title: Synthesis and biological evaluation of novel pyrrolidine-2,5-dione inhibitors as potential anti-tumour agents.
abstract: Several novel pyrrolidine-2,5-dione based compounds have been synthesised and evaluated for their biological activity against human placental aromatase (AR), rat testicular 17 alpha-hydroxylase/17,20-lyase (P450(17) alpha) and bovine cholesterol side chain cleavage (CSCC). The compounds showed good inhibition towards AR with 1-cyclohexyl-3-[2'(4"-aminophenyl) ethyl] pyrrolidine-2,5-dione (3) (IC50 = 23.8 +/- 4.6 microM) and 1-octyl-3-[2'(4"-aminophenyl) ethyl] pyrrolidine-2,5-dione (4) (IC50 = 24.6 +/- 1.8 microM) showing equipotent activity with Aminoglutethimide (AG) (IC50 = 20.0 +/- 2.6 microM, Ki = 11.0 +/- 2.0 microM). Of the compounds tested for P450(17) alpha activity, 3 (IC50 = 18.5 +/- 1.9 microM) again showed the highest activity, being equipotent to Ketoconazole (IC50 = 12.1 +/- 2.9 microM). 3 was a poor inhibitor of CSCC with some 22% inhibitory activity at an inhibitor concentration of 200 microM, as compared to AG with 72% inhibitory activity under the same conditions. The compounds proved themselves to be excellent lead compounds and supported the novel models developed by Ahmed for AR and P450(17) alpha.
authors.affiliation: Department of Pharmacy, Brighton University, UK.
authors.forename: S
authors.initials: S
authors.lastname: Ahmed
authors.forename: J H
authors.initials: JH
authors.lastname: Smith
authors.forename: P J
authors.initials: PJ
authors.lastname: Nicholls
authors.forename: R
authors.initials: R
authors.lastname: Whomsley
authors.forename: P
authors.initials: P
authors.lastname: Cariuk
mesh_terms: D000311:Adrenal Glands / Q000201:enzymology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D047072:Aromatase Inhibitors; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000037:antagonists & inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D015195:Drug Design; D006801:Humans; D008297:Male; D010920:Placenta / Q000201:enzymology; D013254:Steroid 17-alpha-Hydroxylase / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship; D013388:Succinimides / Q000138:chemical synthesis* / Q000494:pharmacology*; D013737:Testis / Q000201:enzymology
chemical_list: D000970:Antineoplastic Agents; D047072:Aromatase Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D013388:Succinimides; D013254:Steroid 17-alpha-Hydroxylase; D002786:Cholesterol Side-Chain Cleavage Enzyme