合成并评价一氧化氮供体型 DDB 衍生物作为潜在的 MCF-7/Adr 细胞中 Pgp 介导的多药耐药逆转剂。
Synthesis and evaluation of nitric oxide-releasing DDB derivatives as potential Pgp-mediated MDR reversal agents in MCF-7/Adr cells.
机构信息
State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, PR China; Center of Drug Discovery, China Pharmaceutical University, Nanjing 210009, PR China.
出版信息
Bioorg Med Chem Lett. 2012 Jan 15;22(2):801-5. doi: 10.1016/j.bmcl.2011.12.065. Epub 2011 Dec 17.
Novel furoxan-based nitric oxide (NO)-releasing DDB derivatives (7a-j) were synthesized. Compounds 7i and 7j significantly reversed the resistance of MCF-7/Adr cells to doxorubicin in the combination treatment, and markedly increased the intracellular accumulation of doxorubicin probably via inhibiting Pgp-mediated intracellular drug efflux as well as down-regulating doxorubicin-induced Pgp expression. It was demonstrated that NO released by 7i and 7j played an important role in increasing intracellular doxorubicin accumulation and chemo-sensitizing MCF-7/Adr cells to doxorubicin, and the synergic effects of DDB and NO-donor moieties in 7i and 7j may contribute to reversing Pgp-mediated MDR in MCF-7/Adr cells to doxorubicin.
新型基于呋咱的一氧化氮（NO）释放 DDB 衍生物（7a-j）被合成。化合物 7i 和 7j 在联合治疗中显著逆转了 MCF-7/Adr 细胞对阿霉素的耐药性，并通过抑制 Pgp 介导的细胞内药物外排以及下调阿霉素诱导的 Pgp 表达，显著增加了细胞内阿霉素的积累。结果表明，7i 和 7j 释放的 NO 在增加细胞内阿霉素积累和增敏 MCF-7/Adr 细胞对阿霉素方面发挥了重要作用，并且 7i 和 7j 中的 DDB 和 NO 供体部分的协同作用可能有助于逆转 MCF-7/Adr 细胞对阿霉素的 Pgp 介导的多药耐药性。
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