Pharmaceutical Institute, University of Bonn, Pharmaceutical Chemistry II, An der Immenburg 4, 53121 Bonn, Germany.
Eur J Med Chem. 2013 Sep;67:115-26. doi: 10.1016/j.ejmech.2013.06.035. Epub 2013 Jun 25.
Multidrug resistance (MDR) often leads to a failure of cancer chemotherapy. Breast Cancer Resistance Protein (BCRP/ABCG2), a member of the superfamily of ATP binding cassette proteins has been found to confer MDR in cancer cells by transporting molecules with amphiphilic character out of the cells using energy from ATP hydrolysis. Inhibiting BCRP can be a solution to overcome MDR. We synthesized a series of flavones, 7,8-benzoflavones and 5,6-benzoflavones with varying substituents at positions 3, 3' and 4' of the (benzo)flavone structure. All synthesized compounds were tested for BCRP inhibition in Hoechst 33342 and pheophorbide A accumulation assays using MDCK cells expressing BCRP. All the compounds were further screened for their P-glycoprotein (P-gp) and Multidrug resistance-associated protein 1 (MRP1) inhibitory activity by calcein AM accumulation assay to check the selectivity towards BCRP. In addition most active compounds were investigated for their cytotoxicity. It was observed that in most cases 7,8-benzoflavones are more potent in comparison to the 5,6-benzoflavones. In general it was found that presence of a 3-OCH3 substituent leads to increase in activity in comparison to presence of OH or no substitution at position 3. Also, it was found that presence of 3',4'-OCH3 on phenyl ring lead to increase in activity as compared to other substituents. Compound 24, a 7,8-benzoflavone derivative was found to be most potent being 50 times selective for BCRP and showing very low cytotoxicity at higher concentrations.
多药耐药（MDR）常常导致癌症化疗失败。乳腺癌耐药蛋白（BCRP/ABCG2）是 ATP 结合盒蛋白超家族的一员，已被发现可通过利用 ATP 水解产生的能量将具有两亲性的分子从细胞内转运出细胞，从而赋予癌细胞 MDR 特性。抑制 BCRP 可能是克服 MDR 的一种解决方案。我们合成了一系列具有不同取代基的黄酮、7,8-苯并黄酮和 5,6-苯并黄酮，取代基位于（苯并）黄酮结构的 3、3'和 4'位。所有合成的化合物均在表达 BCRP 的 MDCK 细胞中，通过 Hoechst 33342 和原卟啉 A 积累测定法测试了对 BCRP 的抑制作用。所有化合物均通过 calcein AM 积累测定法进一步筛选对 P-糖蛋白（P-gp）和多药耐药相关蛋白 1（MRP1）的抑制活性，以检查对 BCRP 的选择性。此外，还研究了大多数活性化合物的细胞毒性。结果表明，在大多数情况下，7,8-苯并黄酮比 5,6-苯并黄酮更有效。一般来说，发现 3-OCH3 取代基的存在会导致活性增加，而 3 位存在 OH 或无取代基则会导致活性降低。此外，还发现苯环上 3',4'-OCH3 的存在会导致活性增加，而其他取代基则会导致活性降低。化合物 24 是一种 7,8-苯并黄酮衍生物，被发现是最有效的化合物，对 BCRP 的选择性高达 50 倍，在较高浓度下显示出非常低的细胞毒性。
