Li Wengang, Abu Samra Dina, Merzaban Jasmeen, Khashab Niveen M
Controlled Release and Delivery Lab, Department of Chemical and Life Sciences and Engineering, King Abdullah University of Science and Technology, Saudi Arabia.
J Nanosci Nanotechnol. 2013 Feb;13(2):1399-402. doi: 10.1166/jnn.2013.6084.
Multi-drug resistance (MDR) is a trend whereby tumor cells exposed to one cytotoxic agent develop cross-resistance to a range of structurally and functionally unrelated compounds. P-glycoprotein (P-gp) efflux pump is one of the mostly studied drug carrying processes that shuttle the drugs out of tumor cells. Thus, P-gp inhibitors have attracted a lot of attention as they can stop cancer drugs from being pumped out of target cells with the consumption of ATP. Using quantitive structure activity relationship (QSAR), we have successfully synthesized a series of novel P-gp inhibitors. The obtained dihydropyrroloquinoxalines series were fully characterized and then tested against bacterial and tumor assays with over-expressed P-gps: All compounds were bioactive especially compound 1 c that had enhanced antibacterial activity. Furthermore, these compounds were utilized as targeting vectors to direct drug delivery vehicles such as silica nanoparticles (SNPs) to cancerous Hela cells with over expressed P-gps. Cell uptake studies showed a successful accumulation of these decorated SNPs in tumor cells compared to undecorated SNPs. The results obtained show that dihydropyrroloquinoxalines constitute a promising drug candidate for targeting cancers with MDR.
多药耐药性（MDR）是一种趋势，即暴露于一种细胞毒性药物的肿瘤细胞会对一系列结构和功能无关的化合物产生交叉耐药性。P-糖蛋白（P-gp）外排泵是研究最多的将药物转运出肿瘤细胞的药物携带过程之一。因此，P-gp抑制剂备受关注，因为它们可以阻止抗癌药物在消耗ATP的情况下被泵出靶细胞。利用定量构效关系（QSAR），我们成功合成了一系列新型P-gp抑制剂。对所得到的二氢吡咯并喹喔啉系列进行了全面表征，然后针对过表达P-gp的细菌和肿瘤试验进行了测试：所有化合物均具有生物活性，尤其是化合物1c具有增强的抗菌活性。此外，这些化合物被用作靶向载体，将诸如二氧化硅纳米颗粒（SNP）等药物递送载体导向过表达P-gp的癌性海拉细胞。细胞摄取研究表明，与未修饰的SNP相比，这些修饰的SNP成功地在肿瘤细胞中积累。所得结果表明，二氢吡咯并喹喔啉是一种有前途的针对多药耐药性癌症的候选药物。
