Second generation 2-aminoimidazole based advanced glycation end product inhibitors and breakers

Furlani, Robert E.; Richardson, Mike A.; Podell, Brendan K.; Ackart, David F.; Haugen, Jessica D.; Melander, Roberta J.; Basaraba, Randall J.

doi:10.1016/j.bmcl.2015.06.080

Cited by 14 publications

(13 citation statements)

References 18 publications

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“…The 2,4,6-trinitrobenzene sulfonic acid (TNBSA) assay was performed to verify the effect of SFN on AGE breakdown, as described previously [ 26 ] with minor changes. Briefly, 1 mL of MGO-BSA was homogenized with either SFN or the positive control (AGD; 1 mM) and incubated for 24 h. At the following day, TNBSA (0.1 %) and NaHCO 3 (4 %) were added, and the mixture was incubated at 37 °C for 2 h. The reaction was stopped by adding 10% SDS and 1 N HCl.…”

Section: Methodsmentioning

confidence: 99%

Sulforaphane Inhibits MGO-AGE-Mediated Neuroinflammation by Suppressing NF-κB, MAPK, and AGE–RAGE Signaling Pathways in Microglial Cells

et al. 2020

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Advanced glycation end products (AGEs) are produced through the binding of glycated protein or lipid with sugar, and they are known to be involved in the pathogenesis of both age-dependent and independent neurological complications. Among dicarbonyl compounds, methylglyoxal (MGO), which is produced from glucose breakdown, is a key precursor of AGE formation and neurotoxicity. Several studies have shown the toxic effects of bovine serum albumin (BSA)-AGE (prepared with glucose, sucrose or fructose) both in in vitro and in vivo. In fact, MGO-derived AGEs (MGO-AGEs) are highly toxic to neurons and other cells of the central nervous system. Therefore, we aimed to investigate the role of MGO-AGEs in microglial activation, a key inflammatory event, or secondary brain damage in neuroinflammatory diseases. Interestingly, we found that sulforaphane (SFN) as a potential candidate to downregulate neuroinflammation induced by MGO-AGEs in BV2 microglial cells. SFN not only inhibited the formation of MGO-AGEs, but it did not show breaking activity on the MGO-mediated AGEs cross-links with protein, indicating that SFN could potentially trap MGO or inhibit toxic AGE damage. In addition, SFN significantly attenuated the production of neuroinflammatory mediators induced by MGO-AGEs in BV2 microglial cells. SFN also lowered the expression levels of AGE receptor (RAGE) in microglial cells, suggesting that SFN could downregulate MGO-AGE-mediated neurotoxicity at the receptor activation level. Altogether, our current study revealed that SFN might show neuropharmacological potential for downregulating MGO-AGEs-mediated neuronal complications thorough attenuating AGE formation and neuroinflammatory responses induced by MGO-AGEs in vitro.

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Section: Methodsmentioning

confidence: 99%

Sulforaphane Inhibits MGO-AGE-Mediated Neuroinflammation by Suppressing NF-κB, MAPK, and AGE–RAGE Signaling Pathways in Microglial Cells

et al. 2020

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“…Beginning with amino acid methyl esters 4 and 5, 2-AI analogs 6 and 7 were synthesized using a previously published procedure, which utilized standard Akabori reduction conditions followed by the condensation of cyanamide in a temperature-and pH-controlled environment (Scheme 1A). 18 The pH of the cyanamide condensation reaction was previously determined to be of importance by Lancini and Lazzari 19 to avoid the production of urea in highly acidic environments or undesired aminoketone formations in neutral or alkaline environments. For SAR purposes, 2-AI derivatives 10 and 13 were accessed using commercially available carboxylic acid 8 or acid chloride 11.…”

Section: Resultsmentioning

confidence: 99%

“…■ PREVIOUSLY REPORTED COMPOUNDS 18,40,41 4-(3-Aminopropyl)-1H-imidazol-2-amine (6). Compound 6 was prepared following a previously published protocol using the general procedure for the Akabori reduction and cyanamide cyclization to obtain compound 6 as a white solid in 41% yield.…”

Section: Acs Infectious Diseasesmentioning

confidence: 99%

Using Small-Molecule Adjuvants to Repurpose Azithromycin for Use against Pseudomonas aeruginosa

et al. 2018

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A major contributor to fatalities in cystic fibrosis (CF) patients stems from infection with opportunistic bacterium Pseudomonas aeruginosa. As a result of the CF patient's vulnerability to bacterial infections, one of the main treatment focuses is antibiotic therapy. However, the highly adaptive nature of P. aeruginosa, in addition to the intrinsic resistance to many antibiotics exhibited by most Gram-negative bacteria, means that multi-drug-resistant (MDR) strains are increasingly prevalent. This makes the eradication of pseudomonal lung infections nearly impossible once the infection becomes chronic. New methods to treat pseudomonal infections are greatly needed in order to eradicate MDR bacteria found within the respiratory tract, and ultimately better the quality of life for CF patients. Herein, we describe a novel approach to combatting pseudomonal infections through the use of bis-2-aminoimidazole adjuvants that can potentiate the activity of a macrolide antibiotic commonly prescribed to CF patients as an anti-inflammatory agent. Our lead bis-2-AI exhibits a 1024-fold reduction in the minimum inhibitory concentration of azithromycin in vitro and displays activity in a Galleria mellonella model of infection.

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“…We performed the TNBSA (2,4,6-trinitrobenzene sulfonic acid) assay to evaluate the ability of the isosamidin to cause the breakdown of MGO-AGEs according to the method described by Furlani et al [ 30 ]. We mixed a 1 mg/mL sample of preformed MGO-AGEs solution with 100 µM and 400 μM of isosamidin.…”

Section: Methodsmentioning

confidence: 99%

Isosamidin from Peucedanum japonicum Roots Prevents Methylglyoxal-Induced Glucotoxicity in Human Umbilical Vein Endothelial Cells via Suppression of ROS-Mediated Bax/Bcl-2

Lee

Ahn

et al. 2020

Antioxidants

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Methylglyoxal (MGO) is a highly reactive metabolite of glucose. Elevated levels of MGO induce the generation of reactive oxygen species (ROS) and cause cell death in endothelial cells. Vascular endothelial cell damage by ROS has been implicated in the progression of diabetic vascular complications, cardiovascular diseases, and atherosclerosis. In this study, the protective effect of isosamidin, isolated from Peucedanum japonicum roots, on MGO-induced apoptosis was investigated using human umbilical vein endothelial cells (HUVECs). Among the 20 compounds isolated from P. japonicum, isosamidin showed the highest effectiveness in inhibiting MGO-induced apoptosis of HUVECs. Pretreatment of HUVECs with isosamidin significantly prevented the generation of ROS and cell death induced by MGO. Isosamidin prevented MGO-induced apoptosis in HUVECs by downregulating the expression of Bax and upregulating the expression of Bcl-2. MGO treatment activated mitogen-activated protein kinases (MAPKs), such as p38, c-Jun N terminal kinase (JNK), and extracellular signal-regulated kinase (ERK). In contrast, pretreatment with isosamidin strongly inhibited the activation of p38 and JNK. Furthermore, isosamidin caused the breakdown of the crosslinks of the MGO-derived advanced glycation end products (AGEs). These findings suggest that isosamidin from P. japonicum may be used as a preventive agent against MGO-mediated endothelial dysfunction in diabetes. However, further study of the therapeutic potential of isosamidin on endothelial dysfunction needs to explored in vivo models.

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Second generation 2-aminoimidazole based advanced glycation end product inhibitors and breakers

Cited by 14 publications

References 18 publications

Sulforaphane Inhibits MGO-AGE-Mediated Neuroinflammation by Suppressing NF-κB, MAPK, and AGE–RAGE Signaling Pathways in Microglial Cells

Sulforaphane Inhibits MGO-AGE-Mediated Neuroinflammation by Suppressing NF-κB, MAPK, and AGE–RAGE Signaling Pathways in Microglial Cells

Using Small-Molecule Adjuvants to Repurpose Azithromycin for Use against Pseudomonas aeruginosa

Isosamidin from Peucedanum japonicum Roots Prevents Methylglyoxal-Induced Glucotoxicity in Human Umbilical Vein Endothelial Cells via Suppression of ROS-Mediated Bax/Bcl-2

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