Novel primary amine diazeniumdiolates—Chemical and biological characterization

Abstract

Hit, Lead & Candidate Discovery Diazeniumdiolates, also known as NONOates, are extensively used in biochemical, physiological, and pharmacological studies due to their ability to release nitric oxide (NO ) and/or their congeneric nitroxyl (HNO). The purpose of this work was to synthesize a series of primary amine-based diazeniumdiolates as HNO/NO donors and to determine their efficacy as anticancer and antifungal agents in vivo. The seven compounds (3a-3g) were successfully synthesized and characterized, one of which had been previously reported in the literature (3g). Two compounds showed anti-proliferative effects against ovarian (ES2 and SKOV3) and AML monocyte-derived cancer cells (THP-1) when tested with standard MTT assays. Compounds 3a and 3g demonstrated reduced ovarian cancer cell proliferation when treated at doses from 0.033 to 1.0 mg/mL at the 24 hr time point. These compounds also exhibited moderate and selective antifungal activity against Fusarium oxysporum f.sp. lycopersici, one cause of opportunistic infections of immunocompromised patients, inhibiting the growth of the fungi at LD at 10 mg/mL. A third compound (3e) did not exhibit similar activities, possibly due to the alkyl chain. Our results suggest that the primary amine diazeniumdiolates may offer a versatile platform for the development of HNO/NO donors for biomedical applications.

Antimicrobial Nitric Oxide Releasing Contact Lens Gels for the Treatment of Microbial Keratitis

“…The majority of research on diazeniumdiolates as NO donors focuses on their formation on secondary amines due to their superior stability and more sustained NO release properties compared to their primary amine and amide counterparts. In this study, diazeniumdiolates were formed on primary amines or amides within the pεK backbone as indicated in Figure . − Although there is a paucity of studies on the formation of diazeniumdiolates on primary amine and amide groups, Saavedra and Schoenfisch have both demonstrated that these can form and that stability can be enhanced by the presence of neighboring amine groups that allow alternative sites for protonation. , The increased stability afforded by neighboring amines was also observed in a study by Taite and West where poly­(ethylene glycol)-lysine dendrimers were functionalized with diazeniumdiolate in view of creating therapeutics for the prevention of arterial disease. These functionalized dendrimers were shown to release NO for over 60 days under physiological conditions .…”

Nitroxyl as a Potential Theranostic in the Cancer Arena

“…MTT assay results have demonstrated that both HNO/NO donor, diazeniumdiolate, exert antiproliferative effects on ovarian cancer cells and acute myeloid leukemia monocytederived cancer cells (116). As discussed above, L-NNP is a stable HNO radical, and L-NNP triggers oxidative stressdependent cell apoptosis in HepG2 liver cancer cells (59).…”

Progress and Prospects of Regulatory Functions Mediated by Nitric Oxide on Immunity and Immunotherapy

“…One mole of N ‐diazeniumdiolates can spontaneously release two moles of NO under physiological conditions. [ 85 ] The biological half‐life of these compounds can be adjusted by the modification of substituents (several minutes to tens of hours), and N ‐diazeniumdiolates bound with specific groups can release quantitative NO at target sites. [ 86 ] Therefore, N ‐diazeniumdiolates are particularly suitable for conjugating specific vectors to prepare the targeted release of NO donor drugs.…”

“…[ 111] Nitroglycerin 3 min [ 112] Isosorbide dinitrate 29 min [ 113] 5-isosorbide mononitrate 7.6 h [ 113] Pentaerythritol tetranitrate 8 h [ 114] Nicorandil 0.7-1.2 h [ 115] Latanoprostene bunod 1.8 h in cornea (rabbit) [ 116] N-diazeniumdiolates Per mole of NONOate spontaneously releases two moles of NO under physiological conditions (GSH or GST), and the release rate is accelerated with the decrease of pH. [85] JS-K 2.8 min [ 117] DETA/NONOate 20 h [ 118] Furoxans Furoxans are attacked by free sulfhydryl or sulfhydryl anion at positions 3 or 4 of the furoxan ring, and then dearomatization occurs to release NO. [90] Furoxans-1 N/A M-NO complex The release of NO in M-NO complex depends on specific enzymes, temperature, pH value, or light, but most of them are not specific.…”