Models for potential dendritic nitric oxide donors: crystal structures of two 2-nitroanilino precursors and nitric oxide-release behavior of the nitrosated derivatives.

Two molecular precursors to dendrimeric materials that could serve as slow and sustained NO-releasing therapeutic agents have been synthesized and characterized. N1,N4-Bis(2-nitrophenyl)butane-1,4-diamine, C16H18N4O4, (I), crystallizes in a lattice with equal populations of two molecules of different conformations, both of which possess inversion symmetry through the central C-C bond. One molecule has exclusively anti conformations along the butyl chain, while the other has a gauche conformation of the substituents on the first C-C bond. N2,N2-Bis[2-(2-nitroanilino)ethyl]-N1-(2-nitrophenyl)ethane-1,2-diamine, C24H27N7O6, (II), crystallizes with one unique molecule in the asymmetric unit. Neighboring pairs of molecules are linked into dimers via N-H...O amine-nitro hydrogen bonds. The dimers are assembled into layers that stack in an A-B-A-B sequence such that the repeat distance in the stacking direction is over 46 Å. Molecular NO-release agents N1,N4-bis(2-nitrophenyl)-N1,N4-dinitrosobutane-1,4-diamine, C16H16N6O6, (III), and N1-(2-nitrophenyl)-N2,N2-bis{2-[(2-nitrophenyl)(nitroso)amino]ethyl}-N1-nitrosoethane-1,2-diamine, C24H24N10O9, (IV), were prepared via treatment of (I) and (II), respectively, with NaNO2 and acetic acid. The release of NO from solid-phase samples of (III) and (IV) suspended in phosphate buffer was monitored spectroscopically over a period of 21 days. Although (IV) released a greater amount of NO, as expected due to it having three NO moieties for every two in (III), the (IV):(III) ratio of the rate and extent of NO release was significantly less than 1.5:1, suggesting that some combination of electronic, chemical, and/or steric factors may be affecting the release process.

Dichotomous effects of isomeric secondary amines containing an aromatic nitrile and nitro group on human aortic smooth muscle cells via inhibition of cystathionine-γ-lyase.

Excessive proliferation of vascular smooth muscle cells (SMC) is an important contributor to the progression of atherosclerosis. Inhibition of proliferation can be achieved by endogenously produced and exogenously supplied nitrogen monoxide, commonly known as nitric oxide (NO). We report herein the dichotomous effects of two isomeric families of secondary amines, precursors to the N-nitrosated NO-donors, on HASMC proliferation. The syntheses of these two families were carried out using two equivalents of homologous, aliphatic monoamines and 2,6-difluoro-3-nitrobenzonitrile (2,6-DFNBN, O family) or 2,4-difluoro-5-nitrobenzonitrile (2,4-DFNBN, P family). The secondary amines belonging to the P family inhibited HASMC proliferation at all concentrations, whereas the O family induced HASMC proliferation at low concentrations, and exhibited inhibitory properties at high concentrations. A probable explanation of these behaviors is proposed herein. l-homocysteine (HCY) is known to induce HASMC proliferation at low concentrations (<1 mM) and inhibit HASMC proliferation at higher concentrations (>2.5 mM). Our findings suggest that these two families of amines inhibit cystathionine-γ-lyase (CSE) to varying extents, which directly results in altered levels of intracellular HCY and consequent changes in HASMC proliferation.

Two N-(2-phenylethyl)nitroaniline derivatives as precursors for slow and sustained nitric oxide release agents.

Notwithstanding its simple structure, the chemistry of nitric oxide (NO) is complex. As a radical, NO is highly reactive. NO also has profound effects on the cardiovascular system. In order to regulate NO levels, direct therapeutic interventions include the development of numerous NO donors. Most of these donors release NO in a single high-concentration burst, which is deleterious. N-Nitrosated secondary amines release NO in a slow, sustained, and rate-tunable manner. Two new precursors to sustained NO-releasing materials have been characterized. N-[2-(3,4-Dimethoxyphenyl)ethyl]-2,4-dinitroaniline, C16H17N3O6, (I), crystallizes with one independent molecule in the asymmetric unit. The adjacent amine and nitro groups form an intramolecular N-H...O hydrogen bond. The anti conformation about the phenylethyl-to-aniline C-N bond leads to the planes of the arene and aniline rings being approximately perpendicular. Molecules are linked into dimers by weak intermolecular N-H...O hydrogen bonds such that each amine H atom participates in a three-center interaction with two nitro O atoms. The dimers pack so that the arene rings of adjacent molecules are not parallel and π-π interactions do not appear to be favored. N-(4-Methylsulfonyl-2-nitrophenyl)-L-phenylalanine, C16H16N2O6S, (II), with an optically active center, also crystallizes with one unique molecule in the asymmetric unit. The L enantiomer was established via the configuration of the starting material and was confirmed by refinement of the Flack parameter. As in (I), there is an intramolecular N-H...O hydrogen bond between adjacent amine and nitro groups. The conformation of the molecule is such that the arene rings display a dihedral angle of ca 60°. Unlike (I), molecules are not linked via intermolecular N-H...O hydrogen bonds. Rather, the carboxylic acid H atom forms a classic, approximately linear, O-H...O hydrogen bond with a sulfone O atom. Pairs of molecules related by twofold rotation axes are linked into dimers by two such interactions. The packing pattern features a zigzag arrangement of the arene rings without apparent π-π interactions. These structures are compared with reported analogues, revealing significant differences in molecular conformation, intermolecular interactions, and packing that result from modest changes in functional groups. The structures are discussed in terms of potential NO-release capability.

The Thermal Instability of 2,4 and 2,6-N-Alkylamino Disubstituted and 2-N-Alkylamino Substituted Nitrobenzenes in Weakly Alkaline Solution: sec-Amino Effect.

We report herein the preparation of two families of secondary amines by the reactions of two equivalents of monoamines with either 2,4 or 2,6-difluoronitrobenzenes in N,N-dimethylacetamide in the presence of anhydrous potassium carbonate, as precursors of biologically important nitric oxide donating N-nitrosamines. In both instances, these compounds could be prepared in quantitative yield when the reaction temperature was held below 130°C. Above this reaction temperature, an unexpected cyclization reaction between the nitro and newly formed adjacent secondary amine group leads to the formation of benzimidazole or quinoxaline rings in low yields. Reasonable reaction mechanisms for the cyclization reaction are proposed.