Palusczak
A
A
Hartmann
R W
RW
D000730:Androstadienes / Q000138:chemical synthesis* / Q000494:pharmacology*; D047072:Aromatase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D006801:Humans; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology; D008958:Models, Molecular; D008968:Molecular Conformation; D010084:Oxidation-Reduction; D013055:Spectrophotometry, Infrared; D013056:Spectrophotometry, Ultraviolet; D017550:Spectroscopy, Fourier Transform Infrared
D000730:Androstadienes; D047072:Aromatase Inhibitors; D007202:Indicators and Reagents; C056516:exemestane