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

ABSTRACT: 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.

SUBMITTER: Badour AR

PROVIDER: S-EPMC6128391 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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

Badour Alec R AR Arnett-Butscher Corey J CJ Mohanty Dillip K DK Squattrito Philip J PJ Lambright Kelly J KJ Kirschbaum Kristin K

Acta crystallographica. Section C, Structural chemistry 20180828 Pt 9

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 conformation ...[more]

PMID: 30191896

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Project description: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 ?-? 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 ?-? 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.

Project description:2,4-Dinitro-N-(2-phenylethyl)aniline, C14H13N3O4, (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 ethyl C-C bond leads to the phenyl and aniline rings being essentially parallel. Molecules are linked into dimers by intermolecular N-H...O hydrogen bonds, such that each amine H atom participates in a three-centre interaction with two nitro O atoms. Though the dimers pack so that the arene rings of adjacent molecules are parallel, the rings are staggered and π-π interactions do not appear to be favoured. 4,6-Dinitro-N,N'-bis(2-phenylethyl)benzene-1,3-diamine, C22H22N4O4, (II), differs from (I) in the presence of a second 2-phenylethylamine group on the substituted ring. Compound (II) also crystallizes with one unique molecule in the asymmetric unit. Both amine groups are involved in intramolecular N-H...O hydrogen bonds with adjacent nitro groups. Although one ethyl group adopts an anti conformation as in (I), the other is gauche, with the result that the pendant phenyl rings are not parallel. The amine group that is part of the gauche conformation participates in a three-centre N-H...O hydrogen bond with the nitro group of a neighbouring molecule, leading to dimers as in (I). The other amine H atom does not form any intermolecular hydrogen bonds. The packing leads to separations of ca 3.4 Å of the parallel anti phenyl and aminobenzene rings. 2-Cyano-4-nitro-N-(2-phenylethyl)aniline, C15H13N3O2, (III), differs from (I) only in having a cyano group in place of the 2-nitro group. The absence of the adjacent nitro group eliminates the intramolecular N-H...O hydrogen bond. Molecules of (III) adopt the same anti conformation about the ethyl group as in (I), but crystallize in the higher-symmetry monoclinic space group P21/n. The molecules are linked into dimers via N-H...N amine-cyano hydrogen bonds, while the nitro groups are not involved in any N-H...O interactions. Owing to the different symmetry, the molecules pack in a herringbone pattern with fewer face-to-face interactions between the rings. The closest such interactions are about 3.5 Å between rings that are largely slipped past one another. 4-Methylsulfonyl-2-nitro-N-(2-phenylethyl)aniline, C15H16N2O4S, (IV), differs from (I) in having a methylsulfonyl group in place of the 4-nitro group. The intramolecular N-H...O hydrogen bond is present as in (I). However, unlike (I), the conformation about the ethyl group is gauche, so the two arene rings are nearly perpendicular rather than parallel. The packing is significantly different from the other three structures in that there are no intermolecular hydrogen bonds involving the N-H groups. The molecules are arranged in tetragonal columns running along the c axis, with the aniline rings mostly parallel and separated by ca 3.7 Å. Taken together, these structures demonstrate that modest changes in functional groups cause significant differences in molecular conformation, intermolecular interactions and packing.

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

Publications

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

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