Institute of Pharmacy, University of Regensburg, D-93040, Regensburg, Germany.
Institute of Organic Chemistry, University of Regensburg, D-93040, Regensburg, Germany.
Eur J Med Chem. 2020 Apr 1;191:112133. doi: 10.1016/j.ejmech.2020.112133. Epub 2020 Feb 10.
Tariquidar derivatives have been described as potent and selective ABCG2 inhibitors. However, their susceptibility to hydrolysis limits their applicability. The current study comprises the synthesis and characterization of novel tariquidar-related inhibitors, obtained by bioisosteric replacement of the labile moieties in our previous tariquidar analog UR-ME22-1 (9). CuAAC ("click" reaction) gave convenient access to a triazole core as a substitute for the labile amide group and the labile ester moiety was replaced by different acyl groups in a Sugasawa reaction. A stability assay proved the enhancement of the stability in blood plasma. Compounds UR-MB108 (57) and UR-MB136 (59) inhibited ABCG2 in a Hoechst 33342 transport assay with an IC value of about 80 nM and belong to the most potent ABCG2 inhibitors described so far. Compound 57 was highly selective, whereas its PEGylated analog 59 showed some potency at ABCB1. Both 57 and 59 produced an ABCG2 ATPase-depressing effect which is in agreement with our precedent cryo-EM study identifying 59 as an ATPase inhibitor that exerts its effect via locking the inward-facing conformation. Thermostabilization of ABCG2 by 57 and 59 can be taken as a hint to comparable binding to ABCG2. As reference substances, compounds 57 and 59 allow additional mechanistic studies on ABCG2 inhibition. Due to their stability in blood plasma, they are also applicable in vivo. The highly specific inhibitor 57 is suited for PET labeling, helping to further elucidate the (patho)physiological role of ABCG2, e.g. at the BBB.
他利奎德衍生物已被描述为有效的、选择性的 ABCG2 抑制剂。然而，其对水解的敏感性限制了它们的适用性。本研究包括合成和表征新型他利奎德相关抑制剂，这些抑制剂是通过对我们之前的他利奎德类似物 UR-ME22-1（9）中的不稳定部分进行生物等排替换得到的。CuAAC（“点击”反应）为三唑核心的取代提供了便利，该核心取代了不稳定的酰胺基团，而不稳定的酯部分在 Sugasawa 反应中被不同的酰基取代。稳定性测定证明了在血浆中的稳定性增强。化合物 UR-MB108（57）和 UR-MB136（59）在 Hoechst 33342 转运测定中抑制 ABCG2，IC 值约为 80 nM，属于迄今为止描述的最有效的 ABCG2 抑制剂。化合物 57 具有高度选择性，而其聚乙二醇化类似物 59 在 ABCB1 中也具有一定的活性。57 和 59 均产生 ABCG2 ATP 酶抑制作用，这与我们之前的冷冻电镜研究一致，该研究表明 59 是一种通过锁定内向构象发挥作用的 ATP 酶抑制剂。57 和 59 对 ABCG2 的热稳定化可被视为与 ABCG2 类似的结合的提示。作为参考物质，化合物 57 和 59 允许对 ABCG2 抑制进行额外的机制研究。由于它们在血浆中的稳定性，它们也可应用于体内。高特异性抑制剂 57 适合于 PET 标记，有助于进一步阐明 ABCG2 的（病理）生理作用，例如在 BBB 处。
