Synthesis and evaluation of sulfur-containing glutethimide derivatives for aromatase and desmolase inhibitory activity.
Novel sulfur-containing glutethimide derivatives, substituted with either thiol or methylsulfide groups in the ortho/para positions of the aromatic ring, were synthesized and tested for both human placental aromatase and bovine adrenocortical desmolase inhibitory activities. The synthesis was achieved by the chlorosulfonation of gluthethimide, which yielded a 3:1 mixture of the para to ortho sulfonyl chlorides 2a/b. The sulfonyl chlorides of gluthethimide were reduced with Zn/H2SO4 to give the thioglutethimides 3a/b, which in turn were methylated with MeI/EtOH to give the corresponding methylsulfides 4a/b. In comparison to aminoglutethimide (AG), 3a/b and 4a/b were weak inhibitors of aromatase, with 3a/b being more potent than 4a/b. Aromatase inhibition by the thiol compound was pH-dependent; 3a/b was most potent at higher pH (7.4) than at lower (6.6). This suggested that the thiolate form of 4 coordinates with the ferric heme of aromatase. Likewise, both 3a/b were less potent at inhibiting bovine adrenal desmolase than AG. Possible reasons for the surprisingly poor aromatase inhibitor activity of these compounds are discussed.
Bednarski
P J
PJ
Lehrstuhl für Pharmazeutische Chemie II, Universität Regensburg, Germany.
Hartmann
R W
RW
D000302:Adrenal Cortex / Q000201:enzymology; D000446:Aldehyde-Lyases / Q000037:antagonists & inhibitors*; D000818:Animals; D047072:Aromatase Inhibitors; D002417:Cattle; D065607:Cytochrome P-450 Enzyme Inhibitors; D005260:Female; D005984:Glutethimide / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D010920:Placenta / Q000201:enzymology; D011247:Pregnancy; D013254:Steroid 17-alpha-Hydroxylase
D047072:Aromatase Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D005984:Glutethimide; D013254:Steroid 17-alpha-Hydroxylase; D000446:Aldehyde-Lyases