Further studies on 6-alkylandrost-4-ene-3,17-diones as aromatase inhibitors: Elongation of the 6-alkyl chain

Abstract

To gain further insight on the relationship between 6-alkylandrost-4-ene-3,17-diones and their aromatase inhibition activity, a series of alkyl steroids with long alkyl chains (n-pentyl, n-hexyl, or n-octyl) at C-6α and 6β were synthesized. All of the steroids studied inhibited human placental aromatase in a competitive manner with apparent K i values ranging from 2.8 to 80 nM. The 6β-pentyl analog 4a (K i = 2.8 nM) was the most potent inhibitor. The inhibitory activities of the 6β-alkyl steroids 4 were more powerful than those of the corresponding 6α-isomers 5 . The addition of one methylene unit to the 6α- and 6β-n-butyl moieties of androst-4-ene-3,17-dione markedly increased the affinity to aromatase, whereas further elongation of the n-pentyl group decreased affinity in relation to the carbon number of the alkyl chain. These results, along with molecular modeling with the PM3 method, suggest that the increased affinities of the pentyl steroids 4a and 5a may essentially depend on the formation of thermodynamically stable enzyme-inhibitor complex in the hydrophobic binding pocket.