Synthesis of N-arylpyridinium salts bearing a nitrone spin trap as potential mitochondria-targeted antioxidants

Abstract

The generation of excess reactive oxygen species (ROS) in mitochondria is responsible for much of the oxidative stress associated with ageing (aging), and mitochondrial dysfunction is part of the pathology of neurodegeneration and type 2 diabetes. Lipophilic pyridinium ions are known to accumulate in mitochondria and this paper describes a general route for the preparation of nitrone-containing N-arylpyridinium salts having a range of lipophilicities, as potential therapeutic antioxidants. The compatibility of nitrones with the Zincke reaction is the key to their synthesis. Their trapping of carbon-centred radicals and the EPR spectra of the resulting nitroxides are reported.

Synthesis of N-(Benzyloxyethyl)- and N-(Alkoxycarbonylmethyl)nitrones

“…Nitrones are used as versatile components in nucleophilic addition reactions with organometallic reagents 1 and in 1,3-dipolar cycloadditions 2 and they have potential for therapeutic applications as anti-inflammatory agents 3 and antioxidants 4 with application in age-related diseases, 5 cerebral ischemia, 6 and acute or progressive neurodegenerative disorders. 7 Typically, nitrones can be prepared by either condensation of a carbonyl compound and a hydroxylamine or by oxidation of the corresponding amine or hydroxylamine (Scheme 1).…”

Photochromic behavior of several new synthesized dyes via Zincke salts

“…Synthesis of N-arylpyridinium salts 5 requires a two-step procedure and is called a Zincke reaction. Several arylpyridinium salts bearing a nitrone spin trap as potential mitochondria-targeted antioxidants were recently reported by Hartley et al [27] We did not make any effort to prepare them in the study. A synthesis sequence for the preparation of 3 and 4 was not previously reported.…”

Triphenylphosphonium (TPP)‐Based Antioxidants: A New Perspective on Antioxidant Design

“…[27] MitoÀ BMPO and MitoÀ Spin have also been synthesized as radical trapping agents, but ability to capture free radicals in mitochondria remains to be tested. [28] Both TPP-modified Mito 10 DEPMPO and MitoDIPPMPO can efficiently trap superoxides and then form stable adducts. [29] In particular, the apparent half-life of the O 2 * À adducts was 22 minutes for Mito 10 DEPMPO and 73 minutes for MitoDIPPM-PO, indicating that Mito 10 DEPMPO and MitoDIPPMPO could be potential spin traps for mitochondrial superoxide.…”