V-PROLI/NO, a prodrug of the nitric oxide donor, PROLI/NO

The sensitivity to decomposition of the nitric oxide (NO) donor ion, 1-[2-(carboxylato)pyrrolidin-1-yl]diazen-1-ium-1,2-diolate (PROLI/NO), complicates direct electrophilic substitution to form useful prodrug derivatives. A modified general synthetic approach involving 1-[2-(hydroxymethyl)pyrrolidin-1-yl]diazen-1-ium-1,2-diolate ion (structure A, above) was used to prepare several PROLI/NO prodrugs including the previously inaccessible O2-vinyl derivative, V-PROLI/NO. Metabolism of V-PROLI/NO by liver microsomes enriched in human cytochrome P450 isoforms was demonstrated.     

An improved synthesis of V-PROLI/NO, a cytochrome P450-activated nitric oxide prodrug

An improved synthesis of V-PROLI/NO, a cytochrome P450-activated nitric oxide (NO) prodrug, in an overall yield of 26% in four steps from prolinol is reported; the previously published yield of this transformation was 1%. Using this revised strategy, the sarcosine analogue (14) of V-PROLI/NO was prepared. Finally, the methyl ester of V-PROLI/NO (15) was found to be an esterase-activated prodrug form of V-PROLI/NO.     

l-Arginine and nitric oxide synthesis in the cells with inducible NO synthase

Russian Chemical Bulletin - The effect of citrulline and ammonium chloride on the nitric oxide formation by peritoneal macrophages and liver tissue cells was studied using ESR spectroscopy. In ex...     

Bis(4-nitrobenzenethiolato)tetranitrosyldiiron: synthesis,structure, and pharmacological activity of a new nitric oxide (NO) donor

Russian Chemical Bulletin - A preparative procedure was developed for the synthesis of new binuclear tetranitrosyl iron complex of the “μ-S” structural type, [Fe2(SC6H4NO2)2(NO)4]...     

Design and synthesis of C5 methylated L-arginine analogues as active site probes for nitric oxide synthase

The role of nitric oxide (NO) as a biological signaling molecule is well established. NO is produced by the nitric oxide synthases (NOSs, EC 1.14.13.39), a class of heme proteins capable of converting l-arginine to NO and l-citrulline. Despite the large body of knowledge associated with the NOSs, mechanistic details relating to the unique oxidative chemistry performed by these enzymes remain to be fully elucidated. Furthermore, a number of disease states are associated with either the over- or underproduction of NO, making the NOS pathway an attractive target for the development of therapeutics. For these reasons, molecular tools capable of providing mechanistic insights into the production of NO and/or the inhibition of the NOSs remain of interest. We report here the stereospecific synthesis and testing of a number of new l-arginine analogues bearing a minimal substitution, methylation at position 5 of the amino acid side chain (such analogues have not been previously reported). The synthetic approach employed a modified photolysis procedure whereby irradiation of the appropriate diacylperoxide precursors at 254 nm gave access to the required unnatural amino acids in good yields. A heme domain construct of the inducible NOS isoform (iNOSheme) was used to assess the binding of each compound to the enzyme active site. The compounds were also investigated as either inhibitors of, or alternate substrates for, the inducible NOS isoform. The results obtained provide new insight into the steric and stereochemical tolerance of the enzyme active site. These findings also further support the role of a conserved active site water molecule previously proposed to be necessary for NOS catalysis.     

First synthesis and in vitro biological assessment of isosideroxylin, 6, 8-dimethylgenistein and their analogues as nitric oxide production inhibition agents

A modular and efficient synthesis of the biologically significant C-methylisoflavones isosideroxylin(1),6,8-dimethylgenistein(2) and their analogues(3-8) is established for the first time.The synthesis is realized in 7-8 steps in overall yields of 16%-24%from commercially inexpensive phloroglucinol and features a high yielding Vilsmeier-Haack reaction,Friedel-Crafts acylation,Gammill's protocol and Suzuki coupling as the pivotal transformations.Next,these compounds evaluated for their inhibitory potency on the production of nitric oxide(NO) in lipopolysaccharide(LPS)-activated RAW-264.7 cells as an indicator of anti-inflammatory activity.The results showed that all the compounds decreased NO production in a dose-dependent manner without marked cytotoxicity and IC_(50) values are found in the range of 10.17-33.88 μmol/L.Of note,compounds 3 followed by 1,7 and 8 show comparable inhibitory activity with positive control(N-monomethyl-L-arginine,L-NMMA).     

Suppression of inducible nitric oxide synthase expression by yakuchinones and their analogues

Analogues of yakuchinones were synthesized as inhibitors of nitric oxide production in lipopolysaccharide-activated macrophage cell line, RAW 264.7 cells. We prepared stronger inhibitors than the original natural molecules, yakuchinones A and B reported from Alpinia oxyphylla. From the limited structural activity relation study of analogues, we concluded that the optimal length of linker between two aryl groups and the presence of enone moiety in the linker were identified as essential for the activity. The IC50 value of the most potent structure was 0.92 microM. The active analogues suppressed the expression of inducible nitric oxide synthase protein and mRNA.     

A scalable synthesis of 1-amino-5-cyanonaphthalene,a precursor for a nitric oxide probe(NO550) designed via the dye assembly principle

A convenient and scalable synthesis of l-amino-5-cyanonaphthalene was described.     

Improved results for the excited states of nitric oxide, including the B/C avoided crossing

The potential energy surfaces of ten electronic states of nitric oxide (NO) have been reexamined computationally, with state energies calculated using ab initio multireference methods. Our wave function expansions of 10x10(6) configurations improve upon the results of de Vivie and Peyerimhoff [J. Chem. Phys. 89, 3028 (1988)], who obtained excellent results from expansions of 16 000 configurations in 1988. We present results for the adiabatic properties r(e), B(e), T(e), and omega(e), demonstrating standard errors of 0.012 A, 0.026 cm(-1), 620 cm(-1), and 41 cm(-1), respectively. Vertical excitation energies and oscillator strengths are also presented, as are potential energy surface curves, with special attention to the B/C avoided crossing. The technical issue of state-averaging effects is also discussed.     

新族亚硝基硫醇分子的设计合成及NO释放稳定性研究

设计合成了一系列新型亚硝基硫醇类NO供体化合物,通过红外光谱、核磁共振氢谱、碳谱和质谱对化合物进行结构表征.考察了铜离子、光和p H值对化合物稳定性的影响,通过紫外-可见分光光度法对亚硝基硫醇官能团特征波长处的吸光度进行测定,以监测新型亚硝基硫醇化合物释放NO的快慢,实验数据反映出亚硝基硫醇分子结构与其稳定性存在一定规律.     

Incarvilleatone, a new cyclohexylethanoid dimer from Incarvillea younghusbandii and its inhibition against nitric oxide (NO) release

Incarvilleatone (1), an unprecedented dimeric cyclohexylethanoid analog with a racemic nature, was isolated from the whole plant of Incarvillea younghusbandii. HPLC chiral separation of 1 gave two enantiomers (-)-incarvilleatone and (+)-incarvilleatone. The structure of 1 was established by spectroscopic methods and single crystal X-ray diffraction. The absolute configurations of enantiomers were determined by quantum mechanical calculation. (-)-Incarvilleatone exhibited a potent inhibitory effect against NO production in LPS-induced RAW264.7 macrophages.     

Design, synthesis and characterization of a novel fluorescent probe for nitric oxide based on difluoroboradiaza-s-indacene fluorophore

Nitric oxide (NO) is a gaseous, free radical, which plays a role as an intracellular second messenger and a diffusible intercellular messenger. To obtain evidence for NO function in vivo, 1,3,5,7-tetramethyl-8-(4'-aminophenyl-N-(2'-amino)-phenzyl)-difluoroboradiaza-s-indacene (TMAPABODIPY) was designed and synthesized as a fluorescent probe for nitric oxide, which features high photostability and no pH dependency over a wide pH range. The fluorescence of TMAPABODIPY itself is very strong. When TMAPABODIPY traps NO in the presence of dioxygen, the weak fluorescent triazole form is obtained, which offers the advantages of specificity, and sensitivity for direct detection of NO. The relationship was obtained between the quenching fluorescence intensity and NO concentration in the range 0.02-4.0 micromol l(-1). The detection limit is 5 nmol l(-1) (S/N = 3). The proposed method has been used to monitor the release of NO from S-nitrosocysteine, a NO-releasing agent.     

An efficient synthesis of a potent anti-inflammatory agent, viscolin, and its inducible nitric oxide synthase inhibitory activity

A new and efficient synthetic pathway employed the aldol condensation between the acetophenone (3) and vanillin derivative (4) resulted in the precursor chalcone intermediate (14). The target compound viscolin (1) could be afforded through the hydrogenation of the chalcone and followed by deprotection. The present strategy described the development of a more efficient procedure that allowed large-scale production of viscolin for the further research of biological activity both in vitro and in vivo.     

Neoorthosiphonone A; a nitric oxide (NO) inhibitory diterpene with new carbon skeleton from Orthosiphon stamineus

From the aerial part of Orthosiphon stamineus from Hainan island of China, a diterpene named neoorthosiphonone A (1), having a novel carbon framework, has been isolated. Neoorthosiphonone A (1) possessed a unique unprecedented structural feature of eight-membered ring C in its structure, which may be biogenetically derived from its isopimarane precursor, orthosiphonone A, through the insertion of vinyl group into the C₁₃-C₁₄ bond. Neoorthosiphonone A (1) displayed potent inhibitory activity on the nitric oxide production in LPS-activated macrophage-like J774.1 cells with an IC₅₀ value of 7.08 μM, more potent than the positive control l-NMMA.     

Synthesis, inhibitory effects on nitric oxide and structure-activity relationships of a glycosphingolipid from the marine sponge Aplysinella rhax and its analogues

The novel glycosphingolipid, β-D-GalNAcp(1-->4)[α-D-Fucp(1-->3)]-β-D-GlcNAcp(1-->)Cer (A), isolated from the marine sponge Aplysinella rhax has a unique structure, with D-fucose and N-acetyl-D-galactosamine moieties attached to a reducing-end N-acetyl-D-glucosamine through an α1-->3 and β1-->4 linkage, respectively. We synthesized glycolipid 1 and some non-natural di- and trisaccharide analogues 2-6 containing a D-fucose residue. Among these compounds, the natural type showed the most potent nitric oxide (NO) production inhibitory activity against LPS-induced J774.1 cells. Our results indicate that both the presence of a D-Fucα1-3GlcNAc-linkage and the ceramide aglycon portion are crucial for optimal NO inhibition.     

First synthesis of P-aryl-phosphinosugars, organophosphorus analogues of C-arylglycosides

The synthesis and X-ray crystal structure of the first example of arylphosphinosugar are reported. The protected polyhydroxylated 1,2-oxaphosphinane is prepared by a two steps sequence (phenylphosphinate addition on protected mannofuranose followed by intramolecular transesterification) on gram scale. Deprotection of the di-isopropylidene derivative using acidic cation-exchange resin affords the free hydroxy organophosphorus heterocycle analogous to C-arylglycosides.     

Cobalt chemistry with mixed aminotroponiminate salicylaldiminate ligands: synthesis, characterization, and nitric oxide reactivity

A new class of mixed aminotroponimine salicylaldimine ligands and their corresponding cobalt(II) complexes are reported. This work expands the family of cobalt(II) aminotroponiminato complexes to include salicylaldiminate and derivatized fluorescein moieties. The H2iPrSATI-n (n = 3, 4) ligands 3 and 4, respectively, contain an aminotroponimine moiety and a salicylaldimine fragment connected with an alkyl linker. In the H2iPrFATI-n (n = 3, 4) ligands 5 and 6, a derivatized fluorescein replaces the salicylaldimine fragment. The cobalt(II) complexes [Co(iPrSATI-3)] (7) and [Co2(iPrSATI-4)(2)] (9) were prepared and structurally characterized. The reaction of NO with both complexes ultimately results in the formation of a dinitrogen-containing species. The mononitrosyl, [Co(iPrSATI-3)(NO)] (8), was isolated and characterized. The reactivity of [Co(iPrFATI-3)] (10) and [Co(iPrFATI-4)] (11) with NO mimics that observed for the salicylaldimine derivatives, as monitored by solution IR spectroscopy. When followed by fluorescence spectroscopy, reaction of 11 with NO evoked a 3-fold increase in emission intensity after 22 h.     

Synthesis and characterization of a multiarm poly(acrylic acid) star polymer for application in sustained delivery of cisplatin and a nitric oxide prodrug

Functionalized polymeric nanocarriers have been recognized as drug delivery platforms for delivering therapeutic concentrations of chemotherapies. Of this category, star‐shaped multiarm polymers are emerging candidates for targeted delivery of anticancer drugs, due to their compact structure, narrow size distribution, large surface area, and high water solubility. In this study, we synthesized a multiarm poly(acrylic acid) star polymer via macromolecular design via the interchange (MADIX)/reversible addition fragmentation chain transfer (MADIX/RAFT) polymerization and characterized it using nuclear magnetic resonance (NMR) and size exclusion chromatography. The poly(acrylic acid) star polymer demonstrated excellent water solubility and extremely low viscosity, making it highly suited for targeted drug delivery. Subsequently, we selected a hydrophilic drug, cisplatin, and a hydrophobic nitric oxide (NO)‐donating prodrug, O²‐(2,4‐dinitrophenyl) 1‐[4‐(2‐hydroxy)ethyl]‐3‐methylpiperazin‐1‐yl]diazen‐1‐ium‐1,2‐diolate, as two model compounds to evaluate the feasibility of using poly(acrylic acid) star polymers for the delivery of chemotherapeutics. After synthesizing and characterizing two poly(acrylic acid) star polymer‐based nanoconjugates, poly(acrylic acid)–cisplatin (acid–Pt) and poly(acrylic acid–NO (acid–NO) prodrug, the in vitro drug release kinetics of both the acid–Pt and the acid–NO were determined at physiological conditions. In summary, we have designed and evaluated a polymeric nanocarrier for sustained‐delivery of chemotherapies, either as a single treatment or a combination therapy regimen. © 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2012