Pharmaceutical and Cellbiological Chemistry, Pharmaceutical Institute, Rheinische Friedrich-Wilhelms-University Bonn, An der Immenburg 4, 53121 Bonn, Germany.
J Med Chem. 2020 Sep 24;63(18):10412-10432. doi: 10.1021/acs.jmedchem.0c00961. Epub 2020 Sep 11.
In the search for highly effective modulators addressing ABCG2-mediated MDR, 23 pyrimidines were synthesized and biologically assessed. Seven derivatives with (a) nitrogen- and/or halogen-containing residue(s) had extraordinary potencies against ABCG2 (IC < 150 nM). The compounds competitively inhibited ABCG2-mediated Hoechst 33342 transport but were not substrates of ABCG2. The most potent MDR reverser, compound , concentration-dependently increased SN-38-mediated cancer cell death at 11 nM (EC), time-dependently doubled SN-38 toxicity in a period of 7 days at 10 nM, and half-maximally accelerated cell death combined with SN-38 at 17 nM. No induction of ABCG2 was observed. Furthermore, 11 pyrimidines were revealed as triple ABCB1/ABCC1/ABCG2 inhibitors. Five possessed IC values below 10 μM against each transporter, classifying them as some of the 50 most potent multitarget ABC transporter inhibitors. The most promising representative, compound , reversed ABCB1-, ABCC1-, and ABCG2-mediated MDR, making it one of the three most potent ABC transporter inhibitors and reversers of ABC transporters-mediated MDR.
在寻找高效的 ABCG2 介导的多药耐药调节剂时，合成并生物评估了 23 种嘧啶类化合物。其中 7 种具有（a）含氮和/或卤素残基的衍生物对 ABCG2 具有非凡的抑制作用（IC < 150 nM）。这些化合物竞争性地抑制 ABCG2 介导的 Hoechst 33342 转运，但不是 ABCG2 的底物。最有效的 MDR 逆转剂化合物 ，在 11 nM（EC）时浓度依赖性地增加 SN-38 介导的癌细胞死亡，在 10 nM 时在 7 天内时间依赖性地将 SN-38 的毒性增加一倍，在 17 nM 时与 SN-38 联合半最大程度地加速细胞死亡。未观察到 ABCG2 的诱导。此外，11 种嘧啶类化合物被揭示为三重 ABCB1/ABCC1/ABCG2 抑制剂。其中 5 种对每种转运蛋白的 IC 值均低于 10 μM，将其归类为 50 种最有效的多靶标 ABC 转运蛋白抑制剂之一。最有前途的代表化合物 ，逆转了 ABCB1、ABCC1 和 ABCG2 介导的多药耐药性，使其成为三种最有效的 ABC 转运蛋白抑制剂和 ABC 转运蛋白介导的多药耐药性逆转剂之一。
