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

Sinreih, Masa and Jójárt, Rebeka and Kele, Zoltán and Budefeld, Tomaz and Paragi, Gábor and Mernyák, Erzsébet and Lanisnik-Rizner, Tea (2021) Synthesis and evaluation of AKR1C inhibitory properties of A-ring halogenated oestrone derivatives. JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY, 36 (1). pp. 1500-1508. ISSN 1475-6366

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Abstract

Enzymes 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 (13b-, 13a-methyl-17-keto halogen derivatives) were the most potent inhibitors of AKR1C1. The lowest IC50 values were for the 13a-epimers 2_2I,4Br and 2_2I,4Cl (IC50, 0.7 lM, 0.8 lM, respectively), both of which selectively inhibited the AKR1C1 isoform. The 13a-methyl-17-keto halogen derivatives 2_2Br and 2_4Cl were the most potent inhibitors of AKR1C2 (IC50, 1.5lM, 1.8 lM, 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 lM; AKR1C3, 1.43 lM). These data show that halogenated derivatives of oestrone represent a new class of potent and selective AKR1C inhibitors as lead compounds for further optimisations.

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