Novel Inhibitors of Advanced Glycation Endproducts

Rahbar, Samuel; Yernini, Kiran Kumar; Scott, Stephen; Gonzales, Noe; Lalezari, I.

doi:10.1006/bbrc.1999.1275

Cited by 95 publications

(87 citation statements)

References 40 publications

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“…2). Both SR compounds were derived originally from our library of compounds that target protein glycation [10]. Based on our preliminary structure-activity relationship analyses, we have obtained a few useful insights about the design of these compounds.…”

Section: Discussionmentioning

confidence: 99%

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Novel dichlorophenyl urea compounds inhibit proliferation of human leukemia HL-60 cells by inducing cell cycle arrest, differentiation and apoptosis

et al. 2011

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Two novel dichlorophenyl urea compounds, SR4 and SR9, were synthesized in our laboratory and evaluated for anti-cancer activities. Specifically, we investigated the antiproliferative properties of these new compounds on promyelocytic HL-60 leukemia cells by analyzing their effects on cell differentiation, cell cycle progression and apoptosis. SR4 and SR9 were both cytotoxic to HL-60 cells in a dose-and time-dependent manner, with IC(50) of 1.2 μM and 2.2 μM, respectively, after 72 h treatment. Both compounds strongly suppressed growth of HL-60 cells by promoting cell cycle arrest at the G0/G1 transition, with concomitant decrease in protein levels of cyclins D1 and E2 and cyclin-dependent kinases (CDK 2 and CDK 4), and increased protein expression of CDK inhibitors p21(WAF1/Cip1) and p27(Kip1). In addition, either compounds induce cell differentiation as detected by increased NBT staining and expression of CD11b and CD14. Treatment with SR compounds also promoted mitochondrial-dependent apoptosis as confirmed by Annexin V-FITC double staining, DNA fragmentation, increased expression of caspase 3, 7 and 9, cytochrome c release, PARP degradation, and collapse in mitochondrial membrane potential (ΔΨ(MT)). Collectively, these results provide evidence that SR4 and SR9 have the potential for the treatment of human leukemia and merit further investigation as therapeutic agents against other types of cancer.

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Section: Discussionmentioning

confidence: 99%

“…Previously, our laboratory had identified several compounds, including derivatives of 3, 5-dichlorophenylureido phenoxy isobutyric acids as inhibitors of advanced glycation endproducts [10]. In screening several of these compounds for anti-cancer activities, a series of novel dichlorophenyl urea compounds were identified and synthesized.…”

Section: Introductionmentioning

confidence: 99%

Novel dichlorophenyl urea compounds inhibit proliferation of human leukemia HL-60 cells by inducing cell cycle arrest, differentiation and apoptosis

et al. 2011

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“…Chelation may, therefore, confound the identification of AGE inhibitors, e.g. in two recent studies in which a large number of heterocyclic AGE inhibitors were described (27,28) but are more likely to inhibit AGE formation through their chelation, rather than carbonyl trapping activity. For AG and PM, however, triazines (29) and amides (30) have been identified as discrete adducts to carbonyl compounds during glycoxidation and lipoxidation reactions, confirming that, in addition to their chelating activity, they also act as true scavengers of carbonyl compounds.…”

Section: Fig 5 Effect Of Age-breakers and Their Hydrolysis Productsmentioning

confidence: 99%

Chelating Activity of Advanced Glycation End-product Inhibitors

Price

Rhett

Thorpe

et al. 2001

Journal of Biological Chemistry

285

205

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The advanced glycation end-product (AGE) hypothesis proposes that accelerated chemical modification of proteins by glucose during hyperglycemia contributes to the pathogenesis of diabetic complications. The two most commonly measured AGEs, N ⑀ -(carboxymethyl)lysine and pentosidine, are glycoxidation products, formed from glucose by sequential glycation and autoxidation reactions. Although several compounds have been developed as AGE inhibitors and are being tested in animal models of diabetes and in clinical trials, the mechanism of action of these inhibitors is poorly understood. In general, they are thought to function as nucleophilic traps for reactive carbonyl intermediates in the formation of AGEs; however alternative mechanisms of actions, such as chelation, have not been rigorously examined. To distinguish between the carbonyl trapping and antioxidant activity of AGE inhibitors, we have measured the chelating activity of the inhibitors by determining the concentration required for 50% inhibition of the rate of copper-catalyzed autoxidation of ascorbic acid in phosphate buffer. All AGE inhibitors studied were chelators of copper, as measured by inhibition of metalcatalyzed autoxidation of ascorbate. Apparent binding constants for copper ranged from ϳ2 mM for aminoguanidine and pyridoxamine, to 10 -100 M for carnosine, phenazinediamine, OPB-9195 and tenilsetam. The AGE-breakers, phenacylthiazolium and phenacyldimethylthiazolium bromide, and their hydrolysis products, were among the most potent inhibitors of ascorbate oxidation. We conclude that, at millimolar concentrations of AGE inhibitors used in many in vitro studies, inhibition of AGE formation results primarily from the chelating or antioxidant activity of the AGE inhibitors, rather than their carbonyl trapping activity. Further, at therapeutic concentrations, the chelating activity of AGE inhibitors and AGE-breakers may contribute to their inhibition of AGE formation and protection against development of diabetic complications.The Maillard or browning reaction between sugars and proteins leads to the formation of chemical modifications and cross-links in proteins, known as advanced glycation end-products (AGEs) 1 (1). These products contribute to the age-dependent chemical modification of long lived tissue proteins (2), and accelerated formation of AGEs during hyperglycemia is implicated in the development of diabetic complications (1, 2). Consistent with the AGE hypothesis, AGE inhibitors, such as aminoguanidine (AG) (3) and pyridoxamine (PM) (4), inhibit the formation of AGEs in various proteins in vitro and in collagen in vivo (5, 6) and retard the development of diabetic complications in animal models. The two most commonly measured AGEs, N ⑀ -(carboxymethyl)lysine (CML) and pentosidine, are glycoxidation products formed by sequential glycation and oxidation reactions (7), and traces of transition metal ions in physiological buffers are potent catalysts of the formation of these AGEs in vitro (8). AGE inhibitors are nucleophilic compounds design...

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“…AG was the first AGE inhibitor to demonstrate pharmacological effects in clinical trials and, thus, provided the initial support for the concept that the inhibition of glycation reactions and AGE formation is beneficial in treatment of diabetic complications [23,24]. Even though a number of different inhibitors of AGE formation have been developed for prospective therapeutic use [25], AG and PM remain the only AGE inhibitors tested in clinical trials. Therefore, the comparison of therapeutic effects and mechanisms of action of PM and AG may provide new insights into the development of safer and more effective therapies targeting glycoxidative reactions and AGE formation.…”

Section: Introductionmentioning

confidence: 99%

Pyridoxamine as a multifunctional pharmaceutical: targeting pathogenic glycation and oxidative damage

Voziyan

Hudson

2005

CMLS, Cell. Mol. Life Sci.

162

112

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The discovery that pyridoxamine (PM) can inhibit glycation reactions and the formation of advanced glycation end products (AGEs) stimulated new interest in this B6 vitamer as a prospective pharmacological agent for treatment of complications of diabetes. The mechanism of action of PM includes: (i) inhibition of AGE formation by blocking oxidative degradation of the Amadori intermediate of the Maillard reaction; (ii) scavenging of toxic carbonyl products of glucose and lipid degradation; and (iii) trapping of reactive oxygen species. The combination of these multiple activities along with PM safety posture it as a promising drug candidate for treatment of diabetic complications as well as other multifactorial chronic conditions in which oxidative reactions and carbonyl compounds confer pathogenicity.

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Novel Inhibitors of Advanced Glycation Endproducts

Cited by 95 publications

References 40 publications

Novel dichlorophenyl urea compounds inhibit proliferation of human leukemia HL-60 cells by inducing cell cycle arrest, differentiation and apoptosis

Novel dichlorophenyl urea compounds inhibit proliferation of human leukemia HL-60 cells by inducing cell cycle arrest, differentiation and apoptosis

Chelating Activity of Advanced Glycation End-product Inhibitors

Pyridoxamine as a multifunctional pharmaceutical: targeting pathogenic glycation and oxidative damage

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