Preparation and Investigation of Vitamin B₆‐Derived Aminopyridinol Antioxidants

Abstract

3-Pyridinols bearing amine substitution para to the hydroxylic moiety have previously been shown to inhibit lipid peroxidation more effectively than typical phenolic antioxidants, for example, α-tocopherol. We report here high-yielding, large-scale syntheses of mono- and bicyclic aminopyridinols from pyridoxine hydrochloride (i.e., vitamin B(6)). This approach provides straightforward, scaleable access to novel, potent, molecular scaffolds whose antioxidant properties have been investigated in homogeneous solutions and in liposomal vesicles. These molecular aggregates mimic cell membranes that are the targets of oxidative damage in vivo.

RETRACTED: BJ-1103, 6-aminopyridin-3-ol skeletal compound, modulates neuroprotective and anti-neuroinflammatory effects in murine hippocampal and microglial cells via Nrf2-mediated heme oxygenase-1 expression

“…BJ-1103, a lipophilic derivative of this series with C 16 -palmityl chain on the C(6)-nitrogen, showed greater radical scavenging activity and, more potent capacity for prevention of lipid peroxidation than ␣-tocopherol, the most effective natural lipophilic antioxidant, both in a model membrane system, 1-palmitoyl-2-linoleoyl-sn-glycero-3-phosphatidylcholine (PLPC) liposomes [12], and in plasma [13]. In this study, we examined whether BJ-1103-induced HO-1 expression can regulate neuroprotective and anti-inflammatory effects in HT22 and BV2 microglia cells.…”

“…The 6-aminopyridin-3-ol skeleton was first proposed as a key structure for the development of novel antioxidants with improved air-stability by the Porter group [11], and a highly practical synthetic method of 6-amino-2,4,5-trimethylpyridin-3-ols starting from pyridoxine·HCl, a major constituent of vitamin B 6 , was developed [12]. BJ-1103, a lipophilic derivative of this series with C 16 -palmityl chain on the C(6)-nitrogen, showed greater radical scavenging activity and, more potent capacity for prevention of lipid peroxidation than ␣-tocopherol, the most effective natural lipophilic antioxidant, both in a model membrane system, 1-palmitoyl-2-linoleoyl-sn-glycero-3-phosphatidylcholine (PLPC) liposomes [12], and in plasma [13].…”

Antioxidants in Chemistry and Biology

“…78,79 Alternatively, HPLC analysis can be performed on samples after reduction of the conjugated diene hydroperoxides to the corresponding alcohols with triphenylphosphine. 80 Several methods have been developed to monitor the formation of a variety of markers of lipid peroxidation. Malondialdehyde (MDA), a decomposition product of oxidized PUFAs, has been monitored upon reaction with thiobarbituric acid to form a colored adduct with strong absorbance at 532 nm.…”

“…Mechanistic studies support a H-atom transfer mechanism as for phenols (k H /k D ∼ 3), 64,106 a negative reaction constant for Hammett-type correlation with σ + , 107,165 HBA solvents slow kinetics, 64,106,166 and theoretical calculations yield transition states consistent with a role for PCET in this process. 92 This development has prompted the study of lipid-soluble analogs of pyridinol 65 (which has the best balance of reactivity to peroxyl radicals and stability in air, and most closely resembles α-TOH) under more physiologically relevant conditions, for 80 Since the peroxidation of membrane lipids has been implicated in virtually all degenerative diseases, the potential for these compounds to…”

“…Besides the tocopherol/ascorbate couple, recent examples of synergism in heterogeneous media include those in liposomes between α-TOH and water-soluble 3-pyridinols, 80 or in water/chlorobenzene biphasic system between several organochalcogen-substituted phenols or 3-pyridinols and N -acetylcysteine. 201 …”