Synthesis and biological evaluation of novel pyrrolidine-2,5-dione inhibitors as potential anti-tumour agents

Several novel pyrrolidine-2,5-dione based compounds have been synthesised and evaluated for their biological activity against human placental aromatase (AR), rat testicular 17α-hydroxylase/17,20-lyase (P450 17α ) 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) (IC 50 = 23.8 ± 4.6 μM) and 1-octyl-3-[2'(4-aminophenyl) ethyl] pyrrolidine-2,5-dione (4) (IC 50 = 24.6 ± 1.8 μM) showing equipotent activity with Aminoglutethimide (AG) (IC 50 = 20.0 ± 2.6 μM, K i = 11.0 ± 2.0 μM). Of the compounds tested for P450 17α activity, 3 (IC 5O = 18.5 ± 1.9 μM) again showed the highest activity, being equipotent to Ketoconazole (IC 50 = 12.1 ± 2.9 μM). 3 was a poor inhibitor of CSCC with some 22% inhibitory activity at an inhibitor concentration of 200 μM, 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 17α