ABSTRACT
High levels of both nitric oxide (NO) and reactive oxygen species (ROS) could act as pro-apoptotic signals in cancerous cells. In this study, we conjugated diazeniumdiolates (NONOates), an important class of NO donors, with a natural occurring plumbagin (PL) which is primarily an excellent ROS inducer. Herein, a total of 12 novel plumbagin/NONOate hybrids have been synthesized and evaluated for their inhibitory effects on a panel of human cancer cell lines (MDA-MB-231, A549, HepG2 and HCT-116â¯cells) and two normal human cells (HK-2 and WRL-68â¯cells). Among them, compounds 10a and 10b demonstrated superior potencies compared to their parent compound (IC50 values of 3.48-6.68⯵M) against the above cancer cell lines but weak inhibitory effects on normal cells. In concordance with their selective cytotoxicities, 10a and 10b released higher level of NO in cancer cells than normal cells. Besides, the potent compound 10a induced apoptosis of A549â¯cells in a concentration-dependent manner and resulted in more ROS generation compared with the parent compound plumbagin.
Subject(s)
Antineoplastic Agents/pharmacology , Azo Compounds/pharmacology , Naphthoquinones/pharmacology , Reactive Oxygen Species/metabolism , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Azo Compounds/chemistry , Cell Line , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Molecular Structure , Naphthoquinones/chemistry , Structure-Activity RelationshipABSTRACT
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.
Subject(s)
Antineoplastic Agents/pharmacology , Azo Compounds/pharmacology , Drug Design , Drug Resistance, Multiple/drug effects , Drug Resistance, Neoplasm/drug effects , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Azo Compounds/chemical synthesis , Azo Compounds/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Molecular Docking Simulation , Molecular Structure , Nitric Oxide/metabolism , Structure-Activity RelationshipABSTRACT
Glutathione S-transferase(GSTπ), one of the phase II detoxification enzymes, is usually over- expressed in many human tumors. It displays a key role in protecting cells through catalyzing the conjugation of glutathione(GSH) with a broad range of electrophilic substrates including chemotherapeutic agents. As the above conjugates can be effluxed from cells easily, the efficacy of various chemotherapeutic agents is reduced. Recent studies suggest that GSTπ also plays an important role in inhibiting apoptosis through blocking the JNK signaling pathway. In this way, GSTπ protects cells from apoptosis. Therefore, GSTπ has become an attractive target against cancers, especially for drug-resistant tumors. A great deal of effort has been devoted to the discovery of GSTπ inhibitors and prodrugs over the last decade. In connection with authors' current research, we provide a review on studies on progress of GSTπ inhibitors and prodrugs along with the future strategies.
