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 (13β-, 13α-methyl-17-keto halogen derivatives) were the most potent inhibitors of AKR1C1. The lowest IC₅₀ values were for the 13α-epimers 2_2I,4Br and 2_2I,4Cl (IC₅₀, 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 (IC₅₀, 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.

摘要

酶 AKR1C 在受体前水平调节雌激素、雄激素和孕酮的作用，并且还与化学抗性有关。在重组 AKR1C 酶上研究了这些雌酮卤化物的活性。在 C-2 和 C-4 位具有卤原子的雌酮卤化物（13β-、13α-甲基-17-酮卤衍生物）是 AKR1C1 最有效的抑制剂。最低的 IC ₅₀值是针对13α-差向异构体2 _2I,4Br 和2 _2I,4Cl（IC ₅₀分别为 0.7 μM、0.8 μM），它们都选择性地抑制了 AKR1C1 异构体。13α-甲基-17-酮卤衍生物2 _2Br 和2 _4Cl 是最有效的 AKR1C2 抑制剂 (IC ₅₀，分别为 1.5 μM 和 1.8 μM），对 AKR1C2 同种型具有高选择性。化合物1 _2Cl，4CL显示出最好的AKR1C3抑制，而且它也能抑制AKR1C1（KI：AKR1C1，0.69μM; AKR1C3，1.43μM）。这些数据表明，雌酮的卤化衍生物代表了一类新的有效且选择性的 AKR1C 抑制剂，作为进一步优化的先导化合物。