Evaluation and optimization of antifibrotic activity of cinnamoyl anthranilates

Zammit, Steven C.; Cox, Alison; Gow, Renae M.; Zhang, Yuan; Gilbert, Richard E.; Krum, Henry; Kelly, Darren J.; Williams, Spencer J.

doi:10.1016/j.bmcl.2009.09.120

Cited by 43 publications

(54 citation statements)

References 15 publications

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“…Similarly in small clinical studies, tranilast has been shown to reduce the accumulation of collagens in the renal tissue in advanced diabetic nephropathy [118] and modestly reduce albuminuria in early disease [119]. More recently, Kelly and colleagues have used structure--activity studies around the antifibrotic activity of tranilast to develop a series of cinnamoyl anthranilates with improved potency and reduced cellular toxicity [120]. The best of these, 3-methoxy-4-propargyloxycinnamoyl anthranilate reduces albuminuria in a rat model of progressive diabetes [120], and thus has potential as a new treatment for diabetic nephropathy.…”

Section: Inhibitors Of Fibrosismentioning

confidence: 96%

“…More recently, Kelly and colleagues have used structure--activity studies around the antifibrotic activity of tranilast to develop a series of cinnamoyl anthranilates with improved potency and reduced cellular toxicity [120]. The best of these, 3-methoxy-4-propargyloxycinnamoyl anthranilate reduces albuminuria in a rat model of progressive diabetes [120], and thus has potential as a new treatment for diabetic nephropathy. It has not yet been clinically tested.…”

Section: Inhibitors Of Fibrosismentioning

confidence: 98%

“…Computing power combined with detailed molecular modelling make possible to put drugs exactly in the right place, while minimising off-target actions. The exciting development of tranilast mimetic by Kelly and colleagues [120] and the design of a selective ACE2 agonist are two good examples of technology in action [169]. It is likely that the future management of diabetic kidney disease will be driven by better (smarter) drugs, rather than new drugs.…”

Section: Expert Opinionmentioning

confidence: 98%

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New approaches to the treatment of nephropathy in diabetes

Thomas

Groop²

2011

Expert Opinion on Investigational Drugs

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Although substantial progress has been made towards understanding the pathogenesis of diabetic nephropathy, at present there are no new drugs that provide the solutions we want for our patients. Even when used in combination with standard medical care, current data indicate that renal complications are at best only modestly reduced, at the expense of additional pill burden and exposure to off-target effects. Given the ever-growing burden of diabetic kidney disease, there is a substantial opportunity for better and more targeted (?smarter?) therapeutic interventions in this context.

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Section: Inhibitors Of Fibrosismentioning

confidence: 96%

Section: Inhibitors Of Fibrosismentioning

confidence: 98%

Section: Expert Opinionmentioning

confidence: 98%

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New approaches to the treatment of nephropathy in diabetes

Thomas

Groop²

2011

Expert Opinion on Investigational Drugs

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“…The treatment was generally well tolerated, however in large clinical trials such as the Prevention of REStenosis with Tranilast and its Outcomes (PRESTO) trial, tranilast was associated with adverse effects [41]. A re-engineered analogue of tranilast (FTo11) exhibits 2-5 times more potency than tranilast [42] and is about to begin early stage clinical trials for its anti-fibrotic potential in patients with DN.…”

Section: Anti-fibrotic Agentsmentioning

confidence: 99%

New Treatments for Diabetic Chronic Kidney Disease

MacIsaac¹

2012

10.4172/2161-0959.10001J Nephrol Therapeutic30

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Despite the availability of current therapies that target hyperglycemia, hypertension, dyslipidemia and blockade of the renin-angiotensin-aldosterone (RAA) system, many people with diabetic chronic kidney disease (CKD) still progress to end stage renal disease (ESRD). Hence, new therapies to slow the progression of this important diabetic complication are urgently needed. Disappointingly many promising interventions for diabetic CKD have not coming to fruition when tested in large clinical trials. A recent clinical trial has shown that estimated GFR increases with bardoxolone. However, this finding awaits confirmation that it reflects changes in true GFR and translation into a reduction in clinical events.Here we discuss studies that have evaluated the effects of novel approaches to inhibiting the pathways involved in the pathogenesis of diabetic CKD.

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“…HCAAs have also shown beneficial effects in humans, including antiviral, melanogenesis, inhibitory, and anticancer activities [7–9]. Among the HCAAs, avenanthramides (anthranilate amides; avns) exhibit anti-genotoxic, anti-inflammatory, anti-fibrotic, anti-itch, and anti-proliferative activities [10–14]. In addition, avns were shown to reduce the risk of atherosclerosis [15].…”

Section: Introductionmentioning

confidence: 99%

Synthesis of avenanthramides using engineered Escherichia coli

et al. 2018

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BackgroundHydroxycinnamoyl anthranilates, also known as avenanthramides (avns), are a group of phenolic alkaloids with anti-inflammatory, antioxidant, anti-itch, anti-irritant, and antiatherogenic activities. Some avenanthramides (avn A–H and avn K) are conjugates of hydroxycinnamic acids (HC), including p-coumaric acid, caffeic acid, and ferulic acid, and anthranilate derivatives, including anthranilate, 4-hydroxyanthranilate, and 5-hydroxyanthranilate. Avns are primarily found in oat grain, in which they were originally designated as phytoalexins. Knowledge of the avns biosynthesis pathway has now made it possible to synthesize avns through a genetic engineering strategy, which would help to further elucidate their properties and exploit their beneficial biological activities. The aim of the present study was to synthesize natural avns in Escherichia coli to serve as a valuable resource.ResultsWe synthesized nine avns in E. coli. We first synthesized avn D from glucose in E. coli harboring tyrosine ammonia lyase (TAL), 4-coumarate:coenzyme A ligase (4CL), anthranilate N-hydroxycinnamoyl/benzoyltransferase (HCBT), and anthranilate synthase (trpEG). A trpD deletion mutant was used to increase the amount of anthranilate in E. coli. After optimizing the incubation temperature and cell density, approximately 317.2 mg/L of avn D was synthesized. Avn E and avn F were then synthesized from avn D, using either E. coli harboring HpaBC and SOMT9 or E. coli harboring HapBC alone, respectively. Avn A and avn G were synthesized by feeding 5-hydroxyanthranilate or 4-hydroxyanthranilate to E. coli harboring TAL, 4CL, and HCBT. Avn B, avn C, avn H, and avn K were synthesized from avn A or avn G, using the same approach employed for the synthesis of avn E and avn F from avn D.ConclusionsUsing different HCs, nine avns were synthesized, three of which (avn D, avn E, and avn F) were synthesized from glucose in E. coli. These diverse avns provide a strategy to synthesize both natural and unnatural avns, setting a foundation for exploring the biological activities of diverse avns.Electronic supplementary materialThe online version of this article (10.1186/s12934-018-0896-9) contains supplementary material, which is available to authorized users.

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Evaluation and optimization of antifibrotic activity of cinnamoyl anthranilates

Cited by 43 publications

References 15 publications

New approaches to the treatment of nephropathy in diabetes

New approaches to the treatment of nephropathy in diabetes

New Treatments for Diabetic Chronic Kidney Disease

Synthesis of avenanthramides using engineered Escherichia coli

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