Review: The potential of chalcones as a source of drugs

Chalcone and dihydrochalcones are intermediates in the biosynthesis of flavonoids and isoflavonoids in plants. These compounds are widely investigated for their anticancer, anti-inflammatory, antimicrobial, antiprotozoal, antifilarial, larvicidal, anticonvulsant, anti-rheumatoid and antioxidant activities and their use as food additives. Chalcones are considered to be an active ingredient in a large number of medicinal herbs. Further chemical investigation of these plants has now resulted in the isolation of chalcone and biologically active derivatives. Chalcone and their derivatives are an attractive molecular scaffold for the search of new biologically active molecules. This review provides a comprehensive analysis of the source plants, chemistry, structure-activity, pharmacological reports of chalcone and derivatives isolated and identified from plants. In recent years a considerable number of investigations conducted on the biological activities of these compounds suggested a wide range of clinical applications.


INTRODUCTION
Chalcones structure differs considerably from the other members of the flavonoid family.Approximately 201 aglycone structures with varied patterns of hydroxylation, and in some cases, methylation and prenylation, are known.Although many chalcones occur as glycosides, the majority are found as free aglycones.Chalcones are isomerized to flavanones in plants by the enzyme chalcone isomerase, but are readily isomerized in vitro in the presence of acid (Seigler, 2002).The biological effect of chalcones was found to be dependent on the presence, the number and position of functional groups such as methoxy, glycosides, hydroxyl, halogens, etc. in both A and B rings (Dhar, 2003).
Chalcones are abundant in edible plants fruits, vegetables, spices, tea and have also been shown to display pharmacologicall varied effects (Chimenti et al., 2009).They present a broad spectrum of biological activities such as anticancer, anti-inflammatory, antimalarial, antifungal, antilipidemic, antiprotozoal (antileishmanial and antitrypanosomal), antibacterial, antifilarial, larvicidal, antioxidant, anticonvulsant antimicrobial and antiviral (Rahman, 2011).There has been a tremendous interest in these compounds (Appendix 1) as evidenced by the voluminous work.Therefore, we aimed to compile an up to date and comprehensive review of chalcones that covers their traditional and folk medicine uses, phytochemistry and pharmacology.

BIOLOGICAL ACTIVITY
Scientific investigations of the medicinal properties of chalcones dates back to the 1980s.A summary of the findings of these studies performed is presented below.

Antiosteoporosis effect
Dimeric dihydrochalcone cycloaltilisin 6 (26) and AC-5-1 (27) were isolated of the bud covers of Artocarpus altilis.All the compounds shown to be potent inhibitors of cathepsin K (is a cysteine protease that has been implicated in osteoporosis).Cycloaltilisin 6 was found to be the most potent inhibitor with an IC 50 of 98 nM followed by AC-5-1 with an IC 50 of 170 nM and cycloaltilisin 7 ( 28) with an IC 50 of 840 nM (Patil et al., 2002).

Anticancer activities
Since apoptosis is one of the most potent defenses against cancer development, efforts have been made to develop a chemoprevention and therapeutic strategies that selectively trigger apoptosis in malignant cancer cells.Particularly interesting are the properties of chalcones in the induction of apoptosis and their ability to change mitochondrial membrane potential (Sabzevari et al., 2004).In cancer, it has been reported that chalcones interfere in several points of the signal transduction pathways related to cellular proliferation, angiogenesis, metastasis, apoptosis and the reversal of multidrug resistance.The largenumber of research articles and patents related to chalcones is already an indication of their importance as a lead class of compounds.Chalcones with fewer hydroxyl groups on rings A and B were more effective in this regards, as compared to chalcones containing more hydroxyl groups.This difference was attributed to the acidity of the phenolic hydroxyl groups.One of the most widely cited mechanisms by which chalcones exert their cytotoxic activity is that of the interference with the mitotic phase of the cell cycle.A large number of methoxylated chalcones with antimitotic activity against HeLa cells was discovered.Other studies show that the capacity of 2'-hydroxychalcones with different methoxy subtitutions on ring B to inhibit cellular proliferation, induce apoptosis and correlate it with the chemical reactive indexes in HepG2 hepatocellular carcinoma cells (Echeverria et al., 2009).
Later, Bertl et al. (2004) studied the potential antiangiogenic effects of xanthohumol (63) and isoxanthohumol (64), chalcones isolated from Humulus lupulus (hopse).In in vitro conditions they observed a reduction of newly formed capillary growth by xanthohumol at a concentration range of 0.5 to 10 µM (lC 50 value of 2.2 µM).The inhibitory effect of isoxanthohumol was weaker.Furthermore, xanthohumol effectively blocksed tumour angiogenesis and tumour growth in vivo and interferes with several steps in the angiogenic process.Xanthohumol also reduced vascular endothelial growth factor (VEGF) secretion, decreased cell invasion and metalloprotease production in acute and chronic myelogenous leukemia cell lines (DellEva et al., 2007).Moreover, licochalcone E (65), a retrochalcone isolated from the roots of Glycyrrhiza inflata, was found to be an inducer of apoptosis in endothelial cells by modulating NFKB and members of the Bcl-2 family (Mojzis et al., 2008).
Similarly, 2',4'-dihydroxy-6'-methoxy-3',5'dimethylchalcone (66), extracted from the dried flower Cleistocalyx operculatus, blocked antiangiogenesis in vitro as well as in vivo.In in vitro conditions it reversibly inhibited VEGF receptor tyrosine kinase phosphorylation.It also inhibited MAPI< and AKT activation of VEGF receptor signal transduction.Systemic administration of this chalcone resulted in the inhibition of subcutaneous tumour growth of human hepatocarcinoma Bel7402 and lung cancer GLC-82 xenografts and a decrease in the tumour vessel density (Zhu et al., 2005).
TRAIL is a naturally occurring anticancer agent appearing in soluble form or expressed in immune cells.TRAIL mediates in vitro and in vivo apoptosis in cancer cells.Cytotoxic effects of chalcones and dihydrochalcone 2',6'-dihydroxy-4'-methoxychalcone (67), 2',6'-dihydroxy-4'-methoxydihydro chalcone (68) 2' 6' -dihydroxy-4,4'dimethoxy dihydrochalcone (69) and phloretin (70) markedly augment TRAIL mediated apoptosis in LNCaP cells.Sensitization of prostate cancer cells to TRIALmediated apoptosis by chalcones and dihydrochalcones suggest the potential role of these compounds in anticancer immune defense in which endogenous TRAIL takes part.The TRAIL-mediated cytotoxic and apoptotic pathways may be a target of the chemopreventive agents in prostate cancer cells and the overcoming TRAILresistance by chalcones and dihydrochalcones may be one of the mechanisms responsible for their cancer preventive effects (Szliszka et al., 2010).The phytochemical study of chloroform extract of Calythropsis aurea (Myrtaceae) yielded two chalcones calythropsin (71) and dihydrocalythropsin (72).Calythropsin showed no detectable activity in vitro tubulin polymerization assay, however it showed weak cytotoxic activity against L1210 cells with IC 50 of 7 µM (Beutler et al., 1993).
In another study, the chalcone derricin (73) and lonchocarpin (74) were isolated from hexanic extract from the roots of Lonchocarpus sericeus (Fabaceae).Both chalcones possessed cytotoxicity against CEM Leukaemia cell line, inhibiting cell growth with IC 50 lower than 20 µg/ml.Lonchocarpin was cytotoxic against tumoral cells, but had no effect on sea urchin egg development at tested concentrations.In fact, lonchocarpin was also the least active substance against leukaemia cells presenting a maximal inhibition of 77% in higher tested concentration, while derricin almost completely stopped cell growth (Cunha et al., 2003).
In another study, the dihydrochalcone 2',4'-dihydroxy-4,6'-dimethoxydihydrochalcone (84) was isolated from the ethyl ether extract of lryanthera juruensis Warb (Myristicaceae) and it was found to be a major cytotoxic metabolite when tested against a panel of cancer cell lines (122).Panduratin A ( 85) is a cyclohexanyl chalcone found in Boesenbergia rotunda induced apoptosis on A375 cancer cells, which was mediated by prolonged ER stress at least in part via the PERK/eIF2α/ATF4/CHOP pathway revealeing that mitochondrion is the primary acting site of Panduratin A on A375 cancer cells (Lai et al., 2015).Flavokawain B (34), a kava chalcone, showed a strong in vitro activity against osteosarcoma cell lines.This compound inhibited cell proliferation, induced apoptosis and cell cycle arrest.Furthermore, in contrast to conventional chemotherapeutic drugs, showed less toxicity in normal bone marrow cells (Tao et al., 2013).Cardomonin (83) inhibited prostate cancer cell proliferation and decreased the expression of NFkB1.Moreover, analysis by flow cytometry showed that this compound induced DNA fragmentation, suggesting an effect on apoptosis induction in the PC-3 cell line (Pascoal et al., 2014).

CONCLUSION
The pharmacological studies conducted on chalcones indicate the immense potential of these compounds in the treatment of conditions such as osteoporosis, cancer, influenza viruses, as inhibitor of the HIV-1, antimicrobial, tyrosinase inhibitor, plasmodial etc.Not surprisingly, chalcones also exhibits antioxidant and anti-inflammatory effects as oxidative injury underlies many of these diseases.However, the diverse pharmacological activities of the chalcones have only been assayed in in vitro tests using laboratory animals, and the results obtained may not necessarily be applicable situation in humans.While there are gaps in the studies conducted so far, which need to be bridged in order to exploit the full medicinal potential of chalcones, it is still very clear that there are compounds which are already widely used and also have an extraordinary potential for the future.ABBREVIATIONS: AGEs, Advanced glycation endprcducts; A-549, human non-small cell lung cancer; AKT, protein kinase B; COX-2, cycloxygenase 2; DPPH, 1,1diphenyl-2-picrylhydrazyl; IFN-y; interferon gamma; IL-6, interleukin 6; IL-13, interleukin 13; iNOS, NO synthetase; HepG-2, liver carcinoma; HT-29, human colon cancer; LPS, lipopolysaccharide; MAPI, multiple activation key; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; NO, nitrous oxide; ORAC, oxygen radical absorbance capacity; P-388, murine leukemia; TNF-α, tumor necrosis factor-α; VEGF, vascular endothelial growth factor.

Conflict of interest
Authors declare that there are no conflicts of interest.