Selective inhibition of cholesterol side-chain cleavage by potential pro-drug forms of aminoglutethimide.
Potential pro-drugs for aminoglutethimide (1) an agent used for the treatment of hormone-dependent breast cancer have been synthesized, namely the azo-(2), azoxy-(3) and hydrazo-(4) derivatives. These compounds have been tested for inhibitory action towards the two main target enzymes for 1, aromatase and the cholesterol side-chain cleavage enzyme complex, P-450scc. None inhibited aromatase but 3 and 4 inhibited P-450scc, the respective IC50 values being about twice and one-half that for 1. Compounds 1 and 3 were also tested as inhibitors of the 17 alpha-hydroxylase-C17,20 lyase complex in comparison with ketoconazole which acts against prostatic cancer by this mechanism. The azoxy-derivative 3 was a weak inhibitor but 1 was inactive.
Jarman
M
M
Section of Drug Development, Institute of Cancer Research, Sutton, Surrey, UK.
Barrie
S E
SE
Leung
C S
CS
Rowlands
M G
MG
D000616:Aminoglutethimide / Q000494:pharmacology*; D000818:Animals; D047072:Aromatase Inhibitors; D002417:Cattle; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000037:antagonists & inhibitors*; D006801:Humans; D066298:In Vitro Techniques; D008190:Lyases / Q000037:antagonists & inhibitors; D011284:Pregnenolone / Q000378:metabolism; D011355:Prodrugs / Q000138:chemical synthesis / Q000494:pharmacology*; D011374:Progesterone / Q000378:metabolism; D013254:Steroid 17-alpha-Hydroxylase / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship
D047072:Aromatase Inhibitors; D011355:Prodrugs; D000616:Aminoglutethimide; D011374:Progesterone; D011284:Pregnenolone; D013254:Steroid 17-alpha-Hydroxylase; D002786:Cholesterol Side-Chain Cleavage Enzyme; D008190:Lyases