Pharmaceutical Institute, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany.
ChemMedChem. 2013 Jan;8(1):125-35. doi: 10.1002/cmdc.201200377. Epub 2012 Nov 13.
The breast cancer resistance protein (BCRP/ABCG2) is a member of the ABC transporter superfamily. This protein has a number of physiological functions, including protection of the human body from xenobiotics. The overexpression of BCRP in certain tumor cell lines causes cross-resistance against various drugs used in chemotherapeutic treatment. In a previous work we showed that a new class of compounds derived from XR9576 (tariquidar) selectively inhibits BCRP. In this work we synthesized more members of this class, with modification on the second and third aromatic rings. The inhibitory activities against BCRP and P-gp were assayed using a Hoechst 33342 assay for BCRP and a calcein AM assay for P-gp. Finally, quantitative structure-activity relationships for both aromatic rings were established. The results obtained show the importance of the electron density on the third aromatic ring, influenced by substituents, pointing to interactions with aromatic residues of the protein binding site. In the second aromatic ring the activity of compounds is influenced by the steric volume of the substituents.
乳腺癌耐药蛋白（BCRP/ABCG2）是 ABC 转运体超家族的一员。该蛋白具有许多生理功能，包括保护人体免受异源物质的侵害。BCRP 在某些肿瘤细胞系中的过度表达导致对化疗治疗中使用的各种药物产生交叉耐药性。在之前的工作中，我们表明，源自 XR9576（tariquidar）的一类新型化合物选择性抑制 BCRP。在这项工作中，我们合成了更多此类化合物，对第二和第三个芳环进行了修饰。使用 Hoechst 33342 测定法测定 BCRP 的抑制活性和 calcein AM 测定法测定 P-gp 的抑制活性。最后，建立了两个芳环的定量构效关系。所得结果表明，第三芳环上的电子密度很重要，受取代基影响，表明与蛋白结合部位的芳族残基相互作用。在第二个芳环中，化合物的活性受取代基的空间体积影响。
