Synthesis of Mutual Azo Prodrugs of Anti-inflammatory Agents and Peptides Facilitated by α-Aminoisobutyric Acid

Kennedy, David; Vembu, Nagarajan; Fronczek, Frank R.; Devocelle, Marc

doi:10.1021/jo201358e

Cited by 39 publications

(19 citation statements)

References 37 publications

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“…The use of azo‐linked compounds for specific drug delivery to the gut remains an area of great interest. 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 , ).…”

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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Section: Azo Drugsmentioning

confidence: 99%

Azoreductases in drug metabolism

Ryan

2016

British J Pharmacology

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“…In 2011, Kennedy et al [268] reported the synthesis of azo mutual prodrugs containing 5-aminophenylacetic acid or 5-aminosalicylic acid (5-ASA) with antimicrobial peptides. The prodrugs were designed to deliver nonsteroidal anti-inflammatory agents (NSAIDs) with an antimicrobial agent to treat both the infection and symptoms caused by C. difficile .…”

Section: Newer Agents For CDImentioning

confidence: 99%

“…The aim was to protect the ammonium terminal of the antimicrobial peptide by an azo bond with an anilinic anti-inflammatory agent so that both components are maintained in an inactive state before reaching its site of action in the colon. This would potentially increase therapeutic outcomes, as it would avoid the ulceration side effects of the NSAID and reduce the disruption of the native microbiota by the antimicrobial peptide while it passes through the upper GI tract [268]. An analog of temporin A, L512TA was used as the antimicrobial peptide portion of the prodrug.…”

Section: Newer Agents For CDImentioning

confidence: 99%

Progress in the Discovery of Treatments for C. difficile Infection: A Clinical and Medicinal Chemistry Review

Tsutsumi¹,

Owusu²,

Hurdle³

et al. 2013

CTMC

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Clostridium difficile is an anaerobic, Gram-positive pathogen that causes C. difficile infection, which results in significant morbidity and mortality. The incidence of C. difficile infection in developed countries has become increasingly high due to the emergence of newer epidemic strains, a growing elderly population, extensive use of broad spectrum antibiotics, and limited therapies for this diarrheal disease. Because treatment options currently available for C. difficile infection have some drawbacks, including cost, promotion of resistance, and selectivity problems, new agents are urgently needed to address these challenges. This review article focuses on two parts: the first part summarizes current clinical treatment strategies and agents under clinical development for C. difficile infection; the second part reviews newly reported anti-difficile agents that have been evaluated or reevaluated in the last five years and are in the early stages of drug discovery and development. Antibiotics are divided into natural product inspired and synthetic small molecule compounds that may have the potential to be more efficacious than currently approved treatments. This includes potency, selectivity, reduced cytotoxicity, and novel modes of action to prevent resistance.

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“…The various methods reported, however, had their own drawbacks: some reactions and/or the by‐products contain mercury, requiring special safety precautions and disposal methods; some reactions have to be performed in an aqueous environment, which would limit the application for moisture‐sensitive substances. Recently, Kennedy et al reported that α‐hydrazo acid can be converted to the α‐azo acid by exposure to air.…”

Section: Resultsmentioning

confidence: 99%

Novel Arylazoarylmethane as Potential Inhibitor of Macrophage Migration Inhibitory Factor

He¹,

Metz²,

Cheng³

et al. 2013

Archiv der Pharmazie

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Macrophage migration inhibitory factor (MIF), a cytokine involved in the pathogenesis of sepsis, diabetes, asthma, arthritis, and cancer, has an enzymatic active site that has proven to be an effective target for small molecule-based inhibitors. Herein, we describe the synthesis of a novel arylazoarylmethane compound (3) from a known arylhydrazone MIF inhibitor (2). This new compound has improved stability and in vivo biological activity.

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Synthesis of Mutual Azo Prodrugs of Anti-inflammatory Agents and Peptides Facilitated by α-Aminoisobutyric Acid

Cited by 39 publications

References 37 publications

Azoreductases in drug metabolism

Azoreductases in drug metabolism

Progress in the Discovery of Treatments for C. difficile Infection: A Clinical and Medicinal Chemistry Review

Novel Arylazoarylmethane as Potential Inhibitor of Macrophage Migration Inhibitory Factor

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