O2-(2,4-dinitrophenyl)diazeniumdiolates derivatives: Design, synthesis, cytotoxic evaluation and reversing MDR in MCF-7/ADR cells

Qixing Li; Pian Zou; Jianbo Sun; Li Chen

doi:10.1016/j.ejmech.2017.11.081

O²-(2,4-dinitrophenyl)diazeniumdiolates derivatives: Design, synthesis, cytotoxic evaluation and reversing MDR in MCF-7/ADR cells

Eur J Med Chem. 2018 Jan 1:143:732-744. doi: 10.1016/j.ejmech.2017.11.081.

Authors

Qixing Li¹, Pian Zou¹, Jianbo Sun², Li Chen³

Affiliations

¹ Department of Natural Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China.
² Department of Natural Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China. Electronic address: sjbcpu@gmail.com.
³ Department of Natural Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China. Electronic address: chenli627@cpu.edu.cn.

PMID: 29220794
DOI: 10.1016/j.ejmech.2017.11.081

Abstract

A series of O²-(2,4-dinitrophenyl)diazeniumdiolates derivatives were designed, synthesized and antiproliferative activities evaluated as novel nitric oxide (NO)-releasing prodrugs that could be activated by glutathione S-transferases π (GSTπ). Most of these derivatives exhibited significant antiproliferative activities compared to the reported NO-donor prodrug JS-K, among which compounds 27 and 36 had superior potency with IC₅₀ below 1 μM. NO released amounts detection of all derivatives indicated that the antiproliferative activities were positively correlated with the levels of intracellular NO release in HCT116 cells. The most potent compound 36 exhibited improved uncatalyzed stability of GSTπ. Additionally, 36 showed remarkably multidrug resistance reversal activity which reversed multidrug resistance of adriamycin (ADR) in MCF-7/ADR cells with IC₅₀ from 84.94 μM to 1.13 μM.

Keywords: Adriamycin; Diazeniumdiolates; JS-K; Multidrug resistance; No-Releasing.

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Azo Compounds / chemical synthesis
Azo Compounds / chemistry
Azo Compounds / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Design*
Drug Resistance, Multiple / drug effects*
Drug Resistance, Neoplasm / drug effects*
Drug Screening Assays, Antitumor
Humans
Molecular Docking Simulation
Molecular Structure
Nitric Oxide / metabolism
Structure-Activity Relationship

Substances

Antineoplastic Agents
Azo Compounds
diazeniumdiolate
Nitric Oxide