School of Pharmacy, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Yantai University, Yantai, 264005, China.
School of Pharmacy, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Yantai University, Yantai, 264005, China.
Eur J Med Chem. 2021 Apr 15;216:113317. doi: 10.1016/j.ejmech.2021.113317. Epub 2021 Mar 3.
The P-glycoprotein (Pgp) is a major transporter involved in multidrug resistance (MDR) of cancer cells leading to chemotherapy failure. In our previous study, we demonstrated that the amide derivatives of pyxinol are promising modulators against Pgp-mediated MDR in cancer. In the present study, we designed and synthesized novel pyxinol derivatives linked to amino acid residues. We evaluated MDR (paclitaxel (Ptx) resistance) reversal potency of forty pyxinol derivatives in KBV cells and analyzed their structure-activity relationships. Half of our derivatives sensitized KBV cells to Ptx at non-toxic concentrations, among which the pyxinol compound bearing a methionine residue (3c) exhibited the best activity in MDR reversal. Compound 3c was found to possess high selectivity toward Pgp and sensitize the KBV cells to Pgp substrates by blocking the efflux function of Pgp. This manifestation may be attributed to its high binding affinity with Pgp, as suggested by docking studies. Overall, the biological profile and ease of synthesizing these pyxinol derivatives render them promising lead compounds for further development for Pgp-mediated MDR.
P-糖蛋白（Pgp）是一种主要的转运蛋白，参与癌细胞的多药耐药（MDR），导致化疗失败。在我们之前的研究中，我们证明了吡嗪醇的酰胺衍生物是一种有前途的 Pgp 介导的癌症 MDR 调节剂。在本研究中，我们设计并合成了与氨基酸残基连接的新型吡嗪醇衍生物。我们评估了四十种吡嗪醇衍生物在 KBV 细胞中的多药耐药（紫杉醇（Ptx）耐药）逆转效力，并分析了它们的构效关系。我们的衍生物中有一半能以非毒性浓度使 KBV 细胞对 Ptx 敏感，其中含有蛋氨酸残基的吡嗪醇化合物（3c）在逆转 MDR 方面表现出最好的活性。研究发现，化合物 3c 对 Pgp 具有很高的选择性，并通过阻断 Pgp 的外排功能使 KBV 细胞对 Pgp 底物敏感。这种表现可能归因于其与 Pgp 的高结合亲和力，这一点通过对接研究得到了提示。总的来说，这些吡嗪醇衍生物的生物学特征和易于合成使它们成为进一步开发 Pgp 介导的 MDR 的有前途的先导化合物。
