Semisynthesis and biological evaluation of prenylated resveratrol derivatives as multi-targeted agents for Alzheimer’s disease

Puksasook, Thanchanok; Kimura, Shinya; Tadtong, Sarin; Jiaranaikulwanitch, Jutamas; Pratuangdejkul, Jaturong; Kitphati, Worawan; Suwanborirux, Khanit; Saito, Naoki; Nukoolkarn, Veena

doi:10.1007/s11418-017-1097-2

Cited by 29 publications

(24 citation statements)

References 60 publications

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“…Puksasook et al [25] found that 4-prenylresveratrol exhibited better anti-Aβ aggregation activity than resveratrol and similar anti-BACE inhibitory activity. Other modifications on resveratrol such as imine resveratrol derivatives, [26] resveratrol tacrine hybrids [27] and resveratrol clioquinol hybrids [28] have also been explored as neuroprotective agents.…”

Section: Fig 1 Resveratrol and Related Natural Productsmentioning

confidence: 99%

“…Methyl, ethyl, isopropyl and butyl resveratrol derivatives were synthesized by random alkylation in DMF using potassium carbonate and the corresponding 1-iodoalkane (Scheme 1) [25,37]. Subsequent chromatographic separation afforded mono-, di-and trialkyl resveratrol derivatives 11-25 although several derivatives such as pterostilbene (3) could not be isolated under the chromatographic conditions used.…”

Section: Chemistrymentioning

confidence: 99%

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Alkylated resveratrol prodrugs and metabolites as potential therapeutics for neurodegenerative diseases

Peñalver

Belmonte-Reche

Adán

et al. 2018

European Journal of Medicinal Chemistry

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Resveratrol is a naturally occurring stilbene which has shown promising results as treatment for several neurodegenerative diseases. However, its application is limited due to its low efficacy and bioavailability. Here, we have designed and synthesized alkylated resveratrol prodrugs combining structural modification to improve antioxidant and anti-inflammatory properties and the preparation of prodrugs to extend drug bioavailability. For comparison we also studied resveratrol prodrugs and alkylated resveratrol derivatives. Methylated and butylated resveratrol derivatives showed the best in vitro neuroprotective and anti-inflammatory activity. The glucosyl- and glucosyl-acyl- prodrugs of these derivatives showed lower toxicity on zebra fish embryo. When neuroprotection was examined on pentylenetetrazole challenged zebra fish, they were capable of reverting neuronal damage but to a lower extent than resveratrol. Nevertheless, 3-O-(6'-O-octanoyl)-β-d-glucopyranoside resveratrol (compound 8) recovered AChE activity over 100% whereas resveratrol only up to 92%. In a 3-nitropropionic acid mice model of Huntington's disease, resveratrol derivative 8 delayed the onset and reduced the severity of HD-like symptoms, by improving locomotor activity and protecting against weight loss. Its effects involved an equal antioxidant but better anti-inflammatory profile than resveratrol as shown by SOD2 expression in brain tissue and circulating levels of IL-6 (11 vs 18 pg/mL), respectively. Finally, the octanoyl chain in compound 8 could be playing a role in inflammation and neuronal development indicating it could be acting as a double-drug, instead of as a prodrug.

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Section: Fig 1 Resveratrol and Related Natural Productsmentioning

confidence: 99%

Section: Chemistrymentioning

confidence: 99%

Alkylated resveratrol prodrugs and metabolites as potential therapeutics for neurodegenerative diseases

Peñalver

Belmonte-Reche

Adán

et al. 2018

European Journal of Medicinal Chemistry

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“…4-isopentenyl-3,5,4Ј-trihydroxystilbene) as a potential lead compound for Alzheimer's disease treatment due to its multitargeting properties. Arachidin-2 inhibited ␤-secretase and amyloid-␤ aggregation and showed antioxidant, neuroprotective, and neuritogenic properties, with no neurotoxicity (23).…”

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confidence: 99%

Stilbenoid prenyltransferases define key steps in the diversification of peanut phytoalexins

Yang

Fang

Sanders

et al. 2018

Journal of Biological Chemistry

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Defense responses of peanut () to biotic and abiotic stresses include the synthesis of prenylated stilbenoids. Members of this compound class show several protective activities in human disease studies, and the list of potential therapeutic targets continues to expand. Despite their medical and biological importance, the biosynthetic pathways of prenylated stilbenoids remain to be elucidated, and the genes encoding stilbenoid-specific prenyltransferases have yet to be identified in any plant species. In this study, we combined targeted transcriptomic and metabolomic analyses to discover prenyltransferase genes in elicitor-treated peanut hairy root cultures. Transcripts encoding five enzymes were identified, and two of these were functionally characterized in a transient expression system consisting of-infiltrated leaves of We observed that one of these prenyltransferases, AhR4DT-1, catalyzes a key reaction in the biosynthesis of prenylated stilbenoids, in which resveratrol is prenylated at its C-4 position to form arachidin-2, whereas another, AhR3'DT-1, added the prenyl group to C-3' of resveratrol. Each of these prenyltransferases was highly specific for stilbenoid substrates, and we confirmed their subcellular location in the plastid by fluorescence microscopy. Structural analysis of the prenylated stilbenoids suggested that these two prenyltransferase activities represent the first committed steps in the biosynthesis of a large number of prenylated stilbenoids and their derivatives in peanut. In summary, we have identified five candidate prenyltransferases in peanut and confirmed that two of them are stilbenoid-specific, advancing our understanding of this specialized enzyme family and shedding critical light onto the biosynthesis of bioactive stilbenoids.

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“…The neuroprotective effect was superior to that presented by RV and was even similar to the positive control with quercetin. The replacement of the -OH groups of RV structure is associated with promising activity presented by the compound against AD (Puksasook et al, 2017).…”

Section: Prenylated Resveratrol Derivativesmentioning

confidence: 99%

Resveratrol Derivatives as Potential Treatments for Alzheimer’s and Parkinson’s Disease

Arbo

André‐Miral

Nasre-Nasser

et al. 2020

Front. Aging Neurosci.

101

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Neurodegenerative diseases are characterized by the progressive loss of neurons in different regions of the nervous system. Alzheimer's disease (AD) and Parkinson's disease (PD) are the two most prevalent neurodegenerative diseases, and the symptoms associated with these pathologies are closely related to the regions that are most affected by the process of neurodegeneration. Despite their high prevalence, currently, there is no cure or disease-modifying drugs for the treatment of these conditions. In the last decades, due to the need for the development of new treatments for neurodegenerative diseases, several authors have investigated the neuroprotective actions of naturally occurring molecules, such as resveratrol. Resveratrol is a stilbene found in several plants, including grapes, blueberries, raspberries, and peanuts. Studies have shown that resveratrol presents neuroprotective actions in experimental models of AD and PD, however, its clinical application is limited due to its rapid metabolism and low bioavailability. In this context, studies have proposed that structural changes in the resveratrol molecule, including glycosylation, alkylation, halogenation, hydroxylation, methylation, and prenylation could lead to the development of derivatives with enhanced bioavailability and pharmacological activity. Therefore, this review article aims to discuss how resveratrol derivatives could represent viable molecules in the search for new drugs for the treatment of AD and PD.

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Semisynthesis and biological evaluation of prenylated resveratrol derivatives as multi-targeted agents for Alzheimer’s disease

Cited by 29 publications

References 60 publications

Alkylated resveratrol prodrugs and metabolites as potential therapeutics for neurodegenerative diseases

Alkylated resveratrol prodrugs and metabolites as potential therapeutics for neurodegenerative diseases

Stilbenoid prenyltransferases define key steps in the diversification of peanut phytoalexins

Resveratrol Derivatives as Potential Treatments for Alzheimer’s and Parkinson’s Disease

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