**2.2. Isoflavonoids and their cytotoxic activities**

tetrahydroxy flavonoid having many health benefits and it effects on short- and long-term growth of BRAF-mutated A375, SK-MEL-28 and RPMI-7951 melanoma cancer cells. Results of MTT assay demonstrated that fisetin (10–60 μM) treatment significantly decreased the growth of A375 8.64–61.75%, SK-MEL-28, 6.94–59.79% and RPMI-7951, 11.60–64.11% cells in a concentration-dependent manner [19]. Hispidulin is found in many herbs and significantly inhibited HepG2 cell growth in a time and dose-dependent manner. Hispidulin (at 200 μM) inhibited the growth of HepG2 cells by nearly 50, 70 and 90% after 24, 48 and 72 h of treatment, respectively, which suggest that hispidulin promotes HepG2 cell death through apoptosis. It inhibited cell growth in a dose-dependent manner in (HRCC) lines 786-0 and Caki-1 cell lines, whereas Caki-1 cells were found to be more resistant to hispidulin treatment [20, 21]. Quercetin is a dietary flavonoid (berries flavonoid) showed strong cytotoxicity as 1.49-fold in MCF-7 cells and 1.98-fold in MCF-7/dox cells. It suppressed proliferation and survival of HepG2 cancer cells and induced apoptosis by enhancing the expression of p53 and BAX through downregulation of ROS, PKC, PI3K and COX-2 [22, 23]. Hesperetin a citrus flavonoid exhibited inhibition of cell growth in a concentration and time-dependent manner with IC50 at 72 h 200 μM. It could significantly promote apoptosis of Eca109 cells in a dose-/time-dependent manner [24]. Apigenin a trihydroxy flavonoid with potential health benefits exhibited strong growth inhibitory activity in HER2/neu breast cancer cells but was much less effective in inhibiting growth of cells expressing basal levels of HER2/neu. It induces apoptosis in MDA-MB-453 breast cancer cells with involving intrinsic and extrinsic apoptotic pathways. It has shown to downregulate levels of cyclin D1, D3 and cdk4 and increases p27 protein levels in breast cancer cells. Apigenin inhibited human cervical carcinoma HeLa cells growth through an apoptotic pathway. In various human colon carcinoma cells, it resulted cell growth inhibition and G2/M cell cycle arrest. The effects of apigenin on lung cancer cells were evaluated and it inhibited A549 lung cancer cell. It has capability to significantly reduce cell number and induce apoptosis in PWR-1E, LNCaP, PC-3 and DU145 cells [25, 27]. Quercetin-3-*O*-β-dglucopyranoside also known as isoquercetin and found in mangoes in high amount and it is an interesting dietary compound worth further investigation as a cytoprotective agent. Pretreatment of PC12 cells with nontoxic concentrations of this compound protect cells from

38 Phenolic Compounds - Natural Sources, Importance and Applications

 induced cytotoxicity with decrease in generation of reactive oxygen species (ROS). These observations qualify it as cytoprotective dietary compound [27]. Amplexicaule A is found in many herbs and it increased levels of cleaved caspase-3,-8,-9 and PARP, resulted from suppression of MCL-1 and BCL-2 expression in cells. This compound inactivated the Akt/mTOR pathway of breast cancer cells. It influenced strongly on breast cancer cells, most likely by induction of apoptosis [28]. Triticuside A a dietary flavonoid found in wheat and induced apoptosis accompanied by a significant decrease in Mcl-1 and Bcl-2 proteins and by increase in cleavage of caspases-3, -7, -9 and PARP. It suppressed the level of phospho-Akt and its downstream targets, mTOR and P70 S6 kinase. LY294002, a specific inhibitor of PI3K, significantly enhanced the triticuside A induced apoptosis. It may a potentially useful wheat bran

Naringin is a diglycoside flavonoid and found in many citrus fruits and it inhibited cell proliferation and promoted cell apoptosis and G1 cycle arrest, accompanied by increased p21 and decreased surviving. Significant inhibitory effects of naringin on the cell proliferation of TNBC cells were observed. MDA-MB-231 and BT-549 cells treatment with naringin (50, 100

component and can used for treatment of breast cancer [29].

H2 O2 Isoflavonoids play very important role in human health-promoting natural chemicals. They belong to plants secondary metabolites, mediate diverse biological functions through numerous pathways. Isoflavonoids are phenolic compounds and possess a 3-phenylchroman skeleton that biogenetically derived from 2-phenyl chroman skeleton of flavonoids. Some studies reported that anticarcinogenic activities of dietary soy isoflavonoids play important role for preventing colorectal cancer. Isoflavonoids have shown to possess many biological properties that can account for cancer prevention. Isoflavones exert their effects through numerous pathways with respect to the cancer prevention; and it use mechanisms of action which appear to be various, complementary and overlapping.

Genistein is a soybeans isoflavones and it decrease the risk of breast cancer and induced downregulation of CIP2A in breast cancer cells MCF-7-C3 and T47D, which correlates with its growth inhibition and apoptotic activities. In a model of human prostate carcinoma, treatment with genistein, decreased the metastatic burden, without changing the size of primary tumor and cell detachment were also decreased. According to studies, patients with PCa effectively tolerate genistein and therapeutic modulation of metastasis, specifically MMP-2 (matrix metallopeptidase 2) is possible [39, 40]. Inhibitory effect of daidzein investigated by

**Figure 1.** Structures of flavonoids **1**–**35**.

bacterial flora in intestines, on DU145, LnCaP and PC3 human prostate cancer cell. The results provide a better understanding of the biomolecular mechanisms of this compound as natural anticancer agent and provide base for development of daidzein and its analogs as potent anticancer molecules [39]. Biochanin A is found in nuts and beers and it effects on pancreatic cancer progression and it induced dose-dependent toxicity on pancreatic cancer cells Panc1 and AsPC-1. It reduced colony formation ability of Panc1 cells and induced dose-dependent apoptosis [40]. The IC50 value of Alpinum isoflavone ranged from 5.91 μM towards leukemia CEM/ADR5000 cell and to 65.65 μM towards drug-resistant breast adenocarcinoma MDA-MB-231-*BCRP* cells. This sioflavone induced apoptosis of CCRF-CEM cells, mediated by the loss of MMP and increase the ROS production [41]. Puerarin prevents the proliferation of breast cancer cells (MDA-MB-231, HS578T and MCF-7) at 50% of cell growth inhibition with concentration of 46, 71 and 69 μM, respectively. Puerarin was further preventing three different types of breast cancer in the G0/G1 phase of the cell cycle and stimulated apoptosis in these cells [42] (**Figure 2**).

**Figure 2.** Structure of isoflavonoids **36**–**40**.

**Figure 1.** Structures of flavonoids **1**–**35**.

40 Phenolic Compounds - Natural Sources, Importance and Applications

### **2.3. Chalcone and their cytotoxic activities**

Chalcones mainly belongs to flavonoids family and known as open chain flavonoid in which two aromatic rings A and B structurally joined by α,β-unsaturated carbonyl system. Plants containing chalcones have been used traditionally as anti-inflammatory, antioxidant, antimalarial, antimicrobial, antifungal, antitubercular, cytotoxic, antiviral, antitumor and chemopreventive agent. These are very common phenolics specially founds in Leguminosae, Moraceae and Asteraceae families.

Butein is a natural dietary chalcone has many traditional uses and a herbal medicine. It reduced the cell viability of cultured human uveal melanoma cells in a dose-dependent manner with IC50 at 13.3 and 15.8 μM in SP6.5 and M17 cell lines, respectively. Similar effects were also found in a highly aggressive and metastatic C918 cell line (IC50 16.7 μM). At 2 μM concentration, it inhibited the incorporation of 14C-labelled thymidine, uridine and leucine into the colon cancer cells whilst 5-fluorouracil (5-FU, a chemotherapeutic drug) at 50 μM concentration. The cytotoxic action of butein was different from 5-FU but may be similar to colchicine, a known HeLa cell inhibitor. Butein inhibit telomerase activity by downregulating hTERT gene expression in human leukemia cells and it causes apoptosis of breast cancer cells, while luminal HER2<sup>+</sup> HCC-1419, HCC-2218 and SKBR-3 breast cancer cells. Treatment with butein (10–30 μM) decreased cell viability in LNCaP (29, 42 and 52%), CWR22Rν1 (20, 31 and 42%) and PC-3 (11, 22 and 35%) cells. It inhibited colony formation, cell viability, migration, invasion, induced cell cycle at G2/M stage, cell apoptosis and enhanced caspase-3, -8 and -9 activity in HeLa cells in a dose-dependent manner [43–47]. Isoliquiritigenin is a natural chalcone and used for the treatment of cancer, it is cytostatic and able to overcome the intrinsic resistance of U373 cancer cells to proapoptotic stimuli. After 72 h treatment with 10 μg mL−1 of isoliquiritigenin, a typical differentiated morphology observed in HL-60 cancer cells, including the decrease in karyoplasmic ratio and the increase in kidney-shape nuclear cells. This compound is able to induce the monocytic differentiation in leukemia cells. It has potential as a drug for leukemia. HepG2 cells are significantly more resistant to isoliquiritigenin when the activity of p53 was blocked. Isoliquiritigenin inducible p53 plays a key apoptotic role and may do so by regulating the expression of specific target molecules that promotes efficient apoptotic cell death following G2/M-cell cycle arrest. It inhibits the proliferation of prostate cancer cells, via inhibition of ErbB3 signaling and PI3K/Akt pathway [48]. 2′,4′-dihydroxy-6-methoxy-3,5-dimethylchalcone tested on human cell lines including liver cancer SMMC-7721 cells, pancreas cancer 8898 cells, tumor of cervix uteri HeLa cells, lung cancer SPC-A-1 cells, high metastatic lung carcinoma 95-D cells and gall bladder carcinoma GBC-SD cell lines was dose-dependent. It observed that different cells had a different sensitivity for inhibition effect of this chalcone. The IC50 values on cytotoxicity were 32.3, 37.2, 37.7, 81.3, 84.6 and 84.8 μM for SMMC-7721, 8898, HeLa, GBC-SD SPC-A-1 and 95-D cells, respectively [49, 50]. 4′-hydroxy-2′,6′-dimethoxychalcone showed IC50 values in a range of 2.54 μM against CEM/ ADR5000 leukemia cells to 58.63 μM towards hepatocarcinoma HepG2 cells. This compound arrested cell cycle between Go/G1 phase and induced apoptosis via disrupted mitochondrial membrane potential MMP and increased production of reactive oxygen species (ROS) in the studied leukemia cell line [51]. Xanthohumol is a prenylated chalcone found in beers; it caused dose dependent (0.1–100 μM) decrease in growth of MCF-7, HT-29 and A-2780 cancer cell lines. After two-day treatment, the concentrations at which growth of MCF-7 cells was inhibited by 50% (IC50) were 13.3 μM for xanthohumol. After four-day treatment, IC50 for xanthohumol was 3.47 μM [52, 53]. Flavokawain B is known as kava chalcone and it induced caspase and mitochondria-dependent apoptosis which characterized by cytochrome c release and Bak translocation to mitochondria. It induces G2/M accumulation, autophagy and apoptosis, leading to HCT116 colon cancer cell growth inhibition. It further induced both MCF-7 and MDA-MB231 and significant G2/M arrest was seen in MDA-MB231 cells [54]. Isolespeol is a geranyl chalcone and it showed inhibitory activity against human liposarcoma cells SW 872 with IC50 values of 3.8 μM. Treatment of SW 872 human liposarcoma cells with this compound stimulated increase protein expression of Fas, FasL and p53 [55]. Xanthoangelol and 4-hydroxyderricin inhibit adipocytes differentiation through AMPK and mitogen-activated protein kinase pathways, resulting in the down-expression of adipocyte-specific transcription factors. Xanthoangelol induce apoptotic cell death by activation of caspase-3 in neuroblastoma and leukemia cells through a mechanism that does not involve Bax/Bcl-2 signal transduction. Therefore, this compound may effective drug for the treatment of neuroblastoma and leukemia. 4-Hydroxyderricin showed significant cytotoxicity in four human tumor cell with IC50 values 4.8 μM (CRL1579), 5.5 μM (HL60), 4.2 μM (AZ521) and 10.2 μM (A549). 4-Hydroxyderricin induced further the early apoptosis of HL60 cells and it observed as membrane lipid exposure in the flow cytometry [56, 57]. The IC50 values for Isobavachalcone is a prenylated chalcone and having wide range of biological activities including anticancer, it ranged from 0.20 μM (towards CCRF-CEMcells) to 195.12 μM (towards leukemia CEM/ADR 5000 cells) for doxorubicin. It induces apoptosis in CCRF-CEM leukemia cells, mediated by caspase activation and the disruption of MMP [58]. Cytotoxicity of Poinsettifolin B assessed against different sensitive and multidrug-resistant cancer cell lines. The IC50 values for this compound ranged from 5.34 to 1.94 μM towards CCRF-CEM leukemia cells, to 33.30 and 28.92 μM towards human breast cells MDA-MB-231-BCRP, respectively and from 0.20 μM against human leukemia cell CCRF-CEM, to 195.12 μM against CEM/ADR5000 cells [59]. *2*′-*hydroxy-3,4,4*′,*5,6*′-*pentamethoxychalcone is very potent in inhibiting* breast adenocarcinoma (MCF-7), lung cancer (NCI-H460) and melanoma (A375-C5) cell lines [60]. Rhuschalcones II−VI showed potent cytotoxic activities against HCT-116 and HT29 human colon cancer cells [61] (**Figure 3**).

### **2.4. Naphthalenes and their cytotoxic activities**

**2.3. Chalcone and their cytotoxic activities**

42 Phenolic Compounds - Natural Sources, Importance and Applications

and Asteraceae families.

while luminal HER2<sup>+</sup>

Chalcones mainly belongs to flavonoids family and known as open chain flavonoid in which two aromatic rings A and B structurally joined by α,β-unsaturated carbonyl system. Plants containing chalcones have been used traditionally as anti-inflammatory, antioxidant, antimalarial, antimicrobial, antifungal, antitubercular, cytotoxic, antiviral, antitumor and chemopreventive agent. These are very common phenolics specially founds in Leguminosae, Moraceae

Butein is a natural dietary chalcone has many traditional uses and a herbal medicine. It reduced the cell viability of cultured human uveal melanoma cells in a dose-dependent manner with IC50 at 13.3 and 15.8 μM in SP6.5 and M17 cell lines, respectively. Similar effects were also found in a highly aggressive and metastatic C918 cell line (IC50 16.7 μM). At 2 μM concentration, it inhibited the incorporation of 14C-labelled thymidine, uridine and leucine into the colon cancer cells whilst 5-fluorouracil (5-FU, a chemotherapeutic drug) at 50 μM concentration. The cytotoxic action of butein was different from 5-FU but may be similar to colchicine, a known HeLa cell inhibitor. Butein inhibit telomerase activity by downregulating hTERT gene expression in human leukemia cells and it causes apoptosis of breast cancer cells,

butein (10–30 μM) decreased cell viability in LNCaP (29, 42 and 52%), CWR22Rν1 (20, 31 and 42%) and PC-3 (11, 22 and 35%) cells. It inhibited colony formation, cell viability, migration, invasion, induced cell cycle at G2/M stage, cell apoptosis and enhanced caspase-3, -8 and -9 activity in HeLa cells in a dose-dependent manner [43–47]. Isoliquiritigenin is a natural chalcone and used for the treatment of cancer, it is cytostatic and able to overcome the intrinsic resistance of U373 cancer cells to proapoptotic stimuli. After 72 h treatment with 10 μg mL−1 of isoliquiritigenin, a typical differentiated morphology observed in HL-60 cancer cells, including the decrease in karyoplasmic ratio and the increase in kidney-shape nuclear cells. This compound is able to induce the monocytic differentiation in leukemia cells. It has potential as a drug for leukemia. HepG2 cells are significantly more resistant to isoliquiritigenin when the activity of p53 was blocked. Isoliquiritigenin inducible p53 plays a key apoptotic role and may do so by regulating the expression of specific target molecules that promotes efficient apoptotic cell death following G2/M-cell cycle arrest. It inhibits the proliferation of prostate cancer cells, via inhibition of ErbB3 signaling and PI3K/Akt pathway [48]. 2′,4′-dihydroxy-6-methoxy-3,5-dimethylchalcone tested on human cell lines including liver cancer SMMC-7721 cells, pancreas cancer 8898 cells, tumor of cervix uteri HeLa cells, lung cancer SPC-A-1 cells, high metastatic lung carcinoma 95-D cells and gall bladder carcinoma GBC-SD cell lines was dose-dependent. It observed that different cells had a different sensitivity for inhibition effect of this chalcone. The IC50 values on cytotoxicity were 32.3, 37.2, 37.7, 81.3, 84.6 and 84.8 μM for SMMC-7721, 8898, HeLa, GBC-SD SPC-A-1 and 95-D cells, respectively [49, 50]. 4′-hydroxy-2′,6′-dimethoxychalcone showed IC50 values in a range of 2.54 μM against CEM/ ADR5000 leukemia cells to 58.63 μM towards hepatocarcinoma HepG2 cells. This compound arrested cell cycle between Go/G1 phase and induced apoptosis via disrupted mitochondrial membrane potential MMP and increased production of reactive oxygen species (ROS) in the studied leukemia cell line [51]. Xanthohumol is a prenylated chalcone found in beers; it caused dose dependent (0.1–100 μM) decrease in growth of MCF-7, HT-29 and A-2780 cancer

HCC-1419, HCC-2218 and SKBR-3 breast cancer cells. Treatment with

Naphthalenes are simplest and most important member of arenas, in which two benzene rings are fused with each other and it based on a C<sup>6</sup> -C<sup>4</sup> skeleton. Many naphthalene-based natural products have been isolated from different sources and showed significant biological activities.

Syriacusin A inhibit activity of human neutrophil elastase HNE, a serine protease to degrade extracellular matrix ECM proteins including elastin, with IC50 values 8.0, 5.2 and 6.1 μM, respectively [62]. Rumexneposide A showed against broad spectrum activity against human cancer cells lines, including lung and breast cancer cells (A549, H522, MCF-7, MCF-10A, SKBR3) with IC50 value 31.0, 15.7, 21.8, 22.8 and 20.7 μM [63]. Parvinaphthol B, parvinaphthols C showed marginal cytotoxicity against the MDA-MB-231 human triple-negative breast cancer cell line with IC50 values ranging from 62.3 to 129.6 μM [64].

**Figure 3.** Structure of chalcones **41**–**57**.

### **2.5. Anthraquinone and their cytotoxic activities**

Anthraquinones are the active constituents of many herbs with a tricyclic C6-C2-C6-based skeleton. They are widely distributed in the *Fabaceae, Liliaceae, Labiate, Polygonaceae* and *Rhamnaceae* families. Anthraquinone found in herbs (*Polgyonum*) in vegetable (cabbage, lettuce and beans).

Chrysophanol was active in the oophoroma SKOV-3 cell line, where the IC50 value was 5.62 μM and with IC50 value 20.4 μM for MCF-7 breast cancer cell line [65]. 9,10-anthraquinone showed strong cytotoxic activity against COLO320 human colon carcinoma cell line. It gave 79.7% cytotoxicity at 300 μg mL−1 concentration of compound with 75 μg mL−1 IC50 value. The treatment of human colon carcinoma cell line COLO320 with 9,10-anthraquinone significantly decreased the proliferation of cells and enhanced the formation of apoptotic bodies and fragmented DNA. The expressions of p53 and caspase-3 was upregulated from 9,10-anthraquinone in colon adenocarcinoma cells [66]. 2-hydroxy-9,10-anthraquinone showed cytotoxic activity against A549 lung and COLO320 cells lines and it showed 62.7% activity at the dose of 500 μg mL−1 with IC50 value of 400 μg mL−1 against COLO320 cells [67]. 2,3-dihydroxy-9,10-anthraquinone inhibits PI3K/AKT activity after treatment. Also, COX-2 enzyme plays a major role in colorectal cancer and significantly reduced COX-2 enzyme in COLO320 cells. It involves in apoptotic pathway, mitochondrial function, cell cycle checkpoint and control the over expression gene during the colorectal cancer [66]. Chrysophanol 8-O-beta-(6′-acetyl) glucopyranoside exhibited relatively higher cytotoxic activities against human oral squamous cell carcinoma HSC-2 and salivary gland tumor HSG cell lines than against normal human gingival fibroblasts HGF cells lines [69] (**Figure 4**).

### **2.6. Xanthone and their cytotoxic activities**

**2.5. Anthraquinone and their cytotoxic activities**

44 Phenolic Compounds - Natural Sources, Importance and Applications

tuce and beans).

**Figure 3.** Structure of chalcones **41**–**57**.

Anthraquinones are the active constituents of many herbs with a tricyclic C6-C2-C6-based skeleton. They are widely distributed in the *Fabaceae, Liliaceae, Labiate, Polygonaceae* and *Rhamnaceae* families. Anthraquinone found in herbs (*Polgyonum*) in vegetable (cabbage, let-

Chrysophanol was active in the oophoroma SKOV-3 cell line, where the IC50 value was 5.62 μM and with IC50 value 20.4 μM for MCF-7 breast cancer cell line [65]. 9,10-anthraquinone showed strong cytotoxic activity against COLO320 human colon carcinoma cell line. It gave 79.7% cytotoxicity at 300 μg mL−1 concentration of compound with 75 μg mL−1 IC50 value. The treatment of human colon carcinoma cell line COLO320 with 9,10-anthraquinone significantly decreased the proliferation of cells and enhanced the formation of apoptotic bodies and fragmented DNA. The expressions of p53 and caspase-3 was upregulated from 9,10-anthraquinone in colon adenocarcinoma cells [66]. 2-hydroxy-9,10-anthraquinone showed cytotoxic activity against A549 lung and COLO320 cells lines and it showed 62.7% activity at the dose of 500 μg mL−1 with IC50 value of 400 μg mL−1 against COLO320 cells [67]. 2,3-dihydroxy-9,10-anthraquinone inhibits PI3K/AKT activity after treatment. Also, COX-2 enzyme plays a major role in colorectal cancer and significantly reduced COX-2 enzyme in COLO320 cells. Xanthones are three-membered ring compounds with (C6-C1-C6) skeleton and are mainly found in higher plants and microorganisms. Now days, they gained great importance due to their significant pharmacological and biological properties. These types of natural compounds have broad biological profile, such as, antihypertensive, anti-inflammatory, antioxidant antithrombiol, anticancer and antiviral activities. Xanthones are commonly found in Gentianaceae, Moraceae, Guttiferae, Clusiaceae, Polygalaceae in citrus fruits and mangosteen.

Formoxanthone C has α,α,β-trimethylfuran ring and it showed potent cytotoxic activity against NCI-H187 with IC50, 0.22 μg mL−1, which is stronger than elliptecine, a standard drug with IC50, 0.45 μg mL−1 [70, 71]. Phomoxanthone A displayed strong anticancer activity, on the treatment against cisplatin resistant (CisR) cancer cell lines or blood cancer cell lines with an IC50 values in sub-micromolar concentration and it was up to 100-folds less active against PBMC peripheral blood cells from a healthy donors [72]. Garcinone C was tested for cytotoxicity against MCF-7, A549, Hep-G2 and CNE cell lines by 3-(4,5-dimethylthiazol2-yl)-2,5-diphenyltetrazolium bromide (MTT) colorimetric assay, while doxorubicin used as positive control. Garcinone C showed strong cytotoxicity against all cell lines with IC50 values from 4.3 ± 0.1 to 7.1 ± 0.5 μM [73]. Morusignin I 70 and cudraxanthone I inhibited proliferation of all cancer cell lines including sensitive and drug-resistant phenotype. 8-hydroxycudraxanthone G showed activity on many cell lines with IC50 values ranged from 16.65 μM against CCRF-CEM leukemia cells to 70.38 μM against HepG2 hepatocarcinoma cells. The IC50 values of different cells ranged from 7.15 μM against CCRF-CEM human leukemic cells to 53.85 μM against U87MG.∆*EGFR* human glioblastoma cells for morusignin I and 2.78 μM against MDA-MB231 BCRP breast cancer cells to 22.49 μM against U87MG human glioblastoma *cell* line for cudraxanthone I [74]. 1,6,8-trihydroxy-2,3,4,5-tetramethoxyxanthone, 1,6-dihydroxy-2,3,4,5,8-pentamethoxyxanthone were tested for preferential cytotoxic activity against human pancreatic cancer cells PANC-1 under nutrient deprived condition. These compound displayed potent cytotoxicity with PC50 of 22.8 and 17.4 μM, respectively. They triggered apoptosis-like PANC-1 cell death in NDM with glucose sensitive mode [75]. Desoxymorellin inhibited the growth of HEL human embryonic lung fibroblasts and HeLa Henrietta Lacks cervical cancer cell with a minimum inhibitory concentration MIC of 0.39 mg mL−1 [76]. Cantleyanone displayed significant cytotoxicity against breast cancer MDA-MB-231 and MCF-7, ovarian cancer CaOV-3 and HeLa cells with EC50 values ranging from 0.22 to 17.17 mg mL−1 [77]. Lateriflorone was cytotoxic against P388 cancer cell line with an ED50 value 5.4 mg mL−1 [78]. Gambogic acid inhibited proliferation of T47D and DLD-1 breast cancer cells with GI50 values of 0.04 and 0.03 mm, respectively [79]. Gaudichaudione displayed strong growth inhibitory activity against parental murine leukemia P388 and P388/doxorubicin resistant cell lines at low μM concentrations [80]. Cowaxanthones G showed potent inhibition on cell viability IC50 < 10 μM, while etoposide was used as positive control [81] (**Figure 5**).

**Figure 4.** Structure of naphthalenes **58**–**61** and Anthraquinones 62–66.

Phenolic Compounds from the Natural Sources and Their Cytotoxicity http://dx.doi.org/10.5772/66898 47

**Figure 4.** Structure of naphthalenes **58**–**61** and Anthraquinones 62–66.

46 Phenolic Compounds - Natural Sources, Importance and Applications

### **2.7. Stilbene and their cytotoxic activities**

Stilbenoids are formed by flavonoid biosynthesis pathway and it consists on C6-C2-C6-based skeleton and usually found in peanuts, grapes and wines. Stilbenoid have a great interest on account due to their promising pharmacological activities including anticancer, antimicrobial, antioxidant and anti-inflammatory. Stilbenoid play important role of phytoalexin in plants. They play very important role in the defense of different pathogen.

Batatasin III inhibited growth of all cell lines including U251 glioma, CNS, MCF-7 breast, NCI-ADR/RES (ovarian expressing phenotype multiple drugs resistance), 786-0 renal NCI-H460 lung, non-small cell, HT29 colon, HaCat human keratinocytes, immortalized non-tumoral cell with GI50 values close to 30 mg mL−1 [82]. The cytotoxicity of Sciryagarol I and II was evaluate by MTT assay against human tumor cell lines MGC803, SMMC7721 and Hela and it showed significant cytotoxicity against Hela cell lines with IC50 values 61.21 and 7.21 μM, respectively [83]. Oligostilbene macrostachyol D showed significant cytotoxicity to HeLa cells with IC<sup>50</sup> value of 4.13 μM. Cajanotone, cajaninstilbene acid, pinosylvin monomethyl ether, longistylin A and longistylin C showed strong cytotoxicities against human hepatoma HepG2, human breast adenocarcinoma MCF-7 and human lung cancer A549 cell lines with IC50 values in the range of 3.5–15.5 μM, while doxorubicin used as a positive control [84]. Arachidin-1 induced human leukemia HL-60 cells death with EC50 value 4.2 μM and it was more potent than resveratrol and induces cell death in HL-60 cells through only the intrinsic apoptotic pathway [85]. Combretastatin A-4 showed strong cytotoxity against human cancer cell lines: HepG2 with IC50 value 9.2, SMMC-7721 with IC50 value 12.8, BGC-803 with IC50 value 12.2, MDA-MB-231 with IC50 value 17.6 μM [86]. Macasiamenenes A2, macasiamenene K, Macasiamenene L, acasiamenenes M exhibited significant cytotoxicity against MOLT-3 cancer cell line with the IC50 values in the range of 0.66–9.78 μM, etoposide used as Positive control standard [87] (**Figure 6**).

### **2.8. Phenanthrene and their cytotoxic activities**

Phenanthrenes consist on three fused aromatic rings and found in *Dendrobium* and *Dioscorea* spp.

Cytotoxicities of 1,4,7-trihydroxy-2-methoxy-9,10-dihydrophenanthrene, 1,3,8-tri (phydroxybenzyl)-4-methoxy-phenanthrene-2,7-diol towards liver carcinoma HepG-2, promyelocytic leukaemia HL-60, ovarian carcinoma Skov-3 and epidermoid carcinoma A431 cancer cell lines were determined by MTT method. 1,4,7-trihydroxy-2-methoxy-9,10-dihydrophenanthrene is the strongest one to HepG-2 and Skov-3 with IC50 of 15.9 and 124.0 mmol L−1, respectively; 1,3,8-tri (phydroxybenzyl)-4-methoxy-phenanthrene-2,7-diol is the strongest one to HL-60 and A431 with IC50 of 34.9 and 46.4 mmol L−1, respectively [88]. Biphenanthrenes bulbophythrins A and B were evaluated in vitro for their inhibitory ability against human leukemia cell lines K562 and HL-60, human lung adenocarcinoma A549, human hepatoma BEL-7402 and human stomach cancer SGC-7901, using cisplatin as a positive control. Bulbophythrins A exhibited some selectivity against HL-60 and BEL-7402 with IC50 values of 1.27 × 10−3 and 1.22 × 10−3 μmol mL−1, respectively, whereas bulbophythrins B was most active against A549 with IC50 value of 1.18 × 10−3 μmol mL−1 [89] (**Figure 7**).

Phenolic Compounds from the Natural Sources and Their Cytotoxicity http://dx.doi.org/10.5772/66898 49

**Figure 6.** Structure of structure of stilbenoids **81**–**95**.

**2.7. Stilbene and their cytotoxic activities**

48 Phenolic Compounds - Natural Sources, Importance and Applications

**2.8. Phenanthrene and their cytotoxic activities**

IC50 value of 1.18 × 10−3 μmol mL−1 [89] (**Figure 7**).

(**Figure 6**).

*Dioscorea* spp.

Stilbenoids are formed by flavonoid biosynthesis pathway and it consists on C6-C2-C6-based skeleton and usually found in peanuts, grapes and wines. Stilbenoid have a great interest on account due to their promising pharmacological activities including anticancer, antimicrobial, antioxidant and anti-inflammatory. Stilbenoid play important role of phytoalexin in

Batatasin III inhibited growth of all cell lines including U251 glioma, CNS, MCF-7 breast, NCI-ADR/RES (ovarian expressing phenotype multiple drugs resistance), 786-0 renal NCI-H460 lung, non-small cell, HT29 colon, HaCat human keratinocytes, immortalized non-tumoral cell with GI50 values close to 30 mg mL−1 [82]. The cytotoxicity of Sciryagarol I and II was evaluate by MTT assay against human tumor cell lines MGC803, SMMC7721 and Hela and it showed significant cytotoxicity against Hela cell lines with IC50 values 61.21 and 7.21 μM, respectively [83]. Oligostilbene macrostachyol D showed significant cytotoxicity to HeLa cells with IC<sup>50</sup> value of 4.13 μM. Cajanotone, cajaninstilbene acid, pinosylvin monomethyl ether, longistylin A and longistylin C showed strong cytotoxicities against human hepatoma HepG2, human breast adenocarcinoma MCF-7 and human lung cancer A549 cell lines with IC50 values in the range of 3.5–15.5 μM, while doxorubicin used as a positive control [84]. Arachidin-1 induced human leukemia HL-60 cells death with EC50 value 4.2 μM and it was more potent than resveratrol and induces cell death in HL-60 cells through only the intrinsic apoptotic pathway [85]. Combretastatin A-4 showed strong cytotoxity against human cancer cell lines: HepG2 with IC50 value 9.2, SMMC-7721 with IC50 value 12.8, BGC-803 with IC50 value 12.2, MDA-MB-231 with IC50 value 17.6 μM [86]. Macasiamenenes A2, macasiamenene K, Macasiamenene L, acasiamenenes M exhibited significant cytotoxicity against MOLT-3 cancer cell line with the IC50 values in the range of 0.66–9.78 μM, etoposide used as Positive control standard [87]

Phenanthrenes consist on three fused aromatic rings and found in *Dendrobium* and

Cytotoxicities of 1,4,7-trihydroxy-2-methoxy-9,10-dihydrophenanthrene, 1,3,8-tri (phydroxybenzyl)-4-methoxy-phenanthrene-2,7-diol towards liver carcinoma HepG-2, promyelocytic leukaemia HL-60, ovarian carcinoma Skov-3 and epidermoid carcinoma A431 cancer cell lines were determined by MTT method. 1,4,7-trihydroxy-2-methoxy-9,10-dihydrophenanthrene is the strongest one to HepG-2 and Skov-3 with IC50 of 15.9 and 124.0 mmol L−1, respectively; 1,3,8-tri (phydroxybenzyl)-4-methoxy-phenanthrene-2,7-diol is the strongest one to HL-60 and A431 with IC50 of 34.9 and 46.4 mmol L−1, respectively [88]. Biphenanthrenes bulbophythrins A and B were evaluated in vitro for their inhibitory ability against human leukemia cell lines K562 and HL-60, human lung adenocarcinoma A549, human hepatoma BEL-7402 and human stomach cancer SGC-7901, using cisplatin as a positive control. Bulbophythrins A exhibited some selectivity against HL-60 and BEL-7402 with IC50 values of 1.27 × 10−3 and 1.22 × 10−3 μmol mL−1, respectively, whereas bulbophythrins B was most active against A549 with

plants. They play very important role in the defense of different pathogen.
