A-环卤代雌酮衍生物的 AKR1C 抑制特性的合成与评价。
Synthesis and evaluation of AKR1C inhibitory properties of A-ring halogenated oestrone derivatives.
机构信息
Faculty of Medicine, Institute of Biochemistry and Molecular Genetics, University of Ljubljana, Ljubljana, Slovenia.
Department of Organic Chemistry, University of Szeged, Szeged, Hungary.
出版信息
J Enzyme Inhib Med Chem. 2021 Dec;36(1):1500-1508. doi: 10.1080/14756366.2021.1937142.
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.
AKR1C 酶调节雌激素、雄激素和孕激素在受体前水平的作用，并且与化疗耐药性有关。研究了这些雌酮卤化物在重组 AKR1C 酶上的活性。在 C-2 和 C-4 位具有卤素原子的雌酮卤化物（13β-、13α-甲基-17-酮卤代衍生物）是 AKR1C1 的最强抑制剂。最低的 IC 值为 13α-差向异构体 _2I,4Br 和 _2I,4Cl（IC50，分别为 0.7 μM、0.8 μM），两者均选择性抑制 AKR1C1 同工型。13α-甲基-17-酮卤代衍生物 _2Br 和 _4Cl 是 AKR1C2 的最强抑制剂（IC50，分别为 1.5 μM、1.8 μM），对 AKR1C2 同工型具有高选择性。化合物 _2Cl,4Cl 对 AKR1C3 的抑制作用最好，对 AKR1C1 也有抑制作用（Ki：AKR1C1，0.69 μM；AKR1C3，1.43 μM）。这些数据表明，雌酮的卤代衍生物代表了一类新的强效和选择性 AKR1C 抑制剂，可作为进一步优化的先导化合物。
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