ABSTRACT
Correction for 'O2-(6-Oxocyclohex-1-en-1-yl)methyl diazen-1-ium-1,2-diolates: a new class of nitric oxide donors activatable by GSH/GSTπ with both anti-proliferative and anti-metastatic activities against melanoma' by Chengfeng Bai et al., Chem. Commun., 2017, 53, 5059-5062.
ABSTRACT
The new nitric oxide (NO) donor O2-(6-oxocyclohex-1-en-1-yl)methyl diazen-1-ium-1,2-diolate 3c could simultaneously liberate NO as well as an active 3-glutathionyl-2-exomethylene-cyclohexanone 2 in the presence of GSH/GSTπ; exhibit potent antiproliferative activity; repress migration, invasion, and lateral migration of metastatic B16-BL6 cells; and significantly decrease hetero-adhesion of B16-BL6 cells to human umbilical vein endothelial cells.
Subject(s)
Antineoplastic Agents/pharmacology , Aza Compounds/chemistry , Cyclohexenes/pharmacology , Glutathione Transferase/metabolism , Glycoside Hydrolases/metabolism , Human Umbilical Vein Endothelial Cells/drug effects , Melanoma/drug therapy , Melanoma/pathology , Neoplasm Metastasis/drug therapy , Nitric Oxide/metabolism , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/metabolism , Cell Line , Cell Proliferation/drug effects , Cyclohexenes/chemistry , Cyclohexenes/metabolism , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Mice , Microscopy, Fluorescence , Molecular Structure , NAD(P)H Dehydrogenase (Quinone)/metabolism , Neoplasm Metastasis/pathology , Structure-Activity RelationshipABSTRACT
Multidrug resistance is a major obstacle to successful chemotherapy for leukemia. In this study, a series of nitric oxide (NO)-releasing bifendate derivatives (7a-n) were synthesized. Biological evaluation indicated that the most active compound (7a) produced relatively high levels of NO and significantly inhibited the proliferation of drug-resistant K562/A02 cells in vitro and in vivo. In addition, 7a induced the mitochondrial tyrosine nitration and the intracellular accumulation of rhodamine 123 by inhibiting P-gp activity in K562/A02 cells. Furthermore, 7a remarkably down-regulated AKT, NF-κB, and ERK activation and HIF-1α expression in K562/A02 cells, which are associated with the tumor cell proliferation and drug resistance. Notably, the antitumor effects were dramatically attenuated by an NO scavenger or elimination of the NO-releasing capability of 7a, indicating that NO produced by 7a contributed to, at least partly, its cytotoxicity against drug-resistant K562/A02 cells. Overall, 7a may be a potential agent against drug-resistant myelogenous leukemia.
Subject(s)
Biphenyl Compounds/pharmacology , Nitric Oxide/metabolism , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Animals , Cell Proliferation , Drug Resistance, Neoplasm , Heterografts , Humans , In Vitro Techniques , K562 Cells , Mice , Mice, NudeABSTRACT
A novel class of O2-(2,4-dinitrophenyl)-1-[N,N-bis(2-substituted ethyl)amino]diazen-1-ium-1,2-diolates 4-6 were designed, synthesized, and biologically evaluated. The most active compound 6 caused significant DNA damage by releasing N,N-bis(2-TsO ethyl)amine and two molecules of nitric oxide (NO) after activation by GST/GSH in cancer cells, being more cytotoxic against three cancer cell lines than a well-known diazeniumdiolate-based anticancer agent JS-K, suggesting that the strategy has potential to extend to other O2-derived diazeniumdiolates to improve anticancer activity.
