Synthesis and evaluation of AKR1C inhibitory properties of A-ring halogenated oestrone derivatives

Enzymes AKR1C regulate the action of oestrogens, androgens, and progesterone at pre-receptor level are also associated with chemo-resistance. The activities these oestrone halides were investigated on recombinant enzymes. halogen atoms both C-2 C-4 positions (13?-, 13?-methyl-17-keto derivatives) most potent inhibitors AKR1C1. lowest IC50 values for 13?-epimers 2_2I,4Br 2_2I,4Cl (IC50, 0.7 ?M, 0.8 respectively), which selectively inhibited AKR1C1 isoform. derivatives 2_2Br 2_4Cl AKR1C2 1.5 1.8 high selectivity Compound 1_2Cl,4Cl showed best AKR1C3 inhibition, it (Ki: AKR1C1, 0.69 ?M; AKR1C3, 1.43 ?M). These data show that halogenated represent a new class selective as lead compounds further optimisations.