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 (13β-, 13α-methyl-17-keto halogen derivatives) were the most potent inhibitors of AKR1C1. The lowest IC values were for the 13α-epimers _2I,4Br and _2I,4Cl (IC, 0.7 μM, 0.8 μM, respectively), both of which selectively inhibited the AKR1C1 isoform. The 13α-methyl-17-keto halogen derivatives _2Br and _4Cl were the most potent inhibitors of AKR1C2 (IC, 1.5 μM, 1.8 μM, respectively), with high selectivity for the AKR1C2 isoform. Compound _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.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8266253 | PMC |
http://dx.doi.org/10.1080/14756366.2021.1937142 | DOI Listing |
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