Send Orders for Reprints to [email protected] Recent Patents on Anti-Cancer Drug Discovery, 2015, 10, 97-115 97 Advances in Chalcones with Anticancer Activities Chandrabose Karthikeyana, Narayana S. H. Narayana Moorthya,b, Sakthivel Ramasamyc, Uma Vanamc, Elangovan Manivannand, Devarajan Karunagaranc and Piyush Trivedia,* aSchool of Pharmaceutical Sciences, Rajiv Gandhi Proudyogiki Vishwavidyalaya, Airport Bypass Road, Gandhi Nagar, Bhopal, MP, 462036, India; bDepartment of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, 687, Rua de Campo Alegre, Porto, 4169-007, Portugal; cCancer Biology Laboratory, Department of Biotechnology, Bhupat & Jyoti Mehta School of Biosciences Building, Indian Institute of Technology Madras, Chennai-600036 (T.N.), India; dSchool of Pharmacy, Devi Ahilya Vishwavidyalaya, Indore 452 017, MP, India Received: January 7, 2014; Accepted: July 21, 2014; Revised: July 29, 2014 Chandrabose Karthikeyan Abstract: Chalcones are naturally occurring compounds exhibiting broad spectrum biological activities including anticancer activity through multiple mechanisms. Literature on anticancer chalcones highlights the employment of three pronged strate- gies, namely; structural manipulation of both aryl rings, replacement of aryl rings with heteroaryl scaffolds, molecular hy- bridization through conjugation with other pharmacologically interesting scaffolds for enhancement of anticancer properties. Methoxy substitutions on both the aryl rings (A and B) of the chalcones, depending upon their positions in the aryl rings ap- pear to influence anticancer and other activities. Similarly, heterocyclic rings either as ring A or B in chalcones, also influence the anticancer activity shown by this class of compounds. Hybrid chalcones formulated by chemically linking chalcones to other prominent anticancer scaffolds such as pyrrol[2,1-c][1,4]benzodiazepines, benzothiazoles, imidazolones have demon- strated synergistic or additive pharmacological activities. The successful application of these three pronged strategies for dis- covering novel anticancer agents based on chalcone scaffold has resulted in many novel and chemically diverse chalcones with potential therapeutic application for many types of cancer. This review summarizes the concerted efforts expended on the design and development of anticancer chalcones recorded in recent literature and also provides an overview of the patents published in this area between 2007 and 2014 (WO2013022951, WO201201745 & US2012029489). Keywords: Anticancer, anticancer chalcones, antioxidant, antiproliferative activity, chalcones, patents. INTRODUCTION Chalcones are open-chain flavonoids, biosynthesized in a variety of plant species [1]. Chemically, chalcones are 1,3- diphenyl-2-propen-1-ones, which consist of two aromatic rings connected by a three-carbon ,-unsaturated carbonyl system [1]. Chalcone is an exceptional chemical template having multifarious biological activities, which include anti- cancer [2, 3], anti-inflammatory [4-6], antioxidant [7], antim- icrobial, anti-tubercular [8], anti-HIV [9], antimalarial [10] and anti-allergic activities [11]. For a comprehensive over- view of a broad spectrum pharmacological activities dis- played by chalcones, the readers are directed to excellent reviews by Dimmock et al. [12], Batovska et al. [13] and Sahu et al. [14]. The anticancer activity of chalcones has been investigated extensively by both the academia and the industry for more than three decades [15]. However, only a few such reports describe the in-depth mechanistic basis of the cytotoxic or anti-proliferative activity exhibited by the chal- cones. Chalcones exert cytotoxic activities through multiple mechanisms which include cell cycle disruption, angiogenesis Fig. (1). Schematic diagram for the cell cycle arrest by chalcones. *Address correspondence to this author at the School of Pharmaceutical Sci- inhibition, tubulin polymerization inhibition, apoptosis in- ences, Rajiv Gandhi Proudyogiki Vishwavidyalaya, Airport Bypass Road, Gandhi Nagar, Bhopal, MP, 462036, India; Tel: +91-755-2678883; Fax: +91- duction and blockade of nuclear factor-kappa B (NF-B) 755-2742001; E-mail: [email protected]; [email protected] signaling pathway (Fig. (1)) [1, 2, 16, 17]. 2212-3970/15 $100.00+.00 © 2015 Bentham Science Publishers 98 Recent Patents on Anti-Cancer Drug Discovery, 2015, Vol. 10, No. 1 Karthikeyan et al. O H C OR3 O O 2 CH3 CH3 R2O OR1 OH HO H3CO OH (1) Licochalcone A (2) Xanthohumol R1 = CH3, R2 = H, R3 = H (3) Xanthoangelol OH O (6) OH O OH H OH HO O O O OH OH HO OH H (4) 4-hydroxyderricin O OH (5) Butein (6) Garcinol OH O OH R HO O HO OH OH HO OH OH HO O O HO HO O (7) Flavokawain A R = OCH3 (8) Flavokawain B R = H OH O O HO OH O (9) Flavokawain C R = OH HO (10) Hydroxy Safflor Yellow A (11) Broussochalcone A OH O O O H3CO OH OCH3 (H3C)2N HO OCH3 O O OCH3O OCH3 O (12) Dimethylaminochalcone (13) Cardamonin (14) HTMC (15) Pyranochalcone from Millettia pachycarpa Fig. (2). Structures of the naturally derived chalcones. Further, chalcones have also been demonstrated to inhibit class of chalcones are licochalcones, xanthohumol, butein, kinases essential for tumor cell survival and proliferation like etc. (Fig. (2)). epidermal growth factor receptor (EGFR), vascular endothe- Licochalcone A (1) (LA), an oxygenated chalcone found lial growth factor receptor-2 (VEGFR-2) and B-Raf (BRAF) in the roots of the Chinese liquorice (Glycyrrhiza uralensis), kinase [18-20]. There are a number of reviews that had dealt has been demonstrated to possess many bioactive properties with the pharmacological and chemical basis of the antican- including anti-parasitic, estrogenic, antimalarial and antitu- cer activities exhibited by the chalcones [15, 21-23]. How- mor activities [24-26]. LA was also reported to elicit growth ever, the present perspective focuses on the medicinal chem- control and induction of apoptosis in androgen-independent istry strategies employed for the design and development of p53-null PC-3 prostate cancer cells [25, 27]. Xanthohumol anticancer chalcones citing the examples reported in recent (2), a prenylated chalcone isolated from the hop cones (Hu- literature and patents (International, United States and Japa- mulus lupulus L.) is suggested to exhibit broad spectrum nese patent databases) published in the last seven years anticancer properties against different types of human cancer (2007 to 2014). The biological significance of these chal- cells primarily through inhibition of the proliferation and cones alongwith their therapeutic potential against different induction of human cancer cell apoptosis [27, 28]. Xantho- types of cancer is also summarized herein. angelol (3), a natural chalcone isolated from stem exudate of Angelica keiskei, induced apoptotic cell death by activation NATURALLY OCCURRING CHALCONES of caspase-3 in neuroblastoma and leukemia cells through a An overall review of the recent literatures reveals a con- mechanism that does not involve Bax/Bcl-2 signal transduc- tinuous search for naturally occurring chalcones with po- tion [29]. 4-Hydroxyderricin (4), another chalcone found in tent anticancer properties and a novel mechanism of action. the roots of Angelica keiskei also induced apoptotic cell Consequently, many naturally occurring chalcones with death in leukemia cells (HL60) via both the death receptor- potent anticancer efficacy against a variety of cancer cell mediated pathway and the mitochondrial pathway by, at least lines have been found. Some prominent examples of this in part, topoisomerase II inhibition [30]. Furthermore, the Anticancer Activities of Chalcones Recent Patents on Anti-Cancer Drug Discovery, 2015, Vol. 10, No. 1 99 chalcone also exhibited excellent cytotoxic activity against mainly focused on both the phenyl rings (A and B) Fig. (3). four human tumor cell lines (HL60 (leukemia), CRL1579 Similar to naturally occurring chalcones, hydroxy and (melanoma), A549 (lung) and AZ521 (stomach). Butein (3, methoxy groups in specific positions on the phenyl rings fa- 4, 2',4'-tetrahydroxychalone) (5), a plant polyphenol, isolated vors the anticancer activity exhibited by these compounds. from the stems of Rhus verniciflua has been shown to inhibit However, there are also reports which indicate that other human colon adenocarcinoma cell proliferation [31]. An- groups such as dimethylamino, aryl/heteroarylrings either other study by Kim et al. in human leukemia HL-60 cell line fused or substituted are also tolerated. suggested that butein induces apoptosis in HL-60 cells via A recent study found 1,3-diphenyl propenone (16) to be positive modulation of caspase-3 activity associated with potent anti-angiogenic compared to heteroaryl chalcones 3- downregulation of Bcl-2 expression and upregulation of Bax phenyl-1-thiophen-2-yl-propenone (PhT2P) (17), 3-phenyl- expression [32]. Garcinol (6), a tri-isoprenylated hydroxy- 1-thiophen-3-yl-propenone (PhT3P) (18) and 1-furan-2-yl-3- chalcone extracted from the plant Garcinia indica, has been phenyl-propenone (FPhP) (19). The study also established shown to possess anti-inflammatory and anticarcinogenic chalcone as a multitargeted kinase inhibitor with inhibitory activities [33]. The mechanism by which garcinol elicits activity against VEGF receptor tyrosine kinase (weak) and these activities involves modulation of arachidonic acid me- several other receptor tyrosine kinases including Tie-2, epi- tabolism by blocking the phosphorylation of cytosolic dermal growth