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Structure-Activity Relationship of Flavonoids

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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Natural Products Chemistry".

Deadline for manuscript submissions: closed (15 January 2014) | Viewed by 60009

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Prof. Dr. H. P. Vasantha Rupasinghe

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Guest Editor

Department of Plant, Food, and Environmental Sciences, Faculty of Agriculture, Dalhousie University, Truro, NS B2N 5E3, Canada
Interests: dietary antioxidants; phytochemicals; polyphenols; flavonoids and their derivatives; chemoprevention; molecular mechanisms of action; DNA damage signaling and DNA repair; postbiotics of polyphenols
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Special Issue Information

Dear Colleagues,

Flavonoids are a sub-class of polyphenols that have been shown to possess numerous biological properties in in vitro and pre-clinical experimental models of many chronic diseases. Flavonoids are ubiquitously present in fruits, vegetables, medicinal plants and their products. Scientific evidence have strongly shown that regular intake of dietary flavonoids reduces the risk of oxidative-stress mediated pathogenesis of human disease such as cardiovascular disease, various cancers and neurological disorders but also against aging. The biological properties of dietary flavonoids have been demonstrated to be due to multiple mechanisms of actions including free radical scavenging, transition metal ion chelation, activation of survival genes and signaling pathways, regulation of mitochondrial function and bioenergetics, modulation of inflammation response and even interactions with micro biota. However, activity of flavonoids are not limited to their health promoting benefits but extend to a wide array of ecological interactions of plants such as acting as a signal and defense molecule. Their industrial applications are beyond the limit of nutraceuticals and drug candidate molecules. The diverse biological activities of flavonoid molecules are due to their structural diversity. However, flavonoids have a common C6-C3-C6 structure consisting of two aromatic rings (A and B) linked through a three carbon chain, mostly organized as an oxygenated heterocycle (ring C). Over 10,000 flavonoids that have been characterized can be classified under isoflavones, flavonols, catechins and proanthocyanidins, anthocyanins, flavones, flavanones and chalcones. Despite a large number of publications available within the disciplines of analytical chemistry, biological effects and applications of flavonoids, our understanding of how structure of these molecules related to their interactions with cell components and subsequent activity is still limited. Therefore, this special issue is dedicated for communications in the form of original research and review articles, which cover the flavonoid structure and activity relationships. Review articles could discuss the specific sub-classes of flavonoid molecules or specific activity or group of related activities. If remain within the scope of structure-activity relationship, other non-flavonoid polyphenols can also be considered for this special issue. Authors considering the submission of a review are kindly asked to provide in advance to the guest editor a brief outline of the subject matter of their work.

Dr. H.P. Vasantha Rupasinghe
Guest Editor

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Keywords

flavonoids
structure-activity
biological properties
antioxidant activity
pharmacological activity
oxidative stress
biochemical mechanism
enzyme inhibition
chemoprevention
cardioprotection
anti-diabetes
neuropathology
anti-microbial
bioavailability
toxicology
flavonols
catechins
anthocyanins
isoflavones
flavones
flavonones
flavonoid analogs and derivatives
flavonolignans
polyphenols

Published Papers (6 papers)

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Research

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826 KiB

Open AccessArticle

Rooibos Flavonoids Inhibit the Activity of Key Adrenal Steroidogenic Enzymes, Modulating Steroid Hormone Levels in H295R Cells

by Lindie Schloms and Amanda C. Swart

Molecules 2014, 19(3), 3681-3695; https://doi.org/10.3390/molecules19033681 - 24 Mar 2014

Cited by 22 | Viewed by 8385

Abstract

Major rooibos flavonoids—dihydrochalcones, aspalathin and nothofagin, flavones—orientin and vitexin, and a flavonol, rutin, were investigated to determine their influence on the activity of adrenal steroidogenic enzymes, 3β-hydroxysteroid dehydrogenase (3βHSD2) and cytochrome P450 (P450) enzymes, P450 17α-hydroxylase/17,20-lyase (CYP17A1), P450 21-hydroxylase (CYP21A2) and P450 11β-hydroxylase (CYP11B1). All the flavonoids inhibited 3βHSD2 and CYP17A1 significantly, while the inhibition of downstream enzymes, CYP21A2 and CYP11B1, was both substrate and flavonoid specific. The dihydrochalcones inhibited the activity of CYP21A2, but not that of CYP11B1. Although rutin, orientin and vitexin inhibited deoxycortisol conversion by CYP11B1 significantly, inhibition of deoxycorticosterone was <20%. These three flavonoids were unable to inhibit CYP21A2, with negligible inhibition of deoxycortisol biosynthesis only. Rooibos inhibited substrate conversion by CYP17A1 and CYP21A2, while the inhibition of other enzyme activities was <20%. In H295R cells, rutin had the greatest inhibitory effect on steroid production upon forskolin stimulation, reducing total steroid output 2.3-fold, while no effect was detected under basal conditions. Nothofagin and vitexin had a greater inhibitory effect on overall steroid production compared to aspalathin and orientin, respectively. The latter compounds contain two hydroxyl groups on the B ring, while nothofagin and vitexin contain a single hydroxyl group. In addition, all of the flavonoids are glycosylated, albeit at different positions—dihydrochalcones at C3' and flavones at C8 on ring A, while rutin, a larger molecule, has a rutinosyl moiety at C3 on ring C. Structural differences regarding the number and position of hydroxyl and glucose moieties as well as structural flexibility could indicate different mechanisms by which these flavonoids influence the activity of adrenal steroidogenic enzymes. Full article

(This article belongs to the Special Issue Structure-Activity Relationship of Flavonoids)

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620 KiB

Open AccessArticle

Structure and Antioxidant Activity Relationships of Isoflavonoids from Dalbergia parviflora

by Worrawat Promden, Orawan Monthakantirat, Kaoru Umehara, Hiroshi Noguchi and Wanchai De-Eknamkul

Molecules 2014, 19(2), 2226-2237; https://doi.org/10.3390/molecules19022226 - 20 Feb 2014

Cited by 31 | Viewed by 9800

Abstract

The antioxidant activities of 24 isoflavonoids that were previously isolated as pure compounds from Dalbergia parviflora were evaluated using three different in vitro antioxidant-based assay systems: xanthine/xanthine oxidase (X/XO), ORAC, and DPPH. The isolates consisted of three subgroups, namely isoflavones, isoflavanones, and isoflavans, each of which appeared to have diversified substituents, and were thus ideal for the study of their structure-activity relationships (SARs). The SAR analysis was performed using the results obtained from both the inter-subgroup isoflavonoids with the same substitution pattern and the intra-subgroup compounds with different substitution patterns. The inter-subgroup comparison showed that the isoflavones exhibited the highest antioxidant activities based on all three assays. The intra-subgroup analysis showed that the additional presence of an OH group in Ring B at either R3′ or R5′ from the basic common structure of the R7-OH of Ring A and the R4′-OH (or -OMe) of Ring B greatly increased the antioxidant activities of all of the isoflavonoid subgroups and that other positions of OH and OMe substitutions exerted different effects on the activities depending on the subgroup and assay type. Therefore, based on the structural diversity of the isoflavonoids in D. parviflora, the present study provides the first clarification of the detailed antioxidant SARs of isoflavonoids. Full article

(This article belongs to the Special Issue Structure-Activity Relationship of Flavonoids)

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334 KiB

Open AccessArticle

Inhibitory Activity of Synthesized Acetylated Procyanidin B₁ Analogs against HeLa S3 Cells Proliferation

by Syuhei Okamoto, Sayaka Ishihara, Taisuke Okamoto, Syoma Doi, Kota Harui, Yusuke Higashino, Takashi Kawasaki, Noriyuki Nakajima and Akiko Saito

Molecules 2014, 19(2), 1775-1785; https://doi.org/10.3390/molecules19021775 - 04 Feb 2014

Cited by 15 | Viewed by 8779

Abstract

Proanthocyanidins, also known as condensed tannins and/or oligomeric flavonoids, occur in many edible plants and have various interesting biological activities. Previously, we reported a synthetic method for the preparation of various procyanidins in pure form and described their biological activities. Here, we describe the synthesis of procyanidin B₁ acetylated analogs and discuss their inhibition activities against HeLa S3 cell proliferation. Surprisingly, the lower-unit acetylated procyanidin B₁ strongly inhibited the proliferation of HeLa S3 cells. This molecule showed much stronger inhibitory activity than did epigallocatechin-3-O-gallate (EGCG), green tea polyphenol, and dimeric compounds that included EGCG as a unit. This result suggests that the phenolic hydroxyl groups of the upper-units in flavan-3-ols are important for their inhibitory activity against cancer cell proliferation and that a hydrophobic lower unit dimer enhances this activity. Full article

(This article belongs to the Special Issue Structure-Activity Relationship of Flavonoids)

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246 KiB

Open AccessArticle

Antimicrobial and Selected In Vitro Enzyme Inhibitory Effects of Leaf Extracts, Flavonols and Indole Alkaloids Isolated from Croton menyharthii

by Mutalib A. Aderogba, Ashwell R. Ndhlala, Kannan R. R. Rengasamy and Johannes Van Staden

Molecules 2013, 18(10), 12633-12644; https://doi.org/10.3390/molecules181012633 - 11 Oct 2013

Cited by 87 | Viewed by 7584

Abstract

Croton species are used in folk medicine in the management of infections, inflammation and oxidative stress-related diseases. In order to isolate, characterize and evaluate the bioactive constituents of Croton menyharthii Pax leaf extracts, repeated column fractionation of the ethyl acetate fraction from a 20% aqueous methanol crude extract afforded three flavonols identified by NMR (1D and 2D) spectroscopic methods as myricetrin-3-O-rhamnoside (myricetrin, 1), quercetin-3-O-rhamnoside (2) and quercetin (3) along with an indole alkaloid, (E)-N-(4-hydroxycinnamoyl)-5-hydroxytryptamine, [trans-N-(p-coumaroyl) serotonin, 4]. All the compounds are reported from the leaf extract of this plant for the first time. The crude extracts, four solvent fractions (hexane, DCM, ethyl acetate and butanol) and isolated compounds obtained from the leaves were evaluated for their inhibitory effects on selected bacteria, a fungus (Candida albicans), cyclooxygenase (COX-2), α-glucosidase and acetylcholinesterase (AChE). Amongst the compounds, quercetin (3) was the most active against Bacillus subtilis and Candida albicans while myricetrin-3-O-rhamnoside (1) and trans-N-(p-coumaroyl) serotonin (4) were the most active compounds against Escherichia coli, Klebsiella pneumonia and Staphylococcus aureus. The inhibitory activity of myricetrin-3-O-rhamnoside (1) against COX-2 was insignificant while that of the other three compounds 2–4 was low. The AChE inhibitory activity of the alkaloid, trans-N-(p-coumaroyl) serotonin was high, with a percentage inhibitory activity of 72.6% and an IC₅₀ value of 15.0 µg/mL. The rest of the compounds only had moderate activity. Croton menyharthii leaf extracts and isolated compounds inhibit α-glucosidase at very low IC₅₀ values compared to the synthetic drug acarbose. Structure activity relationship of the isolated flavonols 1–3 is briefly outlined. Compounds 1–4 and the leaf extracts exhibited a broad spectrum of activities. This validates the ethnomedicinal use of the plant in folk medicine. Full article

(This article belongs to the Special Issue Structure-Activity Relationship of Flavonoids)

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802 KiB

Open AccessArticle

Factors Influencing the Antifolate Activity of Synthetic Tea-Derived Catechins

by Magalí Sáez-Ayala, María Piedad Fernández-Pérez, Soledad Chazarra, Nani Mchedlishvili, Alberto Tárraga-Tomás and José Neptuno Rodríguez-López

Molecules 2013, 18(7), 8319-8341; https://doi.org/10.3390/molecules18078319 - 16 Jul 2013

Cited by 6 | Viewed by 6335

Abstract

Novel tea catechin derivatives have been synthesized, and a structure-activity study, related to the capacity of these and other polyphenols to bind dihydrofolate reductase (DHFR), has been performed. The data showed an effective binding between all molecules and the free enzyme, and the dissociation constants of the synthetic compounds and of the natural analogues were on the same order. Polyphenols with a catechin configuration were better DHFR inhibitors than those with an epicatechin configuration. Antiproliferative activity was also studied in cultured tumour cells, and the data showed that the activity of the novel derivatives was higher in catechin isomers. Derivatives with a hydroxyl group para on the ester-bonded gallate moiety presented a high in vitro binding to DHFR, but exhibited transport problems in cell culture due to ionization at physiologic pHs. The impact of the binding of catechins to serum albumin on their biological activity was also evaluated. The information provided in this study could be important for the design of novel medicinal active compounds derived from tea catechins. The data suggest that changes in their structure to avoid serum albumin interactions and to facilitate plasmatic membrane transport are essential for the intracellular functions of catechins. Full article

(This article belongs to the Special Issue Structure-Activity Relationship of Flavonoids)

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Review

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966 KiB

Open AccessReview

Structure-Activity Association of Flavonoids in Lung Diseases

by João Henrique G. Lago, Alessandra C. Toledo-Arruda, Márcia Mernak, Kaidu H. Barrosa, Milton A. Martins, Iolanda F. L. C. Tibério and Carla M. Prado

Molecules 2014, 19(3), 3570-3595; https://doi.org/10.3390/molecules19033570 - 24 Mar 2014

Cited by 130 | Viewed by 17466

Abstract

Flavonoids are polyphenolic compounds classified into flavonols, flavones, flavanones, isoflavones, catechins, anthocyanidins, and chalcones according to their chemical structures. They are abundantly found in Nature and over 8,000 flavonoids have from different sources, mainly plant materials, have been described. Recently reports have shown the valuable effects of flavonoids as antiviral, anti-allergic, antiplatelet, antitumor, antioxidant, and anti-inflammatory agents and interest in these compounds has been increasing since they can be helpful to human health. Several mechanisms of action are involved in the biological properties of flavonoids such as free radical scavenging, transition metal ion chelation, activation of survival genes and signaling pathways, regulation of mitochondrial function and modulation of inflammatory responses. The anti-inflammatory effects of flavonoids have been described in a number of studies in the literature, but not frequently associated to respiratory disease. Thus, this review aims to discuss the effects of different flavonoids in the control of lung inflammation in some disorders such as asthma, lung emphysema and acute respiratory distress syndrome and the possible mechanisms of action, as well as establish some structure-activity relationships between this biological potential and chemical profile of these compounds. Full article

(This article belongs to the Special Issue Structure-Activity Relationship of Flavonoids)

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