A synopsis on flavonoids from the roots of Scutellaria baicalensis with some insights on baicalein and its anti-cancer properties
Eric Wei Chiang Chan1*, Siu Kuin Wong2, Joseph Tangah3, Tomomi Inoue4, Hung Tuck Chan5
1. Faculty of Applied Sciences, UCSI University, 56000 Cheras, Kuala Lumpur, Malaysia
2. School of Science, Monash University Sunway, 46150 Petaling Jaya, Selangor, Malaysia
3. Forest Research Centre, Sabah Forestry Department, Sandakan 90009, Sabah, Malaysia
4. Centre for Environmental Biology and Ecosystem Studies, National Institute for Environmental Studies (NIES), Onogawa, Tsukuba 305-0053, Japan
5. Secretariat of the International Society for Mangrove Ecosystems, Faculty of Agriculture, University of the Ryukyus, Okinawa 903-0129, Japan
Abstract: Flavones are the most dominant type of flavonoids isolated from the roots of Scutellaria baicalensis (Radix Scutellariae),which is a traditional medicinal plant in East Asian countries, including China, Japan and Korea. Most of the flavones are derivativeswith methoxyl and hydroxyl groups, and they include baicalein, baicalin, chrysin, norwogonin, oroxylin A and wogonin. Baicalein possesses anti-cancer activities against a wide spectrum of human cancer cells by inducing apoptosis and cell cycle arrest, and by inhibiting angiogenesis, metastasis and inflammation. Some examples of the effects of baicalein on apoptosis, cell cycle arrest and metastasis are presented with discussion on the molecular targets and pathways. Studies on the structure-activity relationships of flavonoid cytotoxicity towards human cancer cells show that the potent cytotoxic activities of baicalein can be attributed to its -OH groupsat C5, C6 and C7 (triple hydroxylation) of ring A, carbonyl group at C4 of ring C, and C2–C3 double bond of ring C.Studies on structural modifications of baicalein have shown that the configurations at C6 of ring A are critical factors influencing its anti-proliferative activity. Considering the remarkable anti-cancer properties, the future prospects for developing baicalein into an anti-cancer drug are promising.
Keywords: Radix Scutellariae; Baicalein;Flavones;Structure-activity relationships
CLC number: R284 Document code: A Article ID: 1003–1057(2019)4–217–12
Currently, there is great interest in the use of traditionalChinese medicine (TCM) for the preventionand treatment of cancer. Recent monographs have documented more than 400 species of Chinese medicinal herbs with anti-cancer properties. Major types of phenolic compounds found in these herbs used in TCM include flavonoids, phenolic acids, tannins, coumarins, lignans, quinones, stilbenes and curcuminoids. Among the hundreds of TCM herbs, Scutellaria baicalensis has been traditionally used in the treatment of diarrhea, dysentery, hypertension, hemorrhaging, insomnia, inflammation and respiratory infections. Its roots are rich in flavones, such as baicalein, baicalin, chrysin, wogonoside and wogonin.
This synopsis updates and synthesizes the current knowledge on the ethno-pharmacology and phytochemistry of S. baicalensis. It summarizes the composition of flavonoids from the roots and other plant parts ofS. baicalensis with emphasis on the chemistry, plant sources and anti-cancer properties of baicalein. Particular interests include the molecular targets and pathways, and the structure-activity relationships of baicalein, and its cytotoxicity towards human cancer cells. Other bioactivities of baicalein are also mentioned. Overall, the comprehensive and up-to-date information in this synopsis will be useful reference for scientists interested in studying the anti-cancer properties of baicalein and other flavones from Radix Scutellariae.
Plants of the genus Scutellaria are annual or perennialherbaceous plants up to 1 m tall[3,4]. They have four-angled stems and opposite leaves. Each flower has an upper and lower lip, and a typical shield on the calyx. There are about 350 species of Scutellaria worldwide and 98 species in China.
Traditional herbal medicines formulated from the roots of Scutellaria species (Radix Scutellariae), such as Huang Qin Tang in China and Sho Saiko To in Japan, are consumed to enhance liver health. The roots are conical, twisted or flattened in shape, 5–25 cm long and 0.5–3.0 cm in diameter. Fresh roots are yellowish-brown externally with wrinkles and scars and reddish-brown in the center. Root slices are golden yellow when dried (Fig. 1). The anti-cancer properties of Scutellaria species have been well-documented. Decoctions of Radix Scutellariae have been utilized in folk medicine as remedy for fever, allergy, diarrhea, ulcers, bronchitis, hepatitis, tumors and inflammatory diseases.
Figure 1. Root slices and flowers of Scutellaria baicalensis.
Scutellaria baicalensis Georgi of the family Labiatae or Lamiacae is a flowering plant that is indigenous to China, Japan, Korea, Mongolia and Russia[2−5]. Growing wild in mountain meadows, the 1-m tall plants produce opposite leaves, and stems are tetragonal and thickly haired. In China, S. baicalensis produce bluish-purple flowers (Fig. 1) from July−August, and black-brown nuts as fruits from August−September each year. The species is commonly known as Skullcap with vernacular names of Qinin Huang China, Ogon in Japan and Hwang Gum in Korea[7,8].
2. Flavonoids from Radix Scutellariae
Flavonoids represent the most common and widely distributed group of phenolic compounds. They have a C6-C3-C6 skeleton consisting of two aromatic rings (A &B) linked by an oxygenated heterocycle (C) with three carbons. Flavonoids consist of flavones, flavonols, flavanones, flavanols, isoflavones, flavanonols and anthocyanidins. Flavones (2-phenyl-chromen-4-one), an important class of flavonoids, have a basic molecular formula of C15H10O2. They have three functional components, namely, the hydroxyl and carbonyl groups, and the conjugated double bond.
The history of flavonoid study in S. baicalensis began in 1930 when K. Shibata and S. Hattori first identifiedbaicalin from the roots of this plant. Flavones are the most dominant type of flavonoids from the roots of S. baicalensis (Table 1). They include baicalein(5,6,7-trihydroflavone), baicalin (baicalein-7-O-glucuronide), chrysin (5,7-dihydroxyflavone), norwogonin (5,7,8-trihydroxyflavone),oroxylin A (5,7-dihydroxy-6-methoxyflavone) and wogonin (5,7-dihydroxy-8-methoxyflavone) (Fig. 2). Glycones (e.g. baicalin, scutellarin and wogonoside) are more common than aglycones (e.g. baicalein, scutellarein and wogonin). Most of the flavones are derivatives with methoxyl and hydroxyl groups.
Table 1. Flavonoids isolated from the roots of Scutellaria baicalensis.
*Compounds have also been reported in the aerial parts (stems and leaves) of S. baicalensis.
Figure 2. Dominant flavonoids isolated from the roots of Scutellaria baicalensis. Besides flavonoids, other compounds isolated from Scutellaria species include phenylethanoid glycosides, iridoid glycosides, diterpenes, triterpenoids, alkaloids, phytosterols and polysaccharides[3,4].
Baicalein (5,6,7-trihydroxyflavone) is a flavone originally isolated from the roots of S. baicalensis. The flavone is the aglycone of baicalin (baicalein-7-O-glucuronide). Baicalein has a molecular formula of C15H10O5 and a molecular weight of 270.24 g/mol. The molecule has an -OH group attached to C5, C6 and C7 of ring A (triple hydroxylation), a carbonyl group at C4 of ring C, and a C2-C3 double bond of ring C (Fig. 3). Compounds with similar molecular structures as baicalein are baicalin (baicalein 7-O-glucuronide) with -OGlu at C7, chrysin with -H at C6, and oroxylin A with -OCH3 at C6.
Figure 3. Molecular structure of baicalein.
3.2. Plant sources
An early study on the flavonoid content of Radix Scutellariae in China showed interesting geographical and seasonal variations. Values in seven provinces range from 16.3%−24.4% with the highest content in Chengde and Hebei Province, and harvesting of roots should be in August of each year. Flavonoids and their contents in the roots of S. baicalensis have been reportedto be baicalin (18.5%), wogonoside (3.54%), oroxylin A7-glucuronide (2.84%), baicalein (0.53%), wogonin (0.21%), and oroxylin A (0.06%). Recently, the contents of baicalin, wogonoside, alpinetin, baicalein, wogonin and oroxylin A have been reported to be higher in the roots of S. baicalensis than in other plant parts. Baicalin (90.8 mg/g) and wogonoside (17.4 mg/g) are the dominant flavonoids of the roots, while isocarthamidin-7-O-β-D-glucuronide dominates in the leaves (107 mg/g), stems (22.9 mg/g) and flowers (20.8 mg/g). Baicalein has been reported in the roots of other Scutellaria species, such as S. amoena, S. barbata,S. hypericifolia, S. lateriflora, S. racemosa, S. tomentosa,S. viscidula and S. wrightii.
3.3. Anti-cancer properties
There are several reviews on the anti-cancer properties of baicalein from Radix Scutellariae. They entail cancersin general[33−35]or specific cancers, such as pancreatic,breastand hepatocellular carcinoma.
Evidently, baicalein possesses anti-cancer activities against a wide spectrum of cancer cells, including cervical, breast, esophagus, gastric, colorectal, pancreatic,lung, ovarian, prostate, bladder and skin cancers, includingleukemia, melanoma, myeloma, osteosarcoma and carcinoma. Against cancer cells, baicalein induces apoptosis and cell cycle arrest, and it inhibits angiogenesis, metastasis and inflammation. In this synopsis, the effects of baicalein on apoptosis, cell cycle arrest and anti-metastasis are presented with discussion, in which molecular targets and pathways are briefly discussed.
Baicalein initiates apoptosis of cancer cells through both the mitochondria-mediated (intrinsic) and receptor-mediated(extrinsic) pathways. Apoptosis is induced through multiple mechanisms, such asincreasing reactive oxygen species (ROS) level of osteosarcoma cells, inactivation of the lipoxygenase (LOX) pathways of breast cancer cells, pancreaticcancer cells and colorectal cancer cells; up-regulationof the extracellular receptor kinase (ERK)/p38 mitogen-activated protein kinase (MAPK) pathway of breast cancer cells; modulation of the phosphatidylinositol-3-kinase (PI3K)/Akt pathwayofesophageal carcinoma cells; and inhibition of prostate cancer cell growth and metastasis via the caveolin-1/Akt/mammalian target of rapamycin (mTOR) pathway.
Baicalein induces cell cycle arrest of cancer cells viainhibition of cyclin-dependent kinases (CDK) andcyclins B1, D1 and D3 of prostate cancer cells, lung squamous carcinoma, oral cancer cells and bladder cancer cells.
Baicalein reduces metastasis of cancer cells by down-regulation of the extracellular signal-regulated kinase (ERK) pathway in hepatocellular and colorectalcancer cells; suppression of the p38 signaling pathway in glioma cells and gastric cancer cells; inhibition of the transforming growth factor-β (TGF-β)/SMAD4 pathway in gastric cancer cells; activation of the G protein-coupled receptor (GPR) 30 pathway activation in breast cancer cells; suppression of cell adhesion, migration and invasion in breast cancer cells by inhibiting the expression of matrix metalloproteinases (MMP) 2/9; inhibition of the Ezrin protein expressionin skin carcinoma cells; inhibition of Foxhead Box M1 (FOXM1) and MMP 2 activities in hepatocellularcarcinoma; down-regulation of the zinc finger proteinX-linked (ZFX) expression in gallbladder cancer cells; and down-regulation of the special AT-rich DNA-binding protein 1 (SATB1) expression and Wnt/β-catenin pathway in breast cancer cells[60,61].
3.4. Structure-activity relationships
There are several studies on the structure-activity relationships (SAR) of flavonoid cytotoxicity towards human cancer cells. Against leukemia Jurkat E6-1, the structural components of flavonoids associated with enhanced cytotoxicity have been reported to be the presence of a C2-C3 double bond, a C4 carbonyl group,and hydroxylation in the B ring. Molecules with a C3 hydroxyl group have lower cytotoxicity. O-Methylation and glucuronidation are associated with an increase in cytotoxicity.
Based on EC50 values, baicalein (213 µM) witha triple hydroxylated sites at C5, C6 and C7 of ring A, a C2–C3 double bond, and a C4 carbonyl group (Fig. 1) is more cytotoxic than taxifolin (2247 µM) without these structural components. In addition, taxifolin has a C3 hydroxyl group, and it is hydroxylated atC5 and C7 of ring A, and at C4’ and C5’ of ring B. 7-Methoxy-baicalein (91 µM), methoxylated at C7, is more cytotoxic than baicalein. Glucuronidation at C7 increases cytotoxicity as exemplified by baicaleinglucuronide (137 µM). Catechin (4410 µM), lacking the C2-C3 double bond and C4 carbonyl group, and having aC3 hydroxyl group, displays weak cytotoxicity.
Another SAR study on the cytotoxic effects of flavonoids on B16 melanoma cells shows that a 3’,4’ diydroxylationat ring B and a C2-C3 double bond are important considerations. For example, the IC50 value of baicalein (28 µM) is weaker than that of rhamnetin (10 µM) and luteolin (15 µM), both with the dihydroxylation and double bond.
Analogues of baicalein synthesised by substituting hydrogen of the -OH group at C6 of ring A display significantly stronger cytotoxicity than baicalein (IC50 value of 62.3 µM) when tested against KB carcinoma cells. Among the four analogues, the IC50 values of 6-benzyloxy-5,7-dihydroxyflavone, 6-acetoxy-5,7-dihydroxyflavone, 6-ethoxy-5,7-dihydroxyflavone and 6-methoxy-5,7-dihydroxyflavone (oroxylin A) are 14.5, 5.9, 2.5 and 2.0 times stronger than that of baicalein, respectively.
In a related study, 10 derivatives have been synthesised by introducing a benzyl group to -OH of C7 and a nitrogen-containing hydrophilic ring to -OH of C6 of baicalein. The anti-proliferative activities of eight derivatives against HepG2, A549, BCG-823 cancer cell lines are found to be more potent cytotoxicity than baicalein. The most potent derivative with a pyrrolidinyl substitution at the terminal of 6-O-alkyl has 14, 16 and 6 times IC50 values compared with baicalein.
The cytotoxicity of prenylated derivatives of baicalein are tested against MCF-7 breast cancer,NCI-H460 lung cancer and A375-C5 melanoma cells. Growth inhibition in GI50 values of baicalein is 32.8 µM, 26.7 µM and 7.7 µM, respectively. In comparison, the strongest prenylated derivative (7-(3,7-dimethylocta-2,6-dienyloxy)-5,6-dihydroxy-2-phenyl-4H-chromen-4-one)has values of 4.4 µM, 4.1 µM and 5.3 µM, while the weakest is >150 µM for all three cancer cell lines.
A comparative study on the anti-cancer properties of baicalein reveals that the suppression of invasion and metastasis in hepatoma cells by baicalein is dependent on the -OH substitution at C7 of ring A. Baicalin with -OGlu at C7 does not have any significant effect on the migration and invasion of hepatoma cells.
3.5. Other bioactivities
It has been reported that baicalein possesses other bioactivities, such as antioxidant[68,69], antiviral[70,71], hepatoprotective, hypotensive, α-glucosidaseinhibitory[74,75], anti-diabetic, skin protective, HIV-1integrase inhibitory, gastric ulcer inhibitory,anti-inflammatory, anti-quorum sensing and neuroprotective properties.
Flavones are the most dominant type of flavonoids isolated from the roots of S. baicalensis, a traditional medicinal plant in East Asia. Most of the flavones are derivatives with methoxyl and hydroxyl groups, and they include baicalein, baicalin, chrysin, norwogonin, oroxylin A and wogonin. Baicalein (5,6,7-trihydroxyflavone) is a major flavonoid from the root of S. baicalensis.Many in vitro studies have demonstrated the remarkableanti-cancer properties of baicalein, especially its cytotoxicity towards many human cancer cell lines. Baicalein induces apoptosis and cell cycle arrest, and inhibits angiogenesis, metastasis and inflammation. Animal studies have also accumulated evidence that baicalein inhibits tumour growth.
It is timely that human clinical trials of baicalein be undertaken to provide more evidence for its pharmacological use and to affirm its efficiency as an anti-cancer drug. Constraints that limit its clinical applications include the lack of understanding how baicalein works in the human body, and its inherent low solubility and poor oral bioavailability that need to be improved. With more SAR studies, chemical modification of the baicalein molecule to synthesize derivatives that have more potent cytotoxicity is a practical approach. The use of drugs in combination can also enhance bioavailabilityand cytotoxicity. Designing drugs for targeted therapies and overcoming resistance remain major opportunities and challenges in cancer treatment. With the advent of nanotechnology, the feasibility of using phytochemicals as a nanodrug for cancer can be explored. In recent years, TCM has been used by cancer patients to complementconventional cancer treatments. Needing evidence-based investigations is the belief that TCM in combination with modern medicine can improve symptoms, enhance quality of life, prevent recurrence and metastasis, and prolong the survival of patients. Collectively, the progress of developing baicalein into an anti-cancer drug is still in an infant stage, but its prospects are promising.
 Cai, Y.Z.; Sun, M.; Xing, J.; Luo, Q.; Corke, H. Structure-radical scavenging activity relationships of phenolic compounds from traditional Chinese medicinal plants. Life Sci. 2006, 78, 2872–2888.
 Zhao, Q.; Chen, X.Y.; Martin, C. Scutellaria baicalensis, the golden herb from the garden of Chinese medicinal plants. Sci. Bull.(Beijing).2016, 61, 1391–1398.
 Shang, X.F.; He, X.R.; He, X.Y.; Li, M.X.; Zhang, R.X.; Fan, P.C.; Zhang, Q.L.; Jia, Z.P. The genus Scutellaria: an ethnopharmacological and phytochemical review. J. Ethnopharmacol. 2010, 128, 279–313.
 EghbaliFeriz, S.; Taleghani, A.; Tayarani-Najaran, Z. Scutellaria: Debates on the anticancer property. Biomed. Pharmacother. 2018,105, 1299–1310.
 Li, X.W.; Hedge, I.C. Scutellaria L. Flora China. 1994, 17, 75−103.
 Zhang, Y.Y.; Guo, Y.Z.; Ageta, H.; Harigaya, Y.; Onda, M.;Hashimoto, K.; Ikeya, Y.; Okada, M.; Maruno, M. Quantitative analysis of flavonoids in Scutellariae Radix of different sources and seasonal variation by HPLC.J. Chin. Pharm. Sci. 1998, 7, 138–141.
 Seo, O.N.; Kim, G.S.; Kim, Y.H.; Park, S.; Jeong, S.W.; Lee, S.J.; Jin, J.S.; Shin, S.C. Determination of polyphenol components of Korean Scutellaria baicalensis Georgi using liquid chromatography–tandem mass spectrometry: contribution to overall antioxidant activity. J. Funct. Foods. 2013, 5, 1741–1750.
 Xie, L.H.; Wang, X.; Basnet, P.; Matsunaga, N.; Yamaji, S.; Yang, D.Y.;Cai, S.Q.; Tani, T. Evaluation of variation of acteoside and three major flavonoids in wild and cultivatedScutellaria baicalensis roots by micellar electrokinetic chromatography. Chem. Pharm. Bull. 2002, 50, 896–899.
 Chahar, M.K.; Sharma, N.; Dobhal, M.P.; Joshi, Y.C.Flavonoids: A versatile source of anticancer drugs. Pharmacogn. Rev. 2011, 5, 1–12.
 Singh, M.; Kaur, M.; Silakari, O. Flavones: An important scaffold for medicinal chemistry. Eur. J. Med. Chem. 2014, 84, 206–239.
 Olennikov, D.N.; Chirikova, N.K.; Tankhaeva, L.M. Phenolic compounds of Scutellaria baicalensis Georgi. Russ. J. Bioorg. Chem. 2010, 36, 816–824.
 Shen, J.; Li, P.; He, C.N.; Liu, H.T.; Liu, Y.Z.; Sun, X.B.; Xu, R.; Xiao, P.G. Simultaneous determination of 15 flavonoids from different parts of Scutellaria baicalensisand its chemometrics analysis. Chin. Herb. Med. 2018, 11, 20–27.
 Horvath, C.R.; Martos, P.A.; Saxena, P.K. Identification and quantification of eight flavones in root and shoot tissues of the medicinal plant huang-qin (Scutellaria baicalensis Georgi) using high-performance liquid chromatography with diode array and mass spectrometric detection. J. Chromatogr. A. 2005, 1062, 199–207.
 Takido, M.; Aimi, M.; Takahashi, S.; Yamanouchi, S.; Torii, H. Studies on the constituents in the water extracts of crude drugs. I. On the roots of Scutellaria baicalensis Georgi (Wōgon) (1) (author’s transl). Yakugaku Zasshi. 1975, 95, 108–113.
 Takagi, S.; Yamaki, M.; Inoue, K. Studies on the water-soluble constituents of the roots of Scutellaria baicalensis Georgi (Wogon) (1) (author’s transl). YakugakuZasshi. 1980, 100, 1220–1224.
 Tomimori, T.; Jin, H.; Miyaichi, Y.; Toyofuku, S.; Namba, T. Studies on the constituents of Scutellaria species. VI. On the flavonoid constituents of the root of Scutellaria baicalensis Georgi (5). Quantitative analysis of flavonoids in Scutellaria roots by high-performance liquid chromatography. Yakugaku Zasshi. 1985, 105, 148–155.
 Takino, Y.; Miyahara, T.; Arichi, E.; Arichi, S.; Hayashi, T.; Karikura, M. Determination of some flavonoids in scutellariae radix by high-performance liquid chromatography. Chem. Pharm. Bull. 1987, 35, 3494–3497.
 Li, C.R.; Zhou, L.M.; Zuo, Z. Contents of major bioactiveflavones in proprietary traditional Chinese medicine products and reference herb of radix Scutellariae. J. Pharm. Biomed. Anal. 2009, 50, 298–306.
 Liu, G.Z.; Ma, J.N.; Chen, Y.Z.; Tian, Q.Q.; Shen, Y.; Wang, X.S.; Chen, B.; Yao, S.Z. Investigation of flavonoid profile of Scutellaria bacalensis Georgi by high performance liquid chromatography with diode array detection and electrospray ion trap mass spectrometry. J. Chromatogr. A. 2009, 1216, 4809–4814.
 Ji, S.; Li, R.; Wang, Q.; Miao, W.J.; Li, Z.W.; Si, L.L.; Qiao, X.; Yu, S.W.; Zhou, D.M.; Ye, M. Anti-H1N1 virus, cytotoxic and Nrf2 activation activities of chemical constituents from Scutellaria baicalensis. J. Ethnopharmacol. 2015, 176, 475–484.
 Kosakowska, O. Experimental Paper. Intrapopulation variability of flavonoid content in roots of Baikal skullcap (Scutellaria baicalensis Georgi). Herba Pol. 2017, 63, 20–31.
 Tomimori, T.; Miyaichi, Y.; Imoto, Y.; Kizu, H.; Tanabe, Y. Studies on the constituents of Scutellaria species. III. On the flavonoid constituents of the root of Scutellaria baicalensis Georgi (3). Yakugaku Zasshi. 1984, 104, 524–528.
 Zhang, Y.Y.; Don, H.Y.; Guo, Y.Z.; Ageta, H.; Harigaya, Y.; Onda, M.; Hashimoto, K.; Ikeya, Y.; Okada, M.; Maruno, M. Comparative study of Scutellaria planipes and Scutellaria baicalensis. Biomed. Chromatogr.1998, 12, 31–33.
 Ishimaru, K.; Nishikawa, K.; Omoto, T.; Asai, I.; Yoshihira, K.; Shimomura, K. Two flavone 2’-glucosides from Scutellaria baicalensis. Phytochemistry. 1995, 40, 279–281.
 Tomimori, T.; Miyaichi, Y.; Kizu, H. On the flavonoid constituents from the roots of Scutellaria baicalensis Georgi. I. Yakugaku Zasshi. 1982, 102, 388–391.
 Takagi, S.; Yamaki, M.; Inoue, K. Flavone di-C-glycosides from Scutellaria baicalensis. Phytochemistry. 1981, 20, 2443–2444.
 Tomimori, T.; Miyaichi, Y.; Imoto, Y.; Kizu, H.; Tanabe Y. Studies on the constituents of Scutellaria species. II. On the flavonoid constituents of the root of Scutellaria baicalensis Georgi (2). Yakugaku Zasshi. 1983, 103, 607–611.
 Zhang, Y.Y.; Guo, Y.Z.; Onda, M.; Hashimoto, K.; Ikeya, Y.; Okada, M.; Maruno, M. Four flavonoids from Scutellaria baicalensis. Phytochemistry. 1994, 35, 511–514.
 Takagi, S.; Yamaki, M.; Inoue, K. On the minor constituents of the roots of Scutellaria baicalensis Georgi (Wogon) (author’s transl). Yakugaku Zasshi. 1981, 101, 899–903.
 Tomimori, T.; Miyaichi, Y.; Imoto, Y.; Kizu, H.; Suzuki, C. Studies on the constituents of Scutellaria species. IV. On the flavonoid constituents of the root of Scutellaria baicalensis Georgi (4). Yakugaku Zasshi. 1984, 104, 529–534.
 Liu, H.; Dong, Y.H.; Gao, Y.T.; Du, Z.P.; Wang, Y.T.; Cheng, P.; Chen, A.M.; Huang, H. The fascinating effects of baicalein on cancer: A review. Int. J. Mol. Sci. 2016, 17, E1681.
 Nurul Islam, M.; Downey, F.; Ng, C.K.Y. Comparative analysis of bioactive phytochemicals from Scutellaria baicalensis, Scutellaria lateriflora, Scutellaria racemosa,Scutellaria tomentosa and Scutellaria wrightii byLC-DAD-MS. Metabolomics. 2011, 7, 446–453.
 Li-Weber, M. New therapeutic aspects of flavones: The anticancer properties of Scutellaria and its main active constituents wogonin, baicalein and baicalin. Cancer Treat. Rev. 2009, 35, 57–68.
 Gao, Y.; Snyder, S.A.; Smith, J.N.; Chen, Y.C. Anticancerproperties of baicalein: A review. Med. Chem. Res. 2016, 25, 1515–1523.
 Gong, W.Y.; Zhao, Z.X.; Liu, B.J.; Lu, L.W.; Dong, J.C. Exploring the chemopreventive properties and perspectives of baicalin and its aglycone baicalein in solid tumors. Eur. J. Med. Chem. 2017, 126, 844–852.
 Donald, G.; Hertzer, K.; Eibl, G. Baicalein: an intriguing therapeutic phytochemical in pancreatic cancer. Curr. Drug Targets. 2012, 13, 1772–1776.
 Yan, W.J.; Ma, X.C.; Gao, X.Y.; Xue, X.H.; Zhang, S.Q.Latest research progress in the correlation between baicalein and breast cancer invasion and metastasis. Mol. Clin. Oncol. 2016, 4, 472–476.
 Bie, B.B.; Sun, J.; Guo, Y.; Li, J.; Jiang, W.; Yang, J.; Huang, C.; Li, Z.F. Baicalein: A review of its anti-cancer effects and mechanisms in hepatocellular carcinoma. Biomed. Pharmacother. 2017, 93, 1285–1291.
 Ye, F.F.; Wang, H.H.; Zhang, L.S.; Zou, Y.Y.; Han, H.L.; Huang, J. Baicalein induces human osteosarcoma cell line MG-63 apoptosis via ROS-induced BNIP3 expression. Tumour Biol. 2015, 36, 4731–4740.
 Tong, W.G.; Ding, X.Z.; Adrian, T.E. The mechanisms of lipoxygenase inhibitor-induced apoptosis in human breast cancer cells. Biochem. Biophys. Res. Commun. 2002, 296, 942–948.
 Tong, W.G.; Ding, X.Z.; Witt, R.C.; Adrian, T.E. Lipoxygenaseinhibitors attenuate growth of human pancreatic cancer xenografts and induce apoptosis through the mitochondrial pathway. Mol. Cancer Ther. 2002, 1, 929–935.
 Bednar, W.; Holzmann, K.; Marian, B. Assessing 12(S)-lipoxygenase inhibitory activity using colorectal cancer cells overexpressing the enzyme. Food Chem. Toxicol. 2007, 45, 508–514.
 Zhou, Q.M.; Wang, S.; Zhang, H.; Lu, Y.Y.; Wang, X.F.; Motoo, Y.; Su, S.B. The combination of baicalin and baicalein enhances apoptosis via the ERK/p38 MAPK pathway in human breast cancer cells. Acta Pharmacol. Sin. 2009, 30, 1648–1658.
 Zhang, H.B.; Lu, P.; Guo, Q.Y.; Zhang, Z.H.; Meng, X.Y. Baicalein induces apoptosis in esophageal squamous cell carcinoma cells through modulation of the PI3K/Akt pathway. Oncol. Lett. 2013, 5, 722–728.
 Guo, Z.X.; Hu, X.L.; Xing, Z.Q.; Xing, R.; Lv, R.; Cheng, X.Y.; Su, J.; Zhou, Z.L.; Xu, Z.H.; Nilsson, S.; Liu, Z.X. Baicalein inhibits prostate cancer cell growth and metastasis via the caveolin-1/AKT/mTOR pathway. Mol. Cell. Biochem. 2015, 406, 111–119.
 Pidgeon, G.P.; Kandouz, M.; Meram, A.; Honn, K.V. Mechanisms controlling cell cycle arrest and induction of apoptosis after 12-lipoxygenase inhibition in prostate cancer cells. Cancer Res. 2002, 62, 2721–2727.
 Lee, H.Z.; Leung, H.W.; Lai, M.Y.; Wu, C.H. Baicalein induced cell cycle arrest and apoptosis in human lung squamous carcinoma CH27 cells. Anticancer Res. 2005, 25, 959–964.
 Cheng, Y.H.; Li, L.A.; Lin, P.P.; Cheng, L.C.; Hung, C.H.; Chang, N.W.; Lin, C. Baicalein induces G1 arrest in oral cancer cells by enhancing the degradation of cyclin D1 and activating AhR to decrease Rb phosphorylation. Toxicol. Appl. Pharmacol. 2012, 263, 360–367.
 Wu, B.; Li, J.; Huang, D.M.; Wang, W.W.; Chen, Y.; Liao, Y.X.; Tang, X.W.; Xie, H.F.; Tang, F.Q. Baicalein mediates inhibition of migration and invasiveness of skin carcinoma through Ezrin in A431 cells. BMC Cancer.2011, 11, 527.
 Chen, K.L.; Zhang, S.; Ji, Y.Y.; Li, J.; An, P.; Ren, H.T.; Liang, R.R.; Yang, J.; Li, Z.F. Baicalein inhibits the invasion and metastatic capabilities of hepatocellular carcinoma cells via down-regulation of the ERK pathway. PLoS One. 2013, 8, e72927.
 Chai, Y.X.; Xu, J.Z.; Yan, B.J. The anti-metastatic effect of baicalein on colorectal cancer. Oncol. Rep. 2017, 37, 2317–2323.
 Zhang, Z.N.; Lv, J.; Lei, X.M.; Li, S.Y.; Zhang, Y.; Meng, L.H.; Xue, R.L.; Li, Z.F. Baicalein reduces the invasion of glioma cells via reducing the activity of p38 signaling pathway. PLoS One. 2014, 9, e90318.
 Yan, X.; Rui, X.J.; Zhang K. Baicalein inhibits the invasion of gastric cancer cells by suppressing the activity of the p38 signaling pathway. Oncol. Rep. 2015, 33, 737–743.
 Chen, F.L.; Zhuang, M.K.; Peng, J.; Wang, X.Z.; Huang, T.X.; Li, S.M.; Lin, M.Q.; Lin, H.M.; Xu, Y.T.; Li, J.Y.; Chen, Z.X.; Huang, Y.H. Baicalein inhibits migration and invasion of gastric cancer cells through suppression of the TGF-β signaling pathway. Mol. Med. Rep. 2014, 10, 1999–2003.
 Shang, D.; Li, Z.; Zhu, Z.; Chen, H.; Zhao, L.; Wang, X.; Chen, Y. Baicalein suppresses 17-β-estradiol-induced migration, adhesion and invasion of breast cancer cells via the G protein-coupled receptor 30 signaling pathway. Oncol. Rep. 2015, 33, 2077–2085.
 Wang, L.; Ling, Y.; Chen, Y.; Li, C.L.; Feng, F.; You, Q.D.; Lu, N.; Guo, Q.L. Flavonoid baicalein suppresses adhesion, migration and invasion ofMDA-MB-231 human breast cancer cells. Cancer Lett. 2010, 297, 42–48.
 Wu, B.; Li, J.; Huang, D.M.; Wang, W.W.; Chen, Y.; Liao, Y.X.; Tang, X.W.; Xie, H.F.; Tang, F.Q. Baicalein mediates inhibition of migration and invasiveness of skin carcinoma through Ezrin in A431 cells. BMC Cancer. 2011, 11, 527.
 Park, H.S.; Park, K.I.; Hong, G.E.; Nagappan, A.; Lee, H.J.; Kim, E.H.;Lee, W.S.; Shin, S.C.; Seo, O.N.; Won, C.K.; Cho, J.H.; Kim, G. Korean Scutellaria baicalensis Georgi methanol extracts inhibits metastasisvia the Forkhead Box M1 activity in hepatocellular carcinoma cells. J. Ethnopharmacol. 2014, 155, 847–851.
 Liu, T.Y.; Gong, W.; Tan, Z.J.; Lu, W.; Wu, X.S.; Weng, H.;Ding, Q.; Shu, Y.J.; Bao, R.F.; Cao, Y.;Wang, X.A. Baicalein inhibits progression of gallbladder cancer cells by down-regulating ZFX. PLoS One. 2015, 10, e0114851.
 Gao, X.Y.; Xue, X.H.; Ma, Y.N.; Zhang, S.Q. Effect of baicalein on the expression of SATB1 in human breast cancer cells. Exp. Ther. Med. 2015, 9, 1665–1669.
 Ma, X.C.; Yan, W.J.; Dai, Z.J.; Gao, X.Y.; Ma, Y.N.; Xu, Q.T.; Jiang, J.T.; Zhang, S.Q. Baicalein suppresses metastasis of breast cancer cells by inhibiting EMT via downregulation of SATB1 and Wnt/β-catenin pathway. Drug Des. Devel. Ther. 2016, 10, 1419–1441.
 Plochmann, K.; Korte, G.; Koutsilieri, E.; Richling, E.; Riederer, P.; Rethwilm, A.;Schreier, P.; Scheller, C. Structure-activity relationships of flavonoid-induced cytotoxicity on human leukemia cells. Arch. Biochem. Biophys. 2007, 460, 1–9.
 Touil, Y.S.; Fellous, A.; Scherman, D.; Chabot, G.G. Flavonoid-induced morphological modifications of endothelial cells through microtubule stabilization. Nutr. Cancer. 2009, 61, 310–321.
 Huang, S.T.; Lee, Y.; Gullen, E.A.; Cheng, Y.C. Impacts of baicalein analogs with modification of the 6th position of A ring on the activity toward NF-kappaB-, AP-1-, or CREB-mediated transcription. Bioorg. Med. Chem. Lett. 2008, 18, 5046–5049.
 Luo, R.; Wang, J.B.; Zhao, L.; Lu, N.; You, Q.D.; Guo, Q.L.; Li, Z.Y. Synthesis and biological evaluation of baicalein derivatives as potent antitumor agents. Bioorg. Med. Chem. Lett. 2014, 24, 1334–1338.
 Neves, M.P.; Cidade, H.; Pinto, M.; Silva, A.M.S.; Gales, L.; Damas, A.M.; Lima, R.T.; Vasconcelos, M.H.; de Sao Jose Nascimento, M. ChemInform abstract: prenylatedderivatives of baicalein and 3,7-dihydroxyflavone: synthesis and study of their effects on tumor cell lines growth, cell cycle and apoptosis. Eur. J. Med. Chem. 2011, 46, 2562–2574.
 Chiu, Y.W.; Lin, T.H.; Huang, W.S.; Teng, C.Y.; Liou, Y.S.; Kuo, W.H.; Lin, W.L.; Huang, H.I.; Tung, J.N.; Huang, C.Y.; Liu, J.Y.; Wang, W.H.; Hwang, J.M.; Kuo, H.C. Baicalein inhibits the migration and invasive properties of human hepatoma cells. Toxicol. Appl. Pharmacol. 2011, 255, 316–326.
 Yoshino, M.; Ito, M.; Okajima, H.; Haneda, M.; Murakami,K. Role of baicalein compounds as antioxidant in the traditional herbal medicine. Biomed. Res. 1997, 18, 349–352.
 Shieh, D.E.; Liu, L.T.; Lin, C.C. Antioxidant and free radical scavenging effects of baicalein, baicalin and wogonin. Anticancer Res. 2000, 20, 2861–2865.
 Zandi, K.; Teoh, B.T.; Sam, S.S.; Wong, P.F.; Mustafa, M.R.; Abubakar, S. Novel antiviral activity of baicalein againstdengue virus. BMC Complement. Altern. Med. 2012, 12, 214.
 Oo, A.; Teoh, B.T.; Sam, S.S.; Abu Bakar, S.A.; Zandi, K. Baicalein and baicalin as Zika virus inhibitors. Arch. Virol. 2019,164, 585–593.
 Huang, H.L.; Wang, Y.J.; Zhang, Q.Y.; Liu, B.; Wang, F.Y.; Li, J.J.; Zhu, R.Z. Hepatoprotective effects of baicalein against CCl4-induced acute liver injury in mice. World J. Gastroenterol. 2012, 18, 6605–6613.
 Huang, Y.; Tsang, S.Y.; X.Q.; Chen, Z.N. Biological properties of baicalein in cardiovascular system. Curr. Drug Targets. 2005, 5, 177–184.
 Gao, H.; Kawabata, J. Importance of the B ring and its substitution on the alpha-glucosidase inhibitory activity of baicalein, 5,6,7-trihydroxyflavone. Biosci. Biotechnol. Biochem. 2004, 68, 1858–1864.
 Gao, H.; Nishioka, T.; Kawabata, J.; Kasai, T. Structure-activity relationships for α-glucosidase inhibition of baicalein, 5,6,7-trihydroxyflavone: the effect of A-ring substitution.Biosci. Biotechnol. Biochem. 2004, 68, 369–375.
 Fu, Y.; Luo, J.; Jia, Z.Q.; Zhen, W.; Zhou, K.Q.; Gilbert, E.; Liu, D.M. Baicalein protects against type 2 diabetes via promoting islet β-cell function in obese diabetic mice. Int. J. Endocrinol. 2014, 2014, 846742.
 Oh, M.C.; Piao, M.J.; Fernando, P.M.; Han, X.; MaddumaHewage, S.R.; Park, J.E.;Ko, M.S.; Jung, U.; Kim, I.G.; Hyun, J.W. Baicalein protects human skin cells against ultraviolet B-induced oxidative stress. Biomol. Ther (Seoul). 2016, 24, 616–622.
 Ahn, H.C.; Lee, S.Y.; Kim, J.W.; Son, W.S.; Shin, C.G.; Lee, B.J. Binding aspects of baicalein to HIV-1 integrase. Mol. Cells. 2001, 12, 127–130.
 Ribeiro, A.R.S.; do Nascimento Valença, J.D.N.; da Silva Santos, J.; Boeing, T.; da Silva, L.M.; de Andrade, S.F.; Albuquerque-Júnior, R.L.C.; Thomazzi, S.M. The effects of baicalein on gastric mucosal ulcerations in mice: Protective pathways and anti-secretory mechanisms.Chemico-Biol. Interact. 2016, 260, 33–41.
 Dinda, B.; Dinda, S.; DasSharma, S.; Banik, R.; Chakraborty, A.; Dinda, M. Therapeutic potentials of baicalin and its aglycone, baicalein against inflammatory disorders. Eur. J. Med. Chem. 2017, 131, 68–80.
 Chen, Y.; Liu, T.J.; Wang, K.; Hou, C.C.; Cai, S.Q.; Huang, Y.Y.; Du, Z.Y.; Huang, H.; Kong, J.L.; Chen, Y.Q. Baicalein inhibits Staphylococcus aureus biofilm formation and the quorum sensing system in vitro.PLoS One. 2016,11, e0153468.
 Sowndhararajan, K.; Deepa, P.; Kim, M.; Park, S.J.; Kim, S. Baicalein as a potent neuroprotective agent: A review. Biomed. Pharmacother. 2017, 95, 1021–1032.
Dr Eric Chan, Associate Professor of the Faculty of Applied Sciences, UCSI University, Kuala Lumpur, Malaysia, obtained his PhD (Natural Product Chemistry) from Monash Universityin 2009. His professional affiliations include Associate Editor of Journal of ComplementaryMedicine Research, and Member of the Editorial Board of Journal of Phytology, Asian Councilof Science Editors, and American Chemical Society. He is life member of the Pharmacognosy Network Worldwide, International Society of Mangrove Ecosystems, and Monash University Chapter of the Golden Key International Honour Society. Dr Eric Chan has 80 publications in international refereed journals with 56 as the lead author. His publications have received more than 2173 citations in Google Scholar. He was one of the Top 5 Competitors of the Elsevier Green and Sustainable Chemistry Challenge 2015, out of 500 proposals submitted globally. In April 2016, he presented his proposal at the Green and Sustainable Chemistry Conference in Berlin, Germany. In the same month, he was awarded the Promising Researcher Award by UCSI University.
Received: 2018-12-15; Revised: 2019-01-31; Accepted: 2019-03-22.
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