Part3: Anticancer Activity Of Natural And Synthetic Chalcones

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4. Synthetic Derivatives of Chalcones with Anticancer Properties

Anticancer activities of natural chalcones have led to increased interest in identifying new synthetic chalcones with anticancer properties. Objectives for the synthesis of new biologically active chalcones are the identification of compounds with superior physicochemical and biological properties. To obtain chalcones with superior anticancer properties, three methods of modulation of natural chalcones were used:(1)modulation of the two aromatic residues(the aldehyde and the acetophenone) of chalcones;(2) replacement of aromatic residues with heteroaromatic residues; and (3)obtaining hybrids by conjugation with other molecules with antitumor properties. Different substituents on the two aromatic residues of chalcones, depending on their position, influence the anticancer capacity by interfering with different biological targets [158]. It is known that the biological properties of chalcones are dependent on the presence and number of hydroxy and methoxy groups on the two aromatic subunits. For example, chalcones with three methoxy groups in the molecule on the 3,4, and 5 positions of the acetophenone inhibit the transport activity of P-glycoprotein and prevent the onset of resistance to therapy [155,159]. 

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4.1.XN Acyl Derivatives

Starting from the idea that esterification of flavonoids is a way to modify the hydrophobic character of compounds, a series of mono- and diacetylated derivatives of XN (compounds 14-20, Tables S1 and S2) were synthesized by Zolnierczyk et al. The antiproliferative activities of XN and its derivatives were tested in vitro on HT-29 cell lines. Three compounds from the series(compounds 14-16)showed XN-like bioactivities and four tested compounds(compounds 17-20) had lower bioactivities. From the obtained series, no compound had higher activity than XN [215].

Another series of XN derivatives were obtained by cyclizing the prenyl group from its structure. Thus, a series of six cyclic derivatives of chalcones (Tables S1 and S2, compounds 21-26) were obtained by Poplonski et al. The antiproliferative activity of the obtained compounds was evaluated on three human cell lines(MCF-7, PC-3, and HT-27). The potency of the XN derivatives was evaluated by the SRB method. All compounds obtained showed moderate/increased bioactivity, the most vulnerable cell line being MCF-7. Compounds 21and 23((E)-1-(5-hydroxy-7-methoxy-2,2-dimethyl-2H-chromen-6-yl)-3-(4-hydroxyphenyl)prop-2-en-1-one and(E)-1-(5-hydroxy-7-methoxy-2,2-dimethylchroman-8-yl)-3-(4-hydroxy phenyl) prop-2-en-1-one)showed the best activity on PC-3 lines, their action being comparable to the activity of the standard (cis-platinum) [216].

4.2. Chalcone Derioatioes Containing a Diaryl Ether Moiety

Wang et al. synthesized chalcone derivatives with a diaryl ether residue (Tables S1 and S2, compounds 27-42) in the molecule and evaluated their antiproliferative activity on three cell lines (MCF-7, HepG2, and HCT116). Results show that most of the compounds have a moderate/good activity, on the three cell lines, with an IC50 between 3.44 ±0.19 and 8.89±0.42μM. From the obtained series， the compound substituted with 4-methoxy on the aldehyde(Tables S1 and S2, compound 28) is the most active compound (IC50=3.44±0.19,4.64±0.23, and6.31±0.27uMon MCF-7, HepG2, and HCT116, respectively). Replacement of the 4-methoxy group with 4-dialkylamino (Tables S1 and S2, compound 29)resulted in a significant decrease in inactivity. This compound is a potent inhibitor of tubulin polymerization, with a colchicine-like mechanism. Additionally, 4-methoxychalcone (compound 28) has antiproliferative properties on MCF-7 cells by increasing the percentage of cells in the G2/M phase. In addition, the chalcone induces apoptosis of MCF-7 cells, as determined by the Annexin V-FITC/PI method. Docking studies indicate binding energies of -8.0 kcal/mol for binding the tubulin compound 28, in the pocket of which it adopts a Y-shaped conformation. The 4-methoxy and trimethoxyphenyl groups of the compounds form strong hydrophobic bonds with residues Ala180, Cys241, Leu248, Ala250, Leu255, Ala316, Val318, and Ala354. Additionally, the phenyl group of the compounds forms a cation-Interaction with the Lys254 residue. In addition, the compound forms two hydrogen bonds with residues Asn101 and Ser178. These interactions facilitate the anchoring of compound 28 to the tubulin-binding site [150,217]. 

4.3. Chalcone Derioatioes Containing a Sulfonamide Moiety

α,β-Unsaturated derivatives of sulfonamide(Tables S1 and S2, compounds 43-54)were obtained and physicochemically characterized by Castano et al. From a series of compounds， compounds 43，44， 45， and 50 had a cytotoxic effect at 10 μM. All hybrid molecules were active on the HTC-116 cell line (-78.33-44.62%)and U251(a glioblastoma cell line,-4.20-35.40%). Compounds 44 and 50were the most active on most cell lines （IC50=0.57-12.4 μM for compound 44 and 1.56-40.1 uM for compound 37）. Chalcone 44 had the best activities on K562 leukemic cell lines（IC50=0.57 μM）. The compound also had a good ability to inhibit HCT-116 lines (IC50=1.36 uM, LOX IMVI melanoma lines （IC50 = 1.28 μM）， and MCF-7 （IC50 =1.30 μM） 【218】.

4.4. Bis-Chalcone Derioatioes

Compounds that have two subunits of chalcones in the molecule are called bis-chalcones. Some bis-chalcones are cytotoxic agents on various human cell lines(A549, DU145, KB(a keratin-forming tumor cell line), HeLa, and KB-VN). Bis-chalcones with a biphenyl residue in the molecule are active on MCF-7, MDA-MB 231, HeLa, and HEK-293 (human embryonic kidney)cell lines. Starting from these premises, a series of eight bis-chalcones (Tables S1 and S2, compounds 55-62) were synthesized, whose anticancer activity was evaluated on the MCF-7 and Caco2 cell lines by the MTT method. All compounds from the series had superior cis-platinum activity on the tested cell lines. The bis-chalcone substituted with two fluoro groups in positions 2 and 5 (compound 61)had the best IC50 values on the MCF-7 cell lines（1.9 μM）， indicating an approximately three-fold better activity than the other compounds from the series. Morphological changes determined on MCF-7 cells at 24 h by the bis-chalcone demonstrate a significant decrease in the level of cell confluence compared with other compounds. For the Caco2 cell lines, the results were similar to those for MCF-7. Additionally, compounds 61 and 62 had the highest toxicity on the cell lines, and compounds 58 and 59 had the lowest activity [140].

4.5. Chalcones with Nitrogen in the Molecule

Aminochalcones are known to have strong cytotoxic effects. For example,2-amino chalcones with a methylenedioxy residue in the molecule show very good activity on human nasopharyngeal squamous cell carcinoma (KB-VIN)cell lines. In addition, another study indicates that unsubstituted 2-amino chalcones on the aldehyde have pro-apoptotic effects on 20 apoptotic markers [219].

Starting from the fact that different substituted 2-amino chalcones show cytotoxic activity on different cell lines, such as KB (nasopharyngeal squamous cell carcinoma), MCF-7, A-549, and 1A9(ovarian cancer), and are inducers of apoptosis on HT-29 cells, a series of amino chalcone derivatives were obtained (Tables S1 and S2, compounds 63-80). The anticancer activity of the obtained compounds was evaluated on four cell lines(HT-29, LS180(an intestinal human colon adenocarcinoma cell line), LoVo(a colon cancer cell line), and LoVo/Dx by the SRB method. The standards used were cis-Platine and doxorubicin. Among compounds obtained, the best inhibitory capacity was exhibited by a compound with an unsubstituted aldehyde (compound 63). The activity of the compound on HT-29 cell lines was IC50=1.43 ug/mL, being 12 times higher than the activity of cis-platinum(IC50 = 16.73 ug/mL) and 4 times lower than the activity of doxorubicin (IC50=0.33 ug/mL). From the 4-amino chalcones (compounds 75-80), the unsubstituted compound on the aldehyde (compound75) had the best activity. Similarly, the activity of 3-amino chalcones （compounds 69-74）varied on the tested cell lines（IC50=1.60-2.13 μg/mL）. The potency of these compounds was superior to that of cis-platinum. In the case of the amino carboxylic derivatives (compounds 65, 71, and 77), the position of the amino group had a significant impact on the IC50 value. The activity varied in the following order:2-amino(compound65)>3amino (compound 71)>4-amino (compound 77). It was also observed that the incorporation of a nitro group at position 4 of the aldehyde (compounds 66, 72, and 78) caused decreased inactivity [220].

Series of amino chalcones and nitrochalcones were obtained in order to evaluate their cytotoxicity. The activity was determined by the MTT method on melanoma cell lines. Compared with nitrochalcones, amino chalcones (Tables S1 and S2, compounds 81-91)have the advantage of increased solubility in biological media. It was determined that substitution of chalcones with an amino group is favorable, the activity of these compounds being superior to that of nitrochalcones. The IC50 values showed that the presence of an amino group on the aldehyde caused an increase in cytotoxicity and amino group compounds on the acetophenone to have a weaker activity. For example, compound 87 (in which the amino group is on the aldehyde residue)has higher cytotoxicity than compound 86(in which the amino group is on the acetophenone residue). Additionally, the number of methoxy groups on the acetophenone determines the inhibitory potency of these compounds. Data obtained indicate that amino chalcones substituted with two or three methoxy groups are more active. In the case of chalcones substituted with an amino group on position 3 of the aldehyde(compounds 87 and 90), the cytotoxicity is higher compared with amino-substituted compounds on position 4(compounds 88 and 89). From the chalcones obtained, compound 87 (with an amino group on position 3 of the acetophenone and with four methoxy groups) had the best activity [221].

Wang et al. obtained a series of amino chalcones (compounds 92-103, Tables S1 and S2) that were evaluated for anticancer activity on cell lines (HTC116 and HepG2) by the MTT method. All compounds were found to have a good/moderate cytotoxic capacity. The unsubstituted nitrogen compound (compound 92) had the best activity (IC50=0.28 ± 0.06 for HCT116 and 0.19 ± 0.04 for HepG2). Substitution of the amine with alkyl groups (compounds 93,94,96, and 98) caused a significant decrease in antiproliferative activity. A marked decrease in activity was observed on the amino chalcone with two 4-(tertbutyl)benzyl residues(compound 99). Results obtained from the in vitro evaluation of the tubulin inhibition capacity for compound 92 indicate that its molecular target is tubulin, the IC50 value for amino chalcone being 7.1 uM and for colchicine being 9.0 μM. It was also observed that the amino chalcone (compound 92) had the ability to increase the proportion of cells in the G2/M phase and to block the cell cycle. Docking studies for compound 92 show that it binds to the binding site of colchicine in tubulin. The amino chalcone adopts an"L-shaped" conformation in the tubulin pocket. The 4-methoxynaphthyl group of the amino chalcone is located in the hydrophobic pocket, being surrounded by residues Cys241, Leu248, Ala250, Leu255, le318, and Ala354, with which it forms a strong hydrophobic bond [222].

Modification of the amino group in the structure of amino chalcone determines every time an increase in the anticancer activity of compounds [223]. Starting from this premise, we performed a literature study on the antitumor activity of some heterocyclic chalcones with nitrogen in the molecule (azoles).

4.5.1.Azoles

Azoles (imidazole, oxazole, pyrazole, tetrazole, thiazole, 1,2,3-triazole, and 1,2,4-triazole, Figure 8)constitute the most important class of nitrogen heterocycles. Azoles are important pharmacophores for the identification of new anticancer agents. Some azole derivatives (cicatrizing, carboxyamidotriazole, and AZD8835) are used clinically or are in clinical trials for the treatment of various cancers. Hybridization of chalcones with azoles is considered to be an important way to identify new anticancer agents [162].

4.5.2. Imidazole

Imidazole (Figure8), a five-atom heterocycle, has an increased polarity due to the presence of two nitrogen atoms. The system has an amphoteric character(it can have basic or acidic properties). Imidazole is known to be present in many biologically active compounds with anticancer properties [224,225]. Different substituted 2-benzimidazole derivatives are active on cell lines of breast adenocarcinoma, human hepatocellular carcinoma, and human colon carcinoma [226].

4.6. Iidazole Chalcone Derioatices

Oskuei et al.obtained imidazolechalcones (Tables S1 and S2, compounds 104-121)to evaluate their ability to inhibit tubulin. The antiproliferative activity of the compounds was evaluated on four different cancer cell lines (A549, MCF-7, MCF-7/MX(a mitoxantrone-resistant human breast cancer cell line), and HepG2). Many compounds of the obtained series showed medium/high antiproliferative activities at micromolar concentrations. In general, imidazole chalcones had higher cytotoxicity on A549 cell lines compared with the other cell types analyzed. The compound substituted with three methoxy groups on the acetophenone (Tables S1 and S2, compound 121)had the best activity, which can be explained by the presence of a trimethoxyphenyl subunit as an important pharmacophore for potent tubulin inhibitors (e.g., combretastatin A4, Figure 7). The increased cytotoxicity of theimidazolechalcone with a trimethoxyphenyl residue (compound 121)was due to its interaction with tubulin. Compounds in which the phenyl residue on the acetophenone was replaced by a naphthyl residue (compound 108, compound 117) had a good potency. This can be explained by the ability of these chalcones to penetrate the cell membrane due to the increased lipophilia. These compounds have favorable interactions with active sites of tubulin. Application of the tubulin polymerization method showed that the obtained imidazole chalcones inhibited, in a concentration-dependent manner, tubulin polymerization in a manner similar to combretastatin A4. In addition, the cytotoxicity of the most active compounds in the series was correlated with blockade of the cell cycle in the G2/M phase and induction of cellular apoptosis. Docking studies showed that an imidazolechalcone with three methoxy groups(compound 121)on the acetophenone had the best ability to bind to the colchicine binding site of tubulin. The compound has two interactions through hydrogen bonds with catalytically active residues (Ser178α and Ala316β) and a cation-II interaction with Asn258β. Other hydrophobic interactions were observed between the compound and residues Glu183α, Thr224α, Lys254β, Asn101α, Val351β, Lys352β, and Leu248β. Hydrophobic interactions and hydrogen bonds formed between the compound and tubulin were found to be responsible for its inhibitory effect [227].

4.6.1. Pyrazole

Pyrazole(Figure 8)is an important component of five-membered heterocycles in molecules. Two nitrogen atoms are in adjacent positions. Of these, one is basic and one is neutral. Numerous methods have been identified for obtaining pyrazole derivatives, which are important elements of medicinal chemistry. Studies have shown that some pyrazole derivatives have anticancer properties. For example, pyrazole as a pharmacophore for anticancer compounds such as Ruxolitinib (blood cancer), Axitinib(kidney cancer), and Crizotinib (lung cancer) [228-231].

4.6.2. Pyrazole Chalcone Derivatives

A series of nine chalcones with a pyrazole in the molecule (Tables S1 and S2, com-pounds 122-130) were synthesized in order to evaluate their anticancer potential. Cytotoxicity was evaluated in vitro on A549 cell lines using the MTT method. The compound substituted with a trimethoxyphenyl residue on the acetophenone(compound 124) was the most active, its anticancer potential being present at macromolecular concentrations. Results obtained are in accordance with data from the literature indicating pharmacological activities of pyrazoles with a trimethoxyphenyl residue in the molecule (anticancer, an-

antiproliferative, and anti-tubulin properties). For the obtained compounds, docking studies estimated binding interactions between Lys347, Lys356, and Glu354. Results indicate the presence of strong binding interactions between the methoxy group of the compound with a trimethoxyphenyl residue on the acetophenone and the hydrogen atom of Lys356, between the carbonyl oxygen with the hydrogen atom of Lys356 and LYS347, and between the hydrogen from benzopyrone with the atom of Lys4747 [232]. Hawash et al. obtained hybrid chalcone molecules with 1,34-trisubstituted pyrazoles (Table S1, compounds 131-172)with a heterocycle. Bioactivities of the derivatives were analyzed for HCT116, hepatocellular (Hub7), and MCF-7 cell lines. In general, compounds that had a thienyl subunit in the 3rd position of the pyrazole (compounds 131-138) had a very good antiproliferative activity. Compounds with methoxy groups in positions 3 and 4 or 2 and 5 of the phenyl on the chalcone (compounds 135,136,143,144,160, and 170)had IC50 values of 0.4-3.4 uM on Hub7, MCF-7, and HCT116 cells. Replacement of the thienyl residue with benzo [d][1,3]dioxo-5-yl(compounds 139-150) resulted in a significant decrease in cytotoxicity [233].

4.6.3. Tetrazole

Tetrazole, an unsaturated double heterocycle with five atoms, contains four nitrogen atoms and one carbon atom. Biologically active substances with tetrazole in the molecule have increased bioavailability, and replacement of the carboxylic acid with tetrazole causes an increase in bioavailability and a reduction in adverse effects. The tetrazole derivative letrozole is used clinically for the treatment of tamoxifen-refractory breast cancers [234].

Tetrazole Chalcone Derivatives

Monaem et al. obtained a series of tetrazole chalcones (Tables S1 and S2, compounds 173-179). For the obtained compounds, cytotoxicity was evaluated by the MTT method on HCT116, PC3, and MCF-7 cell lines and on Vero B(African green monkey kidneys). Results were compared with cisplatin and 5-fluorouracil. Many of the compounds obtained had an activity higher than that of the standards on HCT-116 and PC-3 cell lines. Cyclization of chalcones to the corresponding pyrazolines resulted in a decrease in activity [235].

4.6.4. Thiazole

Thiazole, a heterocycle derived from thiosemicarbazide, is present in compounds with antiparasitic, antifungal, and antiproliferative properties. Compounds with 1,3-triazole substituted in positions 2 and 4 are pharmacophores for tumor agents with significant activity. Thiazole derivatives have antiproliferative properties that correlate with inhibition of metalloproteases, some kinases, and Bdl2 family proteins [236]. Two heteroatoms (nitrogen and sulfur) have electron pairs that have the ability to form hydrogen bonds with amino acid residues of receptor proteins. These interactions are responsible for the apoptotic action of thiazole compounds on cancer cells. The heterocycle is a pharmacophore for anticancer agents such as epothilones, ixabepilone, bleomycin, thiazofurine, dasatinib, and kud773[237].

Thiazole Chalcone Derivatives

Farghali et al. obtained thiazole chalcones (Tables S1 and S2, compounds 173-178). The antiproliferative activity of the obtained compounds was determined on three cell lines (HepG2, A549, and MCF-7).Compound 178(3-(4-Methoxyphenyl)-1-(5-methyl-2-(methylaminothiazol-4-yl)propen-2-en-1-one) had superior anticancer activity to doxorubicin and a wide range of activities. The chalcone has IC50=1.56， 1.39， and 1.97 μM on HepG2, A549, and MCF-7 lines, respectively, the values being half of the doxorubicin values （IC50=3.54，3.19， and 4.39 μM， respectively）. From the six thiazole chalcones， five compounds showed very good cytotoxicity on the cell lines tested, and the compound substituted with a 2,4-chlorophenyl residue (compound 178) had a moderate level of activity. To evaluate the selectivity between tumor and normal cells, three chalcones with very good cytotoxic potential were tested on the non-cancerous lung cell line WI-38. Elevated IC50 values(93.44-137.36 uM)indicated selective cytotoxicity in malignant lung cells. The safest chalcone was found to be the one substituted with 4-methoxyphenyl (compound 173). This chalcone inhibited HepG2, A549, and MCF-7 cells 88.04,98.8, and 69.72 times more than WI38 cells. The derivative also significantly blocked the cell cycle in the G2/M phase. The chalcone increased the DNA content in the G2/M phase by 2.6 times and decreased the amount of DNA in the G0/G1 and S phases compared with control cells. In addition, the compound caused a 14.3-fold increase in the percentage of pre-G1 cells compared with the control group, which indicated a possible role of the chalcone in apoptosis. The apoptotic capacity of the compound was assessed by the Annexin V-FITC method. The percentage of apoptotic cells increased significantly, indicating the ability of the compound to induce apoptosis. Docking studies of the three most active chalcones show that they bind to ATP at the CDK1 binding site, the binding energies being-6.373, -5.857, and 5.519. The compounds bind in the same way to amino acid Leu83, by forming two hydrogen bonds between the thiazole sulfur and between the 2-aminomethyl group and Leu83. In addition, two chalcones have the ability to form another hydrogen bond with the Glu81 residue of the target enzyme at the level of the sulfur on the thiazole [238].

Suma et al obtained and physicochemically and biologically characterized ten chalcones with a thiazole-imidazopyridine residue in the molecule (Tables S1 and S2, compounds 179-188). The obtained compounds were tested on four cell lines (MCF-7, A549, DU-145 (a prostate carcinoma cell line), and MDA MB231(a breast carcinoma cell line)). The method by which the anticancer activity was tested was the MTT method, and the standard used was etoposide. The most active compound from the series had three methoxy groups in positions 3, 4, and 5 of the acetophenone (compound 180).IC50 values of compound 180 for MCF-7， A549，DU-145，and MDA MB-231 were 0.18± 0.094 μM，0.66 ± 0.071 μM， 1.03± 0.45 μM， and 0.065±0.082 μM， respectively.

Compound with a single methoxy group on acetophenone (compound 182) had a much lower anticancer activity. From SAR studies, it was observed that the presence of three methoxy groups (electron donors) determines a significant increase in bioactivity in the case of thiazole-imidazopyridine derivatives. Docking studies were performed on three potential targets: protein kinases CLK1(5X81), EGFR (2J5F), and tubulin (1SAO). Scores obtained indicated a correlation between the activity of compounds and their action on CLK1 [239].

4.6.5.Triazole

Triazole is a Penta-atomic heterocyclic organic compound that contains three nitrogen atoms and two carbon atoms. It is present in two isomeric forms, 1,2,3-triazole and 1,2,4-triazole [240]. The heterocycle is an important pharmacophore for molecules with anticancer, anti-HIV, anti-inflammatory, and antituberculosis properties. The compound 1,2,3-Triazole is a basic element of medicinal chemistry because it has the ability to form hydrogen bonds with important biological targets [241]. The compound 1,2,4-triazole also influences the lipophilia, polarity, and ability of molecules to form hydrogen bonds [242].

Triazole Chalcone Derivatives

Studies from literature show that 1,2,3-triazole-chalcone hybrid molecules have re-markable anticancer activities on SK-N-SH cell lines(IC50=1.52 uM) by inducing apoptosis [243]. Hybridization of 1,2,4-triazole ring with a chalcone also caused significant inhibition of cancer cell growth and induced apoptosis of A549 cells dependent on caspase 3 activity with an IC50=4.4 μM（compound 189） compared with-platin's IC50=15.3 μM【244】. Gurrapu et al.synthesized 1，2，3-triazole chalcones （Tables S1 and S2， compounds 190-198) and their cytotoxicity was determined experimentally and in silico. The cancer cell lines on which cytotoxicity was determined were MCF-7, HeLa, and MDA MB231, and the method used was the MTT method. From the nine compounds tested, the triazole derivative with chlorine in the meta position of the substituent attached to the triazole and two methoxy groups on the acetophenone (compound 196) showed the best activity on all lines tested （e.g.， IC50 for MCF-7=1.27 μM and 0.02 μM at 24 and 48 h， respectively）， the results obtained for this compound being comparable to those of cis-platin. A decrease in viable cells was observed by increasing the concentration. Results of the application of the cell viability method showed that triazole chalcones have good oral bioavailability. Drug-likeness was determined by the number of rotating free bonds and rules of Lipinski, Veber, Eagan, and Mugge. All compounds from the series had good pharmacokinetic profiles and satisfied the criteria for drugs. Series comprised pharmacophores having a triazole nucleus bound to a residue -OCH2-. Compounds having electron donor groups, in particular, molecules substituted with chlorine in meta position of triazole ring and two methoxy groups in meta and para positions of acetophenone (compound 150), with chlorine in the meta position of the substituent on the triazole and a hydroxy group in meta position of chalcone(compound 194), or methyl in meta position of the substituent attached to triazole and with two methoxy residues (compound 193) were the most active cytotoxic agents from the series. A possible binding mode for obtained compounds was determined for EGFR kinase. Molecules had a range between -8.102 and -6.008 kcal/mol and values of binding energies between -83.05 and 43.696 kcal/mol. Compound with chlorine in meta position of substituent attached to triazole and a hydroxy group in meta position of chalcone (compound 198) showed highest scores(-8.102 and -83.05 kcal/mol). This compound forms a hydrogen bond interaction with Asp800, strong I-II interaction with Phe856 and Phe997, and an II-cation interaction with Lys745. For all compounds from the series, the phenyl attached to the triazole forms II-II interactions with Phe856. The phenolic hydroxy group forms interactions through hydrogen bonds with amino acid Asp800 [245].

5. Conclusions

Cancer is a disease triggered by many mechanisms and is a major public health problem. Chalcones are precursors to all other flavonoids and to many other heterocyclic compounds. The advantages of these compounds are related to their numerous biological properties, their lack of adverse effects, the possibility of obtaining them easily, and the possibility of forming numerous biologically active compounds by modulating their basic structure. In addition, chalcones are a starting point for the identification of new anticancer compounds. Natural and synthetic chalcones have antitumor properties in vivo and in vitro and are also active in drug-resistant cancers.

An important mechanism of the antiproliferative activity of chalcones is inhibition of tubulin and interference of these compounds with the assembly of microtubules. Substitution of chalcones with three methoxy groups is favorable for their anti-tubulin activity, as these compounds have a structure that is similar to A4 combretastatin. Hybridization of chalcones with anticancer pharmacophores is favorable for their activity. For example, the introduction of an azole into a molecule of these compounds has led to a significant increase in their biological properties. This fact can be correlated with the binding of these compounds and with the favorable change in lipophilic parameters.

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