5-Aminosalicylic Acid Azo-Linked to Procainamide Acts as an Anticolitic Mutual Prodrug via Additive Inhibition of Nuclear Factor kappaB

Kim, Wooseong; Nam, Joon; Lee, Sun Young; Jeong, Seongkeun; Jung, Yunjin

doi:10.1021/acs.molpharmaceut.6b00294

Cited by 18 publications

(18 citation statements)

References 38 publications

(75 reference statements)

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“…In the DNBS-induced rat colitis model, PBA-GA was observed to be as effective against colitis as SSZ. Unlike the suppression of inflammatory signals, such as nuclear factor (NF)-ĸB [ 46 ], by SSZ, PBA-GA is considered to exert its anti-colitic effects by protecting and fortifying the epithelial barrier. In addition, long-term NF-ĸB inhibition may impair epithelial integrity [ 47 , 48 ].…”

Section: Discussionmentioning

confidence: 99%

A Colon-Targeted Prodrug, 4-Phenylbutyric Acid-Glutamic Acid Conjugate, Ameliorates 2,4-Dinitrobenzenesulfonic Acid-Induced Colitis in Rats

Kim

Lee

et al. 2020

Pharmaceutics

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An elevated level of endoplasmic reticulum (ER) stress is considered an aggravating factor for inflammatory bowel disease (IBD). To develop an ER-stress attenuator that is effective against colitis, 4-phenylbutyric acid (4-PBA), a chemical chaperone that alleviates ER stress, was conjugated with acidic amino acids to yield 4-PBA-glutamic acid (PBA-GA) and 4-PBA-aspartic acid (PBA-AA) conjugates. The PBA derivatives were converted to 4-PBA in the cecal contents, and the conversion was greater with PBA-GA than that with PBA-AA. After oral administration of PBA-GA (oral PBA-GA), up to 2.7 mM PBA was detected in the cecum, whereas 4-PBA was not detected in the blood, indicating that PBA-GA predominantly targeted the large intestine. In 2,4-dinitrobenzenesulfonic acid-induced colitis in rats, oral PBA-GA alleviated the damage and inflammation in the colon and substantially reduced the elevated levels of ER stress marker proteins in the inflamed colon. Moreover, PBA-GA was found to be as effective as the currently used anti-IBD drug, sulfasalazine. In conclusion, PBA-GA is a colon-targeted prodrug of 4-PBA and is effective against rat colitis probably via the attenuation of ER stress in the inflamed colon.

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Section: Discussionmentioning

confidence: 99%

A Colon-Targeted Prodrug, 4-Phenylbutyric Acid-Glutamic Acid Conjugate, Ameliorates 2,4-Dinitrobenzenesulfonic Acid-Induced Colitis in Rats

Kim

Lee

et al. 2020

Pharmaceutics

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“…As well as anti‐inflammatory compounds, azo chemistry has been used to target a range of other drugs and they include antibiotics (Kennedy et al , ; Deka et al , ) and anticancer drugs (Sharma et al , ; Plyduang et al , ). Development continues on new azo‐bonded carriers for drugs (Ruiz et al , ; Kim et al , ) as well as linking pairs of drugs together (Ruiz et al , ). Studies are making use of the azo linkage in new systems such as using azo polymers as a coating material, which is degraded to release the drug (Saphier and Karton, ).…”

Section: Azo Drugsmentioning

confidence: 99%

Azoreductases in drug metabolism

Ryan

2016

British J Pharmacology

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Azoreductases are flavoenzymes that have been characterised in a range of prokaryotes and eukaryotes. Bacterial azoreductases are associated with the activation of two classes of drug, azo drugs for the treatment of inflammatory bowel disease and nitrofuran antibiotics. The mechanism of reduction of azo compounds is presented that requires tautomerisation of the azo compound to a quinoneimine and provides a unifying mechanism for the reduction of azo and quinone substrates by azoreductase. The importance of further work in characterisation of azoreductases from enteric bacteria is highlighted to aid in the development of novel drugs for the treatment of colon related disorders.Human azoreductases are known to play a crucial role in the metabolism of a number of quinone containing cancer chemotherapeutic drugs. The mechanism of hydride transfer to quinones, which is shared not only between eukaryotic and prokaryotic azoreductases but the wider family of NAD(P)H quinone oxidoreductases, is outlined. The importance of common SNPs in human azoreductases is described not only in cancer prognosis but also due to their effects on the efficacy of quinone drug based cancer chemotherapeutic regimens. This highlights the need to screen patients for azoreductase SNPs ahead of treatment with these regimens. Non-approved abbreviations5-ASA: 5-aminosalicylate, AcpD: acyl carrier protein phosphodiesterase, ecAzoR: E. coli azoreductase, FAD: flavin adenine dinucleotide, FMN: Flavin mononucleotide, hNQO1/2: human NAD(P)H quinone oxidoreductase 1 and 2, IBD: inflammatory bowel disease, MdaB: Modulator of drug activity B, NAD(P)H: Nicotinamide adenine dinucleotide (phosphate) reduced, NfsB: Nitrofurazone sensitivity protein B, NRH: (Wu et al., 1997) Introduction to azoreductasesAzoreductases are a group of diverse enzymes found in many bacterial and eukaryotic organisms (Fig 1 (Ryan et al., 2014)). The azoreductases discussed in this review are flavin-dependent (typically FMN) enzymes that are able to reductively cleave compounds containing an azo bond. Azo compounds are defined as those that contain an R 1 -N=N-R 2 group, where R 1 and R 2 are typically aromatic groups. Azoreductases are primarily cytosolic enzymes, however they have been shown to be secreted during exposure of bacteria to azo dyes (Morrison et al., 2015). The physiological role of these enzymes in the bacteria remains unclear, however they are constitutively expressed during growth in vitro (Chen et al., 2005;Wang et al., 2007) which suggests a role in homeostasis. The majority of azoreductase research is focused on their use in bioremediation where they can be used for the treatment of waste water contaminated with azo dyes from the textile and cosmetics industries (Singh et al., 2015). This review is unique in focusing on their role in the activation of several classes of drug.To date the majority of studies on azoreductases have been performed on enzymes from aerobic bacteria (Crescente et al., 2016;Nakanishi et al., 2001), in contrast only a single ...

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“…Colitis was induced using DNBS according to the method for colitis induction using 2,4,6-trinitrobenzenesulfonic acid 24. Briefly, before the induction of colitis, the rats (250–260 g) were starved for 24 hours, but had free access to water.…”

Section: Methodsmentioning

confidence: 99%

“…SSZ or an equimolar concentration of MCP-azo-ASA was administered orally to rats once a day 72 hours after induction of colitis, and the rats were euthanized after receiving the treatment for 7 days. A gross colonic damage score (CDS) was calculated according to previously established criteria 24,25. The modified scoring system is as follows: 0, normal appearance; 1, localized hyperemia but no ulcer; 2, linear ulcers without significant inflammation; 3, a 2–4 cm site of inflammation and ulceration; 4, serosal adhesion to other organs and a 2–4 cm site of inflammation and ulceration; 5, stricture, serosal adhesion involving several bowel loops, and a <4 cm site of inflammation and ulceration.…”

Section: Methodsmentioning

confidence: 99%

A colon-specific prodrug of metoclopramide ameliorates colitis in an experimental rat model

Yang¹,

Kim²,

Kim³

et al. 2018

DDDT

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BackgroundWe examined whether metoclopramide (MCP), a modulator of dopamine and serotonin receptors, alleviated colitis and had synergistic effects when coadministered with 5-aminosalicylic acid (5-ASA) in an experimental model of colitis.MethodsMCP azo-linked to 5-ASA (5-[4-chloro-2-{2-(diethylamino)ethylcarbamoyl}– 1-methoxyphenyl]azosalicylic acid, MCP-azo-ASA) was synthesized, where 5-ASA was used as a colon-targeting carrier and an anti-colitic agent, and the ability of MCP-azo-ASA to target the colon in vitro and in vivo was evaluated.ResultsOur results indicate that MCP-azo-ASA was cleaved to MCP and 5-ASA in the cecal contents, but not in the contents of the small intestine. Oral gavage with equimolar concentrations of MCP-azo-ASA and sulfasalazine (SSZ, a colon-specific prodrug of 5-ASA widely used clinically) demonstrated that the two prodrugs delivered comparable amounts of 5-ASA to the cecum. MCP was barely detected in the blood after oral gavage with MCP-azo-ASA. In a rat model of 2,4-dinitrobenzene sulfonic acid hydrate (DNBS)-induced colitis, MCP-azo-ASA alleviated colonic damage in a dose-dependent manner. Moreover, MCP-azo-ASA reduced the concentrations of inflammatory mediators in the inflamed colon. At low equimolar doses, MCP-azo-ASA, but not SSZ, resulted in significant anti-colitic effects, which indicates that MCP has anti-colitic activity. MCP-azo-ASA had anti-colitic effects equal to those of SSZ at high equimolar doses.ConclusionThus, our results indicate that MCP-azo-ASA is a colon-specific prodrug of MCP. Targeted delivery of MCP to the colon ameliorated DNBS-induced colitis in rats, and we did not observe any synergistic effects of MCP after co-delivery with 5-ASA.

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5-Aminosalicylic Acid Azo-Linked to Procainamide Acts as an Anticolitic Mutual Prodrug via Additive Inhibition of Nuclear Factor kappaB

Cited by 18 publications

References 38 publications

A Colon-Targeted Prodrug, 4-Phenylbutyric Acid-Glutamic Acid Conjugate, Ameliorates 2,4-Dinitrobenzenesulfonic Acid-Induced Colitis in Rats

A Colon-Targeted Prodrug, 4-Phenylbutyric Acid-Glutamic Acid Conjugate, Ameliorates 2,4-Dinitrobenzenesulfonic Acid-Induced Colitis in Rats

Azoreductases in drug metabolism

A colon-specific prodrug of metoclopramide ameliorates colitis in an experimental rat model

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