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 (IC₅₀ < 150 nM). The compounds competitively inhibited ABCG2-mediated Hoechst 33342 transport but were not substrates of ABCG2. The most potent MDR reverser, compound 19, concentration-dependently increased SN-38-mediated cancer cell death at 11 nM (EC₅₀), 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 IC₅₀ 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 37, 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.

中文翻译：

---

优异的嘧啶衍生物作为选择性ABCG2抑制剂和广谱ABCB1，ABCC1和ABCG2拮抗剂。

在寻找针对ABCG2介导的MDR的高效调节剂中，合成了23个嘧啶并进行了生物学评估。具有一个或多个含氮和/或卤素的残基的七个衍生物具有抗ABCG2的非凡效能（IC ₅₀ <150 nM）。这些化合物竞争性抑制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19在11 nM浓度依赖性增加SN-38介导的癌细胞死亡（EC ₅₀），SNn-38在10 nM的时间段内在7天内的时间依赖性增加了一倍，而SN-38在17 nM的时间段内最大程度地加速了细胞死亡。没有观察到ABCG2的诱导。此外，还揭示了11种嘧啶类作为三重ABCB1 / ABCC1 / ABCG2抑制剂。五个具有针对每个转运蛋白的IC ₅₀值低于10μM，将其归类为50种最有效的多靶ABC转运蛋白抑制剂中的一些。最有前途的代表化合物37逆转了ABCB1，ABCC1和ABCG2介导的MDR，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MDR的逆转剂之一。