Alkyne-, azide- and triazole-containing flavonoids as modulators for multidrug resistance in cancers

Abstract

A triazole bridged flavonoid dimer compound library was efficiently constructed via the cycloaddition reaction of a series of flavonoid-containing azides (Az 1-15) and alkynes (Ac 1-17). These triazole bridged flavonoid dimers and their precursor alkyne- and azide-continaing flavonoids were screened for their ability to modulate multidrug resistance (MDR) in P-gp-overexpressed cell line (LCC6MDR), MRPl-overexpressed cell line (2008/MRPl) and BCRP-overexpressed cell line (HEK293/R2 and MCF7-MX100). Generally, they displayed very promising MDR reversal activity against P-gp-, MRPl- and BCRP-mediated drug resistance. Moreover, they showed different levels of selectivity for various transporters. Overall, they can be divided into mono-selective, dual-selective and multi-selective modulators for the P-gp, MRPl and BCRP transporters. The EC50 values for reversing paclitaxel resistance (141 - 340 nM) of LCC6MDR cells, DOX (78 - 590 nM) and vincristine (82 - 550 nM) resistance of 2008/MRPl cells and topotecan resistance (0.9 - 135 nM) of HEK293/R2 and MCF7-MX100 cells were at nanomolar range. Importantly, a number of compounds displayed EC50 at or below 10 nM in BCRP-overexpressed cell lines, indicating that these bivalent triazoles more selectively inhibit BCRP transporter than the P-gp and MRPl transporters. Most of the dimers are notably safe MDR chemosensitizers as indicated by their high therapeutic index values. 三唑桥联类黄酮二聚体化合物文库经由一系列含有叠氮化物(Az 1‑15)和炔烃(Ac 1‑17)的类黄酮的环加成反应有效构建。针对这些三唑桥联类黄酮二聚体和其前驱体含炔烃的类黄酮和含叠氮化物的类黄酮在过度表达P‑gp的细胞株(LCC6MDR)、过度表达MRP1的细胞株(2008/MRP1)和过度表达BCRP的细胞株(HEK293/R2和MCF7‑MX100)中调节多药耐药(MDR)的能力对其进行筛选。其通常展示出极有前景的对抗P‑gp介导的、MRP1介导的和BCRP介导的药物耐药的MDR逆转活性。此外，其对各种转运蛋白展示出不同水平的选择性。总的来说，其可针对P‑gp、MRP1和BCRP转运蛋白分成单选择性、双选择性和多选择性调节剂。逆转LCC6MDR细胞的太平洋紫杉醇耐药(141‑340nM)、2008/MRP1细胞的DOX(78‑590nM)和长春新碱(82‑550nM)耐药以及HEK293/R2和MCF7‑MX100细胞的拓扑替康耐药(0.9‑135nM)的EC50值在纳摩尔范围内。重要的是，许多化合物在过度表达BCRP的细胞株中展示出处于或低于10nM的EC50，表明与P‑gp和MRP1转运蛋白相比，这些二价三唑更具选择性地抑制BCRP转运蛋白。大部分二聚体是值得注意的安全MDR化学敏化剂，如由其高治疗指数值所指示