6-Phenylaliphatic-substituted androst-4-ene-3,17-diones as aromatase inhibitors: structure-activity relationships.
Two series of 6alpha- and 6beta-phenylaliphatic-substituted androst-4-ene-3,17-diones (3 and 5) were synthesized as aromatase inhibitors to gain insights of structure-activity relationships of varying the n-alkyl moiety (C2 to C5) of the 6-phenylaliphatic substituents to the inhibitory activity. All of the inhibitors synthesized inhibited human placental aromatase in a competitive manner with apparent Ki values ranging from 16 to 115 nM. The 6alpha-phenethyl analog 3a and the 6beta-phenbutyl analog 5c (Ki=16 nM for the two inhibitors, respectively) were the most potent inhibitors in each series. The inhibitory activities of the 6beta-substituted steroids 5 except for the phenethyl compound 5a were more powerful than those of the corresponding 6alpha-isomers 3. Elongation of the alkyl moiety of the 6-substituent of the 6alpha-phenethyl steroid 3a up to five methylene units decreased affinity to aromatase in all cases, whereas the addition of two more methylene units to the 6-side chain of the 6beta-phenethyl analog 5a increased the affinity in relation to carbon number of the 6-substituent. These results along with molecular modelling with the PM3 method, would give a new information about the formation of thermodynamically stable enzyme-inhibitor complex in a hydrophobic binding pocket in the active site of aromatase.
Numazawa
M
M
Tohoku College of Pharmacy, Aobaku, Sendai, Japan.
Yamaguchi
S
S
D000735:Androstenedione / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D047072:Aromatase Inhibitors; D001667:Binding, Competitive; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D010636:Phenols; D010920:Placenta / Q000201:enzymology; D011247:Pregnancy; D013329:Structure-Activity Relationship
D047072:Aromatase Inhibitors; D004791:Enzyme Inhibitors; D010636:Phenols; D000735:Androstenedione