Pharmaceutical and Cellbiological Chemistry, Pharmaceutical Institute, Rheinische Friedrich-Wilhelms-University of Bonn, An der Immenburg 4, 53121, Bonn, Germany.
Pharmaceutical and Cellbiological Chemistry, Pharmaceutical Institute, Rheinische Friedrich-Wilhelms-University of Bonn, An der Immenburg 4, 53121, Bonn, Germany.
Eur J Med Chem. 2021 Feb 15;212:113045. doi: 10.1016/j.ejmech.2020.113045. Epub 2020 Dec 3.
In the search for novel, highly potent, and nontoxic adjuvant chemotherapeutics to resolve the major issue of ABC transporter-mediated multidrug resistance (MDR), pyrimidines were discovered as a promising compound class of modern ABCG2 inhibitors. As ABCG2-mediated MDR is a major obstacle in leukemia, pancreatic carcinoma, and breast cancer chemotherapy, adjuvant chemotherapeutics are highly desired for future clinical oncology. Very recently, docking studies of one of the most potent reversers of ABCG2-mediated MDR were reported and revealed a putative second binding pocket of ABCG2. Based on this (sub)pocket, a series of 16 differently 6-substituted 4-anilino-2-phenylpyrimidines was designed and synthesized to explore the potential increase in inhibitory activity of these ABCG2 inhibitors. The compounds were assessed for their influence on the ABCG2-mediated pheophorbide A transport, as well as the ABCB1- and ABCC1-mediated transport of calcein AM. They were additionally evaluated in MDR reversal assays to determine their half-maximal reversal concentration (EC). The 6-substitution did not only show increased toxicity against ABCG2-overexpressing cells in combination with SN-38 but also a negative influence on cell viability in general. Nevertheless, several candidates had EC values in the low double-digit nanomolar concentration range, qualifying them as some of the most potent reversers of ABCG2-mediated MDR. In addition, five novel multitarget ABCB1, ABCC1, and ABCG2 inhibitors were discovered, four of them exerting their inhibitory power against the three stated transporters at least in the single-digit micromolar concentration range.
为了解决 ABC 转运蛋白介导的多药耐药（MDR）这一主要问题，人们一直在寻找新型、高效且无毒的佐剂化疗药物，在这一过程中发现嘧啶类化合物是现代 ABCG2 抑制剂中很有前景的一类化合物。由于 ABCG2 介导的 MDR 是白血病、胰腺癌和乳腺癌化疗的主要障碍，因此佐剂化疗药物是未来临床肿瘤学的迫切需求。最近，有报道称对 ABCG2 介导的 MDR 逆转作用最强的抑制剂之一进行了对接研究，揭示了 ABCG2 的一个潜在的第二个结合口袋。基于这个（亚）口袋，设计并合成了一系列 16 种不同的 6-取代的 4-苯胺基-2-苯基嘧啶，以探索这些 ABCG2 抑制剂抑制活性增加的潜力。评估了这些化合物对 ABCG2 介导的原卟啉 A 转运以及 ABCB1 和 ABCC1 介导的 calcein AM 转运的影响。此外，还在 MDR 逆转测定中评估了它们的作用，以确定其半最大逆转浓度（EC）。6-取代不仅显示出与 SN-38 联合使用时对 ABCG2 过表达细胞的毒性增加，而且对一般细胞活力也有负面影响。尽管如此，一些候选化合物的 EC 值在低两位数纳摩尔浓度范围内，使它们成为 ABCG2 介导的 MDR 最强逆转剂之一。此外，还发现了五种新型多靶标 ABCB1、ABCC1 和 ABCG2 抑制剂，其中四种至少在个位数微摩尔浓度范围内对这三种所述转运体发挥抑制作用。
