Flavonoids as Anticancer Agents: Structure-Activity Relationship Study

Departamento de Farmacología, Facultad de Farmacia, Universidad de Sevilla, Spain.
Current Medicinal Chemistry - Anti-Cancer Agents 12/2002; 2(6):691-714. DOI: 10.2174/1568011023353714
Source: PubMed


The protection against some forms of cancer provided by many common foods has been observed in multiple epidemiological studies. Non-nutritive dietary compounds, such as flavonoids, have been considered as the responsible agents for such observations and since then, much research activity has been done about their potential anticancer effect. As a result, these compounds have been shown to regulate proliferation and cell death pathways leading to cancer. Thus, flavonoids such as the synthetic flavone, flavopiridol; the soy isoflavonoid, genistein; the tea catechin epigallocatechin gallate; or the common dietary flavonol, quercetin, are emerging as prospective anticancer drug candidates and some of them have already entered in clinical trials. In view of the therapeutic potential of flavonoids, many researchers have tried to elucidate possible structure-activity relationships that might lead to new drug discovery. However, and possibly due to the information being very scattered, there is very little understanding about a possible relationship between the flavonoid structure and their anticancer activity. Besides their therapeutic potential, since lots of flavonoids are present in our diet, a greater understanding of their anticancer properties might also modify our dietary habits in order to attack cancer with an effective weapon, prevention. This paper seeks to show, in a brief but comprehensive way, the anticancer properties of flavonoids. Through an understanding of the cancer process and its treatment, flavonoids are studied as possible useful compounds in cancer prevention and cancer therapy. Furthermore, this review attempts to compile and discuss the literature studying structure-activity relationships, in order to show structural requirements implicated in the anticancer activity of flavonoids, which might help to rationalize their development as antitumor agents.

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    • "Besides this important feature chalcones and their analogues display considerable chemoprotective, antiangiogenic, antibacterial, antifugal, antiparasitic, antioxidative, anti-inflammatory activity [4] [5] and antimarial activity [6] [7]. Chalcones are also precursors for synthesis of flavonoids, which are also known for their anticancer potential [8]. "
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    ABSTRACT: Chalcones and their derivatives possess a wide range of significant pharmacological activities; among the most important ones is their anticancer activity. For this reason we performed a Quantitative Structure-Activity Relationships (QSAR) study of their anticancer activity against MCF-7 human breast cancer cell lines. In this work, several descriptor options were tested on the dataset containing 93 molecular structures, using ERM (Enhanced Replacement Method). The best models were found using merely two dimensional descriptors. The two dimensional descriptors pool was further expanded using several nonlinear transformations, which resulted in an optimal five molecular descriptor model that showed very good predictive ability. Thus, ERM was capable of finding a simple to interpret and understand model that nonetheless addresses nonlinearities between the descriptors and the activity. Furthermore, the acquired model is very straightforward to use since it does not require the optimization of chemical structures for the calculation of three dimensional descriptors.
    Chemometrics and Intelligent Laboratory Systems 06/2015; DOI:10.1016/j.chemolab.2015.06.011 · 2.32 Impact Factor
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    • "Flavonoids are broadly distributed in higher plant such as citrus fruit, buckwheat, onions (Slimestad and Verheul, 2009) and reported for pharmacological properties. They serve as potential antioxidants (Nijveldt et al., 2001; Pietta, 2000; Ross and Kasum, 2002), anti inflammatory (Guardia et al., 2001; Kim et al., 2004), anti-diabetic (Vessal et al., 2003), immunomodulatory (Kuo et al., 2005; Lien et al., 2003), anticancer (Lopez-Lazaro, 2002; Ren et al., 2003), anti-nociceptive (Toker et al., 2004), and anti rheumatic (Chrubasik and Pollak, 2002) agents. Hesperetin [(S)-2, 3-dihydro-5, 7-dihydroxy-2-(3-hydroxy-4- methoxyphenyl)-4H-1-benzopyran-4one)] derived from the citrus fruit possess wide spectrum of activities including anti-inflammatory (Guardia et al., 2001; Yang et al., 2011, 2012), antioxidant (Choi, 2008; Leelavinothan and Kalist, 2011; Singh et al., 2004), and anti-rheumatic (Adams et al., 2009; Li et al., 2008, 2010). "
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    ABSTRACT: Behavioral, biochemical and gene expression changes were investigated in a rat model of partial sciatic nerve ligation (PSNL) after administration of hesperetin (20, 50mg/kg; p.o.), pregabalin (10mg/kg; p.o.) or vehicle (1ml/kg, p.o.). Thirty-six animals were randomly divided into six groups. Left sciatic nerve was exposed and ligated, animals in the control and test groups were treated orally with respective drugs for fifteen days. Nociceptive threshold was assessed on 0day and thereafter every three days. Three weeks later, sciatic nerve tissue homogenate was prepared and subjected for estimation of oxidative markers namely total protein, nitric oxide, lipid peroxidase, interleukins (IL-1β and IL-6) and TNF-α. Administration of hesperetin resulted in a dose dependent attenuation in PSNL-induced mechanical and thermal hyperalgesia, mechanical allodynia as well as down regulation of IL-1β, IL-6 and TNF-α, and biochemical markers. Consequently, it can be concluded that anti-hyperalgesic effect of hesperetin in rats after PSNL may be attributed to various oxidative markers as well as the pro-inflammatory mediators secreted at the injury site. Hesperetin appears to be a promising candidate for the development as a novel therapeutic for the patients suffering from the neuropathic pain.
    Pharmacology Biochemistry and Behavior 05/2014; 124. DOI:10.1016/j.pbb.2014.05.013 · 2.78 Impact Factor
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    • "Polyphenolic derivatives of flavone, flavonol and their isoforms are more effective for cancer chemoprevention in experimental animals than flavone and flavonol [25] [26] [27] [28] [29] [30]. Thus, silibinin, quercetin and genistein have been well investigated for in vitro and in vivo cancer chemoprevention experiments [25] [26] [27] [28] [29] [30]. To study detailed mechanisms of cancer chemoprevention, we asked questions if chemoprevention of flavonoids is attributable to reduction of mutagenesis through an inhibitory interaction with annexin A1 by employing silibinin, quercetin and genistein as active and potent chemopreventive agents, and flavone and flavonol as weak chemopreventive agents, since gene mutation plays an important role in cell transformation and/or malignant transformation [1]. "
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    ABSTRACT: In order to investigate mechanisms of anti-mutagenic action by dietary flavonoids, we investigated if they inhibit mutation of the thymidine kinase (tk) gene in L5178Ytk(+/-) lymphoma cells. Silibinin, quercetin and genistein suppressed mutation of the tk gene induced in L5178Ytk(+/-) lymphoma cells by methyl methansulfonate (MMS) and As(3+). Flavone and flavonol were less effective. To establish that mutation of the tk gene in L5178Ytk(+/-) lymphoma cells by MMS and As(3+) is mediated through mono-ubiquitinated annexin A1, L5178Ytk(+/-) lymphoma cells were treated with annexin A1 anti-sense oligonucleotide. The treatment reduced mRNA as well as protein levels of annexin A1, and suppressed mutation of the tk gene. Nuclear extracts from L5178Ytk(+/-) lymphoma cells catalyzed translesion DNA synthesis with an oligonucleotide template containing 8-oxo-guanosine in an annexin A1 dependent manner. This translesion DNA synthesis was inhibited by the anti-mutagenic flavonoids, silibinin, quercetin and genistein, in a concentration dependent manner, but only slightly by flavone and flavonol. Because these observations implicate involvement of annexin A1 in mutagenesis, we examined if flavonoids suppress nuclear annexin A1 helicase activity. Silibinin, quercetin and genistein inhibited ssDNA binding, DNA chain annealing and DNA unwinding activities of purified nuclear mono-ubiquitinated annexin A1. Flavone and flavonol were ineffective. The apparent direct binding of anti-mutagenic flavonoids to the annexin A1 molecule was supported by fluorescence quenching. Taken together, these findings illustrate that nuclear annexin A1 may be a novel and productive target protein of prevention for DNA damage induced gene mutation, ultimately conferring cancer chemoprevention.
    Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 11/2013; 759. DOI:10.1016/j.mrfmmm.2013.11.002 · 3.68 Impact Factor
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