Bioorganic & Medicinal Chemistry 2013-03-01

Secondary amines containing one aromatic nitro group: preparation, nitrosation, sustained nitric oxide release, and the synergistic effects of released nitric oxide and an arginase inhibitor on vascular smooth muscle cell proliferation.

Brandon Curtis, Thomas J Payne, David E Ash, Dillip K Mohanty

Index: Bioorg. Med. Chem. 21(5) , 1123-35, (2013)

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Abstract

Atherosclerosis, a leading cause of death worldwide, is associated with the excessive proliferation of vascular smooth muscle cells. Nitrogen monoxide, more commonly known as nitric oxide, inhibits this uncontrolled proliferation. Herein we report the preparation of two families of nitric oxide donors; beginning with the syntheses of secondary amine precursors, obtained through the reaction between 2 equiv of various monoamines with 2,4 or 2,6-difluoronitrobenzene. The purified secondary amines were nitrosated then subjected to a Griess reagent test to examine the slow and sustained nitric oxide release rate for each compound in both the absence and presence of reduced glutathione. The release rate profiles of these two isomeric families of NO-donors were strongly dependent on the number of side chain methylene units and the relative orientations of the nitro groups with respect to the N-nitroso moieties. The nitrosated compounds were then added to human aortic smooth muscle cell cultures, individually and in tandem with S-2-amino-6-boronic acid (ABH), a potent arginase inhibitor. Cell viability studies indicated a lack of toxicity of the amine precursors, in addition to anti-proliferative effects exhibited by the nitrosated compounds, which were enhanced in the presence of ABH.Copyright © 2013 Elsevier Ltd. All rights reserved.