Send Orders of Reprints at [email protected] Current Topics in Medicinal Chemistry, 2012, 12, 2785-2809 2785 SAR, QSAR and Docking of Anticancer Flavonoids and Variants: A Review Luciana Scotti1, Francisco Jaime Bezerra Mendonça Junior2, Diogo Rodrigo Magalhaes Moreira3, Marcelo Sobral da Silva1, Ivan R. Pitta4 and Marcus Tullius Scotti5,* 1Federal University of Paraíba, Centre for Biotechnology, 50670-910, João Pessoa, PB, Brazil; 2State University of Paraiba, Biological Science Department, Laboratory of Synthesis and Drug Delivery, 58070-450, João Pessoa, PB, Brazil; 3Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz, CEP 40296-710, Salvador, BA, Brazil; 4Federal University of Pernambuco, Departamento de Antibióticos, Recife-PE 50670-910, Brazil; 5Federal University of Paraíba, Department of Engineering and the Environment, Campus IV; 58297-000, Rio Tinto, PB, Brazil Abstract: Flavonoids are phenolic compounds, secondary metabolites of plants that cause several benefits to our health, including helping the treatment against cancer. These pharmacological properties are associated with the ability of flavon- oids in attenuating the generation of reactive oxygen species, acting as chelate compounds or affecting the oxi-redox cy- cle. In spite of the large number of information in term of SAR and QSAR, no recent review has tabulated and discussed in detail these data. In view of this, we bring here a detailed discussion of the structure-activity relationships (SAR) and quantitative structure-activity relationships (QSAR) models. We have also analyzed the correlation between the chemical structure of flavonoids and analogues to their anticancer activities. A large number of methodologies have been used to identify the characteristics of these compounds with their potential anticancer: multiple linear regression, principal com- ponents analysis, comparative molecular field analysis, comparative molecular similarity indices analysis, partial least squares, neural networks, configuration of classification and regression trees, Free-Wilson, docking; using topological, structural and enthalpies’ descriptors. We also discussed the use of docking models, together with QSAR models, for the virtual screening of anticancer flavonoids. The importance of docking models to the medicinal chemistry of anticancer flavonoids has increased in the last decade, especially to help in identifying the structural determinants responsible for the activity. We tabulated here the most important examples of virtual screening determined for anticancer flavonoids and we highlighted the structural determinants. The mode of action, the most potent anticancer flavonoids and hints for the struc- tural design of anticancer flavonoids are revised in details and provided here. Keywords: Cancer, descriptors, docking, flavonoids, SAR, QSAR. 1. INTRODUCTION In spite of the extreme search for new anticancer drugs for medical application, cancer remains a leading cause of Flavonoids are polyphenolic compounds present in the death. As the time of writing, the anticancer properties of leaves, flowers and stems of more than 4,000 higher plants. flavonoids are the most explored. We can find a large num- In plants, these compounds provide protection against the ber of examples where the flavone core was used during the ultraviolet radiation, pathogens and herbivores. Flavonoids structural planning. act also as pigments, providing colors from red to violet, and Many studies have ascertained the mode of action and the attracting pollinating vectors [1, 2]. In special, these com- functional properties of anticancer flavonoids, including the pounds have therapeutic properties in the food, cosmetic, and carcinogen bioactivation, cell signaling and cycle regulation, medicine fields. angiogenesis, oxidative stress and anti-inflammatory proper- According to VAYA et al. (2003) and CARDOSO et al. ties. Compelling data from laboratory studies, epidemiologi- (2005) [3, 4], this class of secondary metabolite exhibits the cal investigations, and human clinical trials indicate that fla- same chemical skeleton, therefore can be classified into five vonoids have important effects on cancer chemoprevention and chemotherapy. Some of these functional properties in- main groups as shown in Fig. (1). clude: carcinogen inactivation, antiproliferation, cell cycle The major groups of flavonoids are endowed with phar- arrest, induction of apoptosis and differentiation, inhibition macological properties. Among them, we can cite the anti- of angiogenesis and, reversal of multidrug resistance or a cancer properties, cardioprotective as the most relevant of combination of these mechanisms. Based on these results, them [5-9]. flavonoids are promising anticancer agents [5-9]. *Address correspondence to this author at the Federal University of Paraíba, Regarding the structural determinants of flavonoids and Department of Engineering and the Environment, Campus IV; 58297-000, analogues for the anticancer properties, it is possible to iden- Rio Tinto, PB, Brazil; Tel/Fax: 83-55-9941-2680; tify relevant chemical descriptors and correlations between E-mail: [email protected] the flavonoid structures versus anticancer activity. In the 1873-5294/12 $58.00+.00 © 2012 Bentham Science Publishers 2786 Current Topics in Medicinal Chemistry, 2012, Vo l. 12, No. 24 Scotti et al. light of this, we here aimed here to tabulate and analyze in • The position of the hydroxyl group in ring B is crucial for detail most the existing literature describing structure- the antioxidant activity and cannot be removed. In regard activity relationships (SAR), quantitative structure-activity to the position, a para position is better, while little or no relationships (QSAR) and docking studies of anticancer fla- activity is observed in ortho and meta positions; vonoids [10]. • The presence of a second hydroxyl group in ring B en- 2. SAR hances the antioxidant activity; The main functional property of flavonoids is their ability • The presence of two ortho-dihydroxy substitution on ring to act as antioxidants, preventing heart diseases and cancers. B, and the double bond C2-C3 conjugated to the carbonyl The mode of how flavonoids display antioxidant activity group (C4) in ring C (as seen in flavones) is essential for depends on two factors: the electron-proton transfer and the the antioxidant activity; stabilization of the formed free radical. Phenolic antioxidant • A hydroxyl group located in C3 of the ring C increases agents (Ar-OH) need to scavenger the produced free radicals the antioxidant activity; faster than other endogenous molecules, thereby conferring protection for the cells. The protective effects of a flavonoid • The presence of a hydroxyl in C4 increases the antioxi- dant activity in compounds having a hydroxylin C3 be- is due to its capacity into transferring electrons to free radi- cause of the intense conjugation (resonance); cals, like as a metal chelator, therefore reducing tocoferoxyl radicals as well as inhibiting oxidases [1,2,11]. • Hydroxyl groups in positions C5 and C7 of the ring A have no importance; The main reasons for the antioxidant activity of flavon- oids in terms of magnitude are: the position and the number • Compounds with three hydroxyl groups are more active of phenol hydroxyl attached to the carbon skeleton, the phys- than dihydroxyl compounds. The reason for is because icochemical properties of other substituent, and the possibil- these compounds adopt a mechanism of action involving ity of formation of intramolecular hydrogen bonds [12, 13]. electron donation, resulting to the formation of a semiquinone specie, and subsequently a quinine [1, 16]. It is well-know the location of the phenolic hydroxyl af- fects the magnitude of the antioxidant activity. It is also de- The C2-C3 double bond also appears to be important for scribed that compounds containing the hydroxyl in para (po- the anticancer activity, it is clear when we compare sition 4) are more potent than those substituted in ortho or flavanones and flavones derivatives (Fig. 2). These flavonoid meta (positions 2 and 3, respectively). The relationship be- variants inhibit the breast cancer resistance protein (BCRP), tween the number of phenolic hydroxyls and the antioxidant a membrane efflux transporter that belongs to the ABC (ATP activity shows that the greater the number of hydroxyl binding cassette) transporter superfamily. ABCG2 expres- groups greater is the antioxidant activity. As a result, di- sion in cancer cells is related to the multidrug resistance (most common) and tri-substituted compounds have higher process [16-18]. antioxidant properties than the mono-hydroxylated ones [13, Two years later, it was reported the presence of a hy- 14]. droxyl group in C-5 along to a methoxy group in C-3 are In compounds containing a heteroatom (nitrogen and also important for the inhibitory activity of BCRP. The most oxygen), or a hydroxyl group located in ortho and/or para active compounds identified were the ayanin and retusin position are more potent antioxidant agents because of the (Fig. 3) [19]. resonance involving the pair of electrons of the heteroatom In another interesting work, Cheng and colleagues (2002, and the resulting phenoxyl radical [15]. 2003) [14, 21] compared the antioxidant properties of 15 In 2001, Pannala and colleagues (2001) [1] used pharma- phenolic compounds by molecular modeling. They found cokinetic data to evaluate the antioxidant capacity of flavone that gallic acid and pyrogallol (Fig. 4) exhibit a different and flavonol derivatives (see Fig. 1). In view of this study, reactivity and functional profile. In this model, gallic acid we can summarize important structural determinants: and pyrogallol were not predicted as antioxidant agents, be- 1 3' 3' 8 O 2 2' 4' 2' 4' 7 1 B 8 1 B A C 8 1' 1' 2' O 5' O 2 5' 6 1' 2 7 3 3' 7 6' 4 A C 6' A C 5 B 6 O 4' 6 3 Isoflavone 6' 3 Flavone 4 Flavanone 5 4 5 5' O O 3' 3' 2' 4' 2' 4' 1 B 1 B 8 1' 8 1' O 2 5' O 2 5' 7 7 A C 6' A C 6' 6 6 3 OH 3 OH 5 4 5 4 Flavon-3-ol Flavonol O O Fig. (1). Five main groups of flavonoids [3]. SAR, QSAR and Docking of Anticancer Flavonoids Current Topics in Medicinal Chemistry, 2012, Vol.