A facile, stereoselective, one-pot synthesis of resveratrol derivatives

Birar, Vishal C.; Sheerin, Angela; Milkovicova, Jana; Faragher, R. G. A.; Ostler, Elizabeth L.

doi:10.1186/s13065-015-0102-7

Cited by 5 publications

(6 citation statements)

References 22 publications

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“…1a ) with the goal of identifying compounds that could restore splicing factor expression to levels comparable with those seen in young cells, but with differing effects on SIRT1 activation and the senescence-associated secretory phenotype (SASP) to allow assessment of molecular mechanism. Synthesis of the backbone was achieved as previously reported [ 26 ], with additional functionality and diversity achieved via functional group interconversion (Fig. 1b ).…”

Section: Resultsmentioning

confidence: 99%

“…Resveratrol (Sigma Aldrich, UK; 1 ) was used to synthesise dihydroresveratrol 2 as reported previously [ 47 ]. ( E )-N-(4-(3,5-Dimethoxystyryl)phenyl) methanesulfonamide 3 was synthesised from the previously reported nitro-substituted analogue 7 via an Fe/NH 4 Cl reduction to give amine 8 [ 26 ], followed by sulfonylation with methanesulfonyl chloride (Fig. 1b ).…”

Section: Methodsmentioning

confidence: 99%

“…The product 9 was subjected to demethylation (BBr 3 , CH 2 Cl 2 ) to give the target compound ( E )-N-(4-(3,5-dihydroxystyryl)phenyl)acetamide 4 . ( E )-5-(4-(3,5-dimethoxystyryl)phenyl)-1 H –tetrazole 5 and the isomeric 2-1 H -tetrazole analogue 6 were prepared directly via acid-catalysed cycloaddition with azide ion from the 4- and 2-cyanostilbenes [ 26 ] ( 10 and 11 respectively). (Fig.…”

Section: Methodsmentioning

confidence: 99%

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Small molecule modulation of splicing factor expression is associated with rescue from cellular senescence

et al. 2017

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BackgroundAltered expression of mRNA splicing factors occurs with ageing in vivo and is thought to be an ageing mechanism. The accumulation of senescent cells also occurs in vivo with advancing age and causes much degenerative age-related pathology. However, the relationship between these two processes is opaque. Accordingly we developed a novel panel of small molecules based on resveratrol, previously suggested to alter mRNA splicing, to determine whether altered splicing factor expression had potential to influence features of replicative senescence.ResultsTreatment with resveralogues was associated with altered splicing factor expression and rescue of multiple features of senescence. This rescue was independent of cell cycle traverse and also independent of SIRT1, SASP modulation or senolysis. Under growth permissive conditions, cells demonstrating restored splicing factor expression also demonstrated increased telomere length, re-entered cell cycle and resumed proliferation. These phenomena were also influenced by ERK antagonists and agonists.ConclusionsThis is the first demonstration that moderation of splicing factor levels is associated with reversal of cellular senescence in human primary fibroblasts. Small molecule modulators of such targets may therefore represent promising novel anti-degenerative therapies.Electronic supplementary materialThe online version of this article (10.1186/s12860-017-0147-7) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Small molecule modulation of splicing factor expression is associated with rescue from cellular senescence

et al. 2017

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“…Resveratrol (trans-3,5,4'-trihydroxystilbene) is an excellent candidate for a molecule which modulates multiple hallmark mechanisms simultaneously. Although initially proposed to act as a dietary restriction mimetic based in part on the observation that resveratrol supplementation of the standard diet of laboratory mice induces shifts in gene expression similar to those seen when animals undergo calorie restriction (Barger et al 2008, Bhullar and Hubbard;2015). A wealth of data have subsequently become available consistent with resveratrol affecting proteostasis (Corpas et al 2019), stem cell exhaustion (Safaeinejad et al 2018), mitochondrial dysfunction (de Oliveira et al 216), genomic instability (Stopper et al 2005) and intercellular communication (Huang et al 2020).…”

Section: Introductionmentioning

confidence: 99%

Novel resveratrol derivatives have diverse effects on the survival, proliferation and senescence of primary human fibroblasts

et al. 2020

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Resveratrol alters the cytokinetics of mammalian cell populations in a dose dependent manner. Concentrations above 25-50µM typically trigger growth arrest, senescence and/or apoptosis in multiple different cell types. In contrast, concentrations below 10µM enhance the growth of log phase cell cultures and can rescue senescence in multiple strains of human fibroblasts.To better understand the structural features that regulate these effects, a panel of 24 structurallyrelated resveralogues were synthesised and evaluated for their capacity to activate SIRT1, as determined by an ex-vivo SIRT1 assay, their toxicity, as measured by lactate dehydrogenase release, and their effects on replicative senescence in MRC5 human fibroblasts as measured by their effects on Ki67 immunoreactivity and senescence-associated β galactosidase activity.Minor modifications to the parent stilbene, resveratrol, significantly alter the biological activities of the molecules. Replacement of the 3,5-dihydroxy substituents with 3,5-dimethoxy groups significantly enhances SIRT1 activity, and reduces toxicity. Minimising other strong conjugative effects also reduces toxicity, but negatively impacts SIRT1 activation.At 100µM many of the compounds, including resveratrol, induce senescence in primary MRC5 cells in culture. Modifications that reduce or remove this effect match those that reduce toxicity leading to a correlation between reduction in labelling index and increase in LDH release.At 10µM, the majority of our compounds significantly enhance the growth fraction of log phase cultures of MRC5 cells, consistent with the rescue of a subpopulation of cells within the culture from senescence. SIRT1 activation is not required for rescue to occur but enhances the size of the effect.

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“…Several synthetic approaches have been described for the synthesis of resveratrol, carried out by Wittig [ 149 ] or Horner-Wadsworth-Emmons reactions [ 150 ], Perkin condensations [ 151 ], and also through metal-catalysed processes, such as cross-metathesis [ 152 ] or cross-coupling reactions [ 153 , 154 ]. The most recent synthesis of resveratrol has been carried out by El-Deeb et al [ 155 ] and is shown in Scheme 29 .…”

Section: Synthesis and Mode Of Action Of Glyco-based And Aromatic mentioning

confidence: 99%

Exploring Anti-Prion Glyco-Based and Aromatic Scaffolds: A Chemical Strategy for the Quality of Life

2017

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Prion diseases are fatal neurodegenerative disorders caused by protein misfolding and aggregation, affecting the brain progressively and consequently the quality of life. Alzheimer’s is also a protein misfolding disease, causing dementia in over 40 million people worldwide. There are no therapeutics able to cure these diseases. Cellular prion protein is a high-affinity binding partner of amyloid β (Aβ) oligomers, the most toxic species in Alzheimer’s pathology. These findings motivate the development of new chemicals for a better understanding of the events involved. Disease control is far from being reached by the presently known therapeutics. In this review we describe the synthesis and mode of action of molecular entities with intervention in prion diseases’ biological processes and, if known, their role in Alzheimer’s. A diversity of structures is covered, based on glycans, steroids and terpenes, heterocycles, polyphenols, most of them embodying aromatics and a structural complexity. These molecules may be regarded as chemical tools to foster the understanding of the complex mechanisms involved, and to encourage the scientific community towards further developments for the cure of these devastating diseases.

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A facile, stereoselective, one-pot synthesis of resveratrol derivatives

Cited by 5 publications

References 22 publications

Small molecule modulation of splicing factor expression is associated with rescue from cellular senescence

Small molecule modulation of splicing factor expression is associated with rescue from cellular senescence

Novel resveratrol derivatives have diverse effects on the survival, proliferation and senescence of primary human fibroblasts

Exploring Anti-Prion Glyco-Based and Aromatic Scaffolds: A Chemical Strategy for the Quality of Life

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