Synthesis and evaluation of AKR1C inhibitory properties of A-ring halogenated oestrone derivativesSinreih, Maša (Avtor) Jójárt, Rebeka (Avtor) Kele, Zoltán (Avtor) Büdefeld, Tomaž (Avtor) Paragi, Gábor (Avtor) Mernyák, Erzsébet (Avtor) Lanišnik-Rižner, Tea (Avtor) aldo-keto reductasesinhibitionhalogenated oestrone derivativesstructure–activity relationshipsEnzymes AKR1C regulate the action of oestrogens, androgens, and progesterone at the pre-receptor level and are also associated with chemo-resistance. The activities of these oestrone halides were investigated on recombinant AKR1C enzymes. The oestrone halides with halogen atoms at both C-2 and C-4 positions (13β-, 13α-methyl-17-keto halogen derivatives) were the most potent inhibitors of AKR1C1. The lowest IC$_{50}$ values were for the 13α-epimers 2_2I,4Br and 2_2I,4Cl (IC$_{50}$, 0.7 μM, 0.8 μM, respectively), both of which selectively inhibited the AKR1C1 isoform. The 13α-methyl-17-keto halogen derivatives 2_2Br and 2_4Cl were the most potent inhibitors of AKR1C2 (IC$_{50}$, 1.5 μM, 1.8 μM, respectively), with high selectivity for the AKR1C2 isoform. Compound 1_2Cl,4Cl showed the best AKR1C3 inhibition, and it also inhibited AKR1C1 (Ki: AKR1C1, 0.69 μM; AKR1C3, 1.43 μM). These data show that halogenated derivatives of oestrone represent a new class of potent and selective AKR1C inhibitors as lead compounds for further optimisations.20212023-03-13 10:09:29Članek v reviji144791sl