Synthesis of a Novel Radical Trapping and Carbonyl Group Trapping Anti-AGE Agent:  A Pyridoxamine Analogue for Inhibiting Advanced Glycation (AGE) and Lipoxidation (ALE) End Products

Culbertson, Sean M.; Enright, Gary D.; Ingold, K. U.

doi:10.1021/ol0348147

Cited by 26 publications

(24 citation statements)

References 26 publications

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“…On the basis of their structures, many of the AGE inhibitors tested are probably multifunctional but, nevertheless, they can still be classified as follows: 1) radical traps: 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (Trolox or Tx), dmaPM, and dmaPN (these three compounds have been shown to have comparable abilities to retard allophycocyanin fluorescence quenching induced by peroxyl radicals (59), and allophycocyanin fluorescence quenching was retarded by o-PD at a level intermediate between PN and Tx); 2) carbonyl traps: dmaPM, PM, AG, and o-phenylenediamine (o-PD); and 3) chelators: dmaPM, PM, and diPM (other potential weaker chelators are AG, o-PD, dmaPN and PN). The three compounds classified as radical-trapping antioxidants, Tx, dmaPM, and dmaPN, gave an astonishing increase in the yields of pentosidine in both ϩM buffer (3-6-fold) and ϪM buffer (4.5-7-fold), as shown in Fig.…”

Section: Unexpected Increase In Pentosidine Yields During Ribosementioning

confidence: 99%

“…Pratt et al (36) have shown that strong electron-donating groups (such as dimethylamino) para to the phenolic hydroxyl group of 3-pyridinols and 5-pyrimidinols decrease the O-H bond dissociation enthalpy and greatly increase radical trapping rates but do not lower the ionization potential to the point that there is a direct reaction with oxygen. Therefore, PM was modified by the addition of a 6-dimethylamino substituent (6-dimethylaminopyridoxamine, dmaPM) (59). A pyridoxine (PN) derivative (6-dimethylaminopyridoxine, dmaPN) was also tested to study the importance of the nucleophilic amine group during glycation reactions.…”

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confidence: 99%

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Paradoxical Impact of Antioxidants on Post-Amadori Glycoxidation

Culbertson

Vassilenko

Morrison

et al. 2003

Journal of Biological Chemistry

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The inhibition of post-Amadori advanced glycation end product (AGE) formation by three different classes of AGE inhibitors, carbonyl group traps, chelators, and radical-trapping antioxidants, challenge the current paradigms that: 1) AGE inhibitors will not increase the formation of any AGE product, 2) transition metal ions are required for oxidative formation of AGE, and 3) screening AGE inhibitors only in systems containing transition metal ions represents a valid estimate of potential in vivo mechanisms. This work also introduces a novel multifunctional AGE inhibitor, 6-dimethylaminopyridoxamine (dmaPM), designed to function as a combined carbonyl trap, metal ion chelator, and radicaltrapping antioxidant. Other AGE inhibitors including pyridoxamine, aminoguanidine, o-phenylenediamine, dipyridoxylamine, and diethylenetriaminepentaacetic acid were also examined. The results during uninterrupted and interrupted ribose glycations show: 1) an unexpected increase in the yield of pentosidine in the presence of radical-trapping phenolic antioxidants such as Trolox and dmaPM, 2) significant formation of N ⑀ -carboxymethyllysine (CML) in the presence of strong chelators and phenolic antioxidants, which implies that there must be nonradical routes to CML, 3) prevention of intermolecular cross-links with radical-trapping inhibitors, and 4) that dmaPM shows excellent inhibition of AGE. Glucose glycations reveal the expected inhibition of pentosidine and CML with all compounds tested, but in a buffer free of trace metal ions the yield of CML in the presence of radical-trapping antioxidants was between the metal ion-free and metal ion-containing controls. Protein molecular weight analyses support the conclusion that Amadori decomposition pathways are constrained in the presence of metal ion chelators and radical traps.Nonenzymatic protein glycation by reducing sugars, such as glucose or ribose, is a complicated cascade of condensations, rearrangements, fragmentations, and oxidative modifications that lead to a plethora of compounds collectively called advanced glycation end products (AGEs) 1 (1). AGE products slowly build up and contribute to the age-dependent chemical modification of long-lived tissue proteins. Once formed, AGE products may prevent normal protein function and recognition or stimulate potentially detrimental interactions in signaling pathways (2, 3). Glycation reactions are believed to have a significant role in the progression of diabetic complications largely because of elevated levels of glucose. Indeed, the formation of AGE has been increasingly implicated in pathogenesis of diabetic complications, atherosclerosis, and Alzheimer's disease (4 -6). Inhibitors that act to reduce AGE formation may prove useful for limiting nonenzymatic protein modification associated in the pathology of these and other chronic agerelated diseases. The reaction of amino compounds, such as lysine, with reducing sugars is known as the Maillard reaction (7, 8). The "classical" or Hodge pathway begins with reversible formation of...

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Section: Unexpected Increase In Pentosidine Yields During Ribosementioning

confidence: 99%

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confidence: 99%

Paradoxical Impact of Antioxidants on Post-Amadori Glycoxidation

Culbertson

Vassilenko

Morrison

et al. 2003

Journal of Biological Chemistry

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“…Pyridoxamine is one of the three natural forms of vitamin B6. To date, many independent in vitro and in vivo studies have shown that pyridoxamine strongly inhibits the production of AGEs (12,13). Reactive carbonyl compounds are the precursors of AGEs.…”

Section: Discussionmentioning

confidence: 99%

“…Studies have shown that pyridoxamine strongly inhibits the production of AGEs both in vitro and in vivo (12,13). Pyridoxamine is also a free radical scavenger.…”

Section: Introductionmentioning

confidence: 99%

Synergistic effects of telmisartan and pyridoxamine on early renal damage in spontaneously hypertensive rats

et al. 2011

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Abstract. The aim of this study was to investigate the protective effects of telmisartan and/or pyridoxamine on spontaneously hypertensive rats (SHRs). Rats were treated with telmisartan (T group) or pyridoxamine (P group), or telmisartan and pyridoxamine (TP group). The serum levels of advanced glycation end products (AGEs), superoxide dismutase (SOD), malonaldehyde and the level of 24-h urinary albumin were measured. Morphological changes in renal tissues were observed under light (H&E or Masson's trichrome) and transmission electron microscopy. Expression of NF-κBp65 and p-ERK1/2 in renal tissue was detected by immunohistochemistry. Expression of receptors for advanced glycation end products (RAGE) and TGF-β in the renal cortex was investigated by western blotting. We found that early renal structural and functional damage was alleviated in the three intervention groups. SOD activity was significantly elevated in the P and TP groups (P<0.05) compared to that in the T group. Of note, both the positive expression of NF-κBp65 (P<0.01 vs. the T and P groups) and p-ERK1/2 (P<0.05 vs. the P group) was lowest in the TP group. Our results suggest that the combined use of telmisartan and pyridoxamine is superior to the single use of either drug on renoprotection, which may result from the alleviation of oxidative stress and the reduction of NF-κBp65 and p-ERK1/2 activation.

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“…Drugs like metformin [112][113][114] and buformin [115] also showed the potential to protect proteins against in vitro glycation and cross-linking [116,117]. Furthermore, a series of compounds, such as calcium antagonists [118], amlodipine [119], kinetin [120], quinine [121], and synthetic 6-dimethylaminopyridoxamine [122], retarded or suppressed AGE formation possibly due to radical scavenging properties. In one study, the inhibitory activity of isoferulic acid (IFA) on fructose-and glucose-mediated protein glycation and the oxidation of bovine serum albumin (BSA) was investigated [123].…”

Section: Therapy For Age-mediated Neurodegenerative Diseases With Synmentioning

confidence: 99%

The role of advanced glycation end products in various types of neurodegenerative disease: a therapeutic approach

Salahuddin

Rabbani

Khan

2014

Cellular and Molecular Biology Letters

148

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of advanced glycation end products; ROS -reactive oxygen species; SNCA -synuclein alpha; sRAGE -soluble receptor of advanced glycation end products; TTR -transthyretin; TKtransketolase; TNF -tumor necrosis factor-α; TPP -thiamine pyrophosphate Review THE ROLE OF ADVANCED GLYCATION END PRODUCTS IN VARIOUS TYPES OF NEURODEGENERATIVE DISEASE:A THERAPEUTIC APPROACH Abstract: Protein glycation is initiated by a nucleophilic addition reaction between the free amino group from a protein, lipid or nucleic acid and the carbonyl group of a reducing sugar. This reaction forms a reversible Schiff base, which rearranges over a period of days to produce ketoamine or Amadori products. The Amadori products undergo dehydration and rearrangements and develop a cross-link between adjacent proteins, giving rise to protein aggregation or advanced glycation end products (AGEs). A number of studies Unauthenticated Download Date | 5/11/18 1:17 PM

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Synthesis of a Novel Radical Trapping and Carbonyl Group Trapping Anti-AGE Agent: A Pyridoxamine Analogue for Inhibiting Advanced Glycation (AGE) and Lipoxidation (ALE) End Products

Cited by 26 publications

References 26 publications

Paradoxical Impact of Antioxidants on Post-Amadori Glycoxidation

Paradoxical Impact of Antioxidants on Post-Amadori Glycoxidation

Synergistic effects of telmisartan and pyridoxamine on early renal damage in spontaneously hypertensive rats

The role of advanced glycation end products in various types of neurodegenerative disease: a therapeutic approach

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