Synthesis and evaluation of nitric oxide-releasing DDB derivatives as potential Pgp-mediated MDR reversal agents in MCF-7/Adr cells

Xiaobo Tang; Xiaoke Gu; Hua Ai; Guangji Wang; Hui Peng; Yisheng Lai; Yihua Zhang

doi:10.1016/j.bmcl.2011.12.065

Synthesis and evaluation of nitric oxide-releasing DDB derivatives as potential Pgp-mediated MDR reversal agents in MCF-7/Adr cells

Bioorg Med Chem Lett. 2012 Jan 15;22(2):801-5. doi: 10.1016/j.bmcl.2011.12.065. Epub 2011 Dec 17.

Authors

Xiaobo Tang¹, Xiaoke Gu, Hua Ai, Guangji Wang, Hui Peng, Yisheng Lai, Yihua Zhang

Affiliation

¹ State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, PR China; Center of Drug Discovery, China Pharmaceutical University, Nanjing 210009, PR China.

PMID: 22209486
DOI: 10.1016/j.bmcl.2011.12.065

Abstract

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.

Publication types

Evaluation Study
Research Support, Non-U.S. Gov't

MeSH terms

ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Biphenyl Compounds / chemical synthesis
Biphenyl Compounds / chemistry
Biphenyl Compounds / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Dicarboxylic Acids / chemical synthesis
Dicarboxylic Acids / chemistry
Dicarboxylic Acids / pharmacology*
Doxorubicin / chemistry
Doxorubicin / pharmacology
Drug Resistance, Multiple / drug effects*
Drug Resistance, Neoplasm / drug effects*
Drug Screening Assays, Antitumor
Humans
Molecular Structure
Nitric Oxide / chemistry*

Substances

ATP Binding Cassette Transporter, Subfamily B, Member 1
Antineoplastic Agents
Biphenyl Compounds
Dicarboxylic Acids
dimethyl-4,4'-dimethoxy-5,6,5',6'-dimethylene dioxybiphenyl-2,2'-dicarboxylate
Nitric Oxide
Doxorubicin