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.

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.

A group of photochemical nitric oxide (NO) delivery agents, O2-(4-hydroxyphenacyl) diazeniumdiolates 1–2 as well as O2-(3-(benzothiazole-2-yl)-4-hydroxyphenacyl) diazeniumdiolates 3–4, could be triggered by ultraviolet light (365–400 nm) and visible light (≥410 nm), respectively, to produce NO in cancer cells and generate potent antitumor activity. Importantly, with the photolysis of 3 being initiated, the accompanying distinct fluorescence color change (from green to blue) may act as a qualitative real-time optical indicator for NO release in cancer cells.

Nitric oxide (NO) has recently joined the clinical arena of cancer therapy because high levels of NO could not only induce cytotoxicity and apoptosis of cancer cells, but also sensitize the cells to chemo- and radio-therapies. Diazeniumdiolates are an important class of NO donors, and the O2-alkylation, arylation and sulfonylation of diazeniumdiolates result in more stable and potent anticancer agents. However, O2-phosphorylation has so far not been reported yet. Herein, we describe the design, synthesis and biological evaluation of a group of phosphorodiamidate mustard-based O2-phosphorylated diazeniumdiolates, 6–9. The most active compound, 7, was comparable, or even more potent, than a known anticancer agent, O2-2,4-dinitrobenzene diazeniumdiolate JS-K, against six cancer cell lines. Furthermore, 7 released larger amounts of NO, caused more significant DNA damage and cancer cell apoptosis than JS-K in the cancer cells. Our findings suggest that this new type of O2-substituted diazeniumdiolate could be potentially applied in the fight against cancer.

Nitric oxide (NO) has recently joined the clinical arena of cancer therapy because high levels of NO could not only induce cytotoxicity and apoptosis of cancer cells, but also sensitize the cells to chemo- and radio-therapies. Diazeniumdiolates are an important class of NO donors, and the O2-alkylation, arylation and sulfonylation of diazeniumdiolates result in more stable and potent anticancer agents. However, O2-phosphorylation has so far not been reported yet. Herein, we describe the design, synthesis and biological evaluation of a group of phosphorodiamidate mustard-based O2-phosphorylated diazeniumdiolates, 6–9. The most active compound, 7, was comparable, or even more potent, than a known anticancer agent, O2-2,4-dinitrobenzene diazeniumdiolate JS-K, against six cancer cell lines. Furthermore, 7 released larger amounts of NO, caused more significant DNA damage and cancer cell apoptosis than JS-K in the cancer cells. Our findings suggest that this new type of O2-substituted diazeniumdiolate could be potentially applied in the fight against cancer.

Nitric oxide (NO) has recently joined the clinical arena of cancer therapy because high levels of NO could not only induce cytotoxicity and apoptosis of cancer cells, but also sensitize the cells to chemo- and radio-therapies. Diazeniumdiolates are an important class of NO donors, and the O2-alkylation, arylation and sulfonylation of diazeniumdiolates result in more stable and potent anticancer agents. However, O2-phosphorylation has so far not been reported yet. Herein, we describe the design, synthesis and biological evaluation of a group of phosphorodiamidate mustard-based O2-phosphorylated diazeniumdiolates, 6–9. The most active compound, 7, was comparable, or even more potent, than a known anticancer agent, O2-2,4-dinitrobenzene diazeniumdiolate JS-K, against six cancer cell lines. Furthermore, 7 released larger amounts of NO, caused more significant DNA damage and cancer cell apoptosis than JS-K in the cancer cells. Our findings suggest that this new type of O2-substituted diazeniumdiolate could be potentially applied in the fight against cancer.

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.

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.

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.