Parveen Zahida, Brunhofer Gerda, Jabeen Ishrat, Erker Thomas, Chiba Peter, Ecker Gerhard F
Institute of Medical Chemistry, Medical University Vienna, Waehringer Strasse 10, 1090 Vienna, Austria; Abdul Wali Khan University Mardan, Malakand Mardan Rd, Mardan, Pakistan.
University of Vienna, Department of Medicinal Chemistry, Althanstrasse 14, 1090 Vienna, Austria.
Bioorg Med Chem. 2014 Apr 1;22(7):2311-9. doi: 10.1016/j.bmc.2014.02.005. Epub 2014 Feb 15.
P-glycoprotein (P-gp) is an ATP-dependent multidrug resistance efflux transporter that plays an important role in anticancer drug resistance and in pharmacokinetics of medicines. Despite a large number of structurally and functionally diverse compounds, also flavonoids and chalcones have been reported as inhibitors of P-gp. The latter share some similarity with the well studied class of propafenones, but do not contain a basic nitrogen atom. Furthermore, due to their rigidity, they are suitable candidates for 3D-QSAR studies. In this study, a set of 22 new chalcone derivatives were synthesized and evaluated in a daunomycin efflux inhibition assay using the CCRF.CEM.VCR1000 cell line. The compound 10 showed the highest activity (IC50=42nM), which is one order of magnitude higher than the activity for an equilipohillic propafenone analogue. 2D- and 3D-QSAR studies indicate the importance of H-bond acceptors, methoxy groups, hydrophobic groups as well as the number of rotatable bonds as pharmacophoric features influencing P-gp inhibitory activity.
P-糖蛋白（P-gp）是一种依赖ATP的多药耐药性外排转运蛋白，在抗癌药物耐药性和药物药代动力学中发挥着重要作用。尽管有大量结构和功能各异的化合物，但黄酮类化合物和查耳酮也被报道为P-gp的抑制剂。后者与已被深入研究的普罗帕酮类有一些相似之处，但不含碱性氮原子。此外，由于它们的刚性，它们是三维定量构效关系（3D-QSAR）研究的合适候选物。在本研究中，合成了一组22种新的查耳酮衍生物，并使用CCRF.CEM.VCR1000细胞系在柔红霉素外排抑制试验中进行了评估。化合物10表现出最高活性（IC50 = 42 nM），比同等亲脂性的普罗帕酮类似物的活性高一个数量级。二维和三维定量构效关系研究表明，氢键受体、甲氧基、疏水基团以及可旋转键的数量作为药效基团特征对P-gp抑制活性具有重要影响。
