Phytochemical and Pharmacological Properties of Flavonols

Abstract

Flavonoids are polyphenolic compounds, which are ubiquitous in nature and have been categorised into flavonols, flavones, flavanones, isoflavones, catechins, anthocyanidins and chalcones according to their chemical structure. Currently more than 4000 flavonoids have been identified, which were isolated from fruits, vegetables and beverages (tea, coffee, beer, wine and fruit drinks). The flavonoids have aroused interest recently because of their beneficial effects on human health especially reported to have antiviral, antiallergic, anti‐inflammatory, antitumour and antioxidant activities. Flavonoids may enrich the immunogenic potential against such diseases of human body. Epidemiological studies have shown that flavonoid intake is inversely proportional to mortality rate because of coronary heart disease and heart attacks. However, recent studies have demonstrated that flavonoids found in fruits and vegetables may act as antioxidants. Current article mainly focuses upon the structure–function relationship of flavonols, one of the key components of flavonoids for their potential therapeutic use.

Key Concepts

  • Flavonols are phytochemical compounds, which are associated with beneficial health effects.
  • Antioxidants are molecules that inhibit the oxidation of other molecules in living organisms.
  • Enzymes are macromolecules biocatalysts, which accelerate the chemical reactions.
  • Metastasis is a pathogenic agent's spread from an initial position or primary site to a secondary site within the host cell.
  • Angiogenesis is the physiological process in which new blood vessels form from preexisting vessels.
  • Tumour is an abnormal mass of tissue or cell that may be solid or fluid‐filled. Tumours can be benign (not cancerous), premalignant (precancerous) or malignant (cancerous).
  • Apoptosis is a process of programmed cell death, which occurs in multicellular organisms.
  • Astrogliosis or astrocytosis is an abnormal increase in the number of astrocytes because of the destruction of nearby neurons from CNS trauma, infection, ischaemia, stroke, autoimmune responses and neurodegenerative disease.

Keywords: flavonols; structure–function; derivatives; biosynthesis; action mechanism; therapeutic

Figure 1. The basic carbon skeleton of flavonoid (a) as well as flavonol subclass (b) with chemical structure of flavonols (c) and some flavonol derivatives (d).
Figure 2. Schematic pathway of flavonol biosynthesis, starting with general phenylpropanoid metabolism of conversion of phenylalanine into 4‐coumaroyl‐CoA and its reaction with malonyl‐CoA resulting in the formation of tetrahydroxychalcone. The chalconaringenin converted into flavonols by various enzymes that have shown outside the black dotted line. The biosynthetic production pathway of fisetin from microorganism is given inside the black dotted line. The names of enzymes have been abbreviated as follows: phenylalanine ammonialyase (PAL); cinnamate‐4‐hydroxylase (C4H); 4‐coumarate:CoA ligase (4CL); chalcone synthase (CHS); chalcone reductase (CHR); flavanone 3‐hydroxylase (F3H); flavonoid 3′ hydroxylase (F3'H); flavonoid 3′,5′‐hydroxylase (F3'5'H); flavonol synthase (FLS); flavonoid 3′‐monooxygenase (FMO); cytochrome P450 reductase (CPR).
Figure 3. (A) General synthetic reactions scheme of flavonols via Kostanecki's approach; (B) synthesis of quercetin by using phloroacetophenone and veratraldehyde as starting materials; (C) synthesis of kaempferol involves the reactions of 2,4,6‐trimethoxyacetophenone and 4‐methoxybenzaldehyde; (D) fisetin synthesis involves 4‐ethoxy‐2‐hydroxyacetophenone and veratraldehyde as reactants.
Figure 4. (A) General Allan and Robison's method scheme of flavonols synthesis; (B) quercetin synthesis by condensation of ω‐methoxyphloroacetophenone, veratric anhydride and potassium veratrate; (C) synthesis of kaempferol involves condensation of ω‐benzoyloxyphloracetophenone, p‐acetyloxybenzoic anhydride and sodium p‐acetyloxybenzoate; (D) fisetin synthesised using ω‐methoxyresacetophenone, veratric anhydride and potassium veratrate as starting material; (E) synthesis of myricetin carried out by the condensation of ω‐methoxyphloroacetophenone, trimethylgallic anhydride and sodium trimethylgallate.
Figure 5. The structure of quercetin prodrug under clinical trial phase 1 and its synthetic derivatives were significantly effective against human oesophageal squamous cell EC109 as compared to 5‐florouracil.
Figure 6. Representation of flavonols mediated modulation of multiple cellular signalling pathways including apoptosis induction, cell cycle arrest, antimetastasis, antiangiogenesis, anti‐inflammatory and antioxidant.
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References

Allan J and Robinson R (1926) CCCIX‐ a new synthesis of fisetin and of quercetin. Journal of the Chemical Society 129: 2334–2336. DOI: 10.1039/JR9262902334.

Ashok D, Kifah MA, Vijaya B, et al. (2016) Microwave‐assisted one‐pot synthesis of some new flavonols by modified Algar–Flynn–Oyamada reaction and their antimicrobial activity. Chemistry of Heterocyclic Compounds 52: 172–176. DOI: 10.1007/s10593-016-1852-4.

Chang WS, Lee YJ, Lu FJ, et al. (1993) Inhibitory effects of flavonoids on xanthine oxidase. Anticancer Research 13 (6A): 2165–2170.

Chen P, Cao Y, Bao B, et al. (2017) Antioxidant capacity of Typha angustifolia extracts and two active flavonoids. Pharmaceutical Biology 55 (1): 1283–1288. DOI: doi.org/10.1080/13880209.2017.1300818.

Choi SJ, Tai BH, Cuong NM, et al. (2012) Antioxidative and anti‐inflammatory effect of quercetin and its glycosides isolated from mampat (Cratoxylumformosum). Food Science and Biotechnology 21 (2): 587–595.

Christensen LP and Christensen KB (2014) In: Watson RR, Preedy VR and Zibadi S (eds) Polyphenols in Human Health and Disease. Amsterdam: Elsevier.

Erlund I (2004) Review of the flavonoids quercetin, hesperetin, and naringenin. Dietary sources, bioactivities, bioavailability, and epidemiology. Nutrition Research 24: 851–874.

Gao J, Chen G, He H, et al. (2017) Therapeutic effects of breviscapine in cardiovascular diseases: a review. Frontiers in Pharmacology 8: 289. DOI: 10.3389/fphar.2017.00289.

Gong MY, Du C and Yuan BY (2013) The effect of breviscapine on myocardial ischemia reperfusion in rats serum TNF‐ and IL‐6. Journal of Materials Science: Materials in Medicine 24: 1615–1616.

Guangyu Z, Zitong Y, Wentao Q et al. (2014) Application of quercetin derivative in preparation of antitumor medicine. CN103239437B.

Han Y, Yu H, Wang J, et al. (2015) Quercetin alleviates myocyte toxic and sensitizes anti‐leukemic effect of Adriamycin. Hematology 20: 276–283.

Herrmann K and Entus R (2001) Shikimate pathway: aromatic amino acids and beyond. Encyclopedia of Life Sciences. DOI: 10.1038/npg.els.0001315.

Iio M, Kawaguchi H, Sakota Y, et al. (1993) Effects of polyphenols, including' flavonoids, on glutathione s transferase and glutathione reductase. Bioscience Biotechnology and Biochemistry 57 (10): 1678–1680.

Jomova K and Valko M (2011) Advances in metal‐induced oxidative stress and human disease. Toxicology 283: 65–87.

Kalff J and Robinson R (1925) A synthesis of myricetin and of a galanginmonomethyl ether occurring in galanga root. Journal of the Chemical Society, Transactions 127: 181–184. DOI: 10.1039/CT9252700181.

Kashyap D, Mittal S, Sak K, et al. (2016) Molecular mechanisms of action of quercetin in cancer: recent advances. Tumor Biology 37: 12927–12939. DOI: 10.1007/s13277-016-5184-x.

Kashyap D, Sharma A, Tuli HS, et al. (2017) Kaempferol – a dietary anticancer molecule with multiple mechanisms of action: recent trends and advancements. Journal of Functional Foods 30: 203–219. DOI: 10.1016/j.jff.2017.01.022.

Kasprzak MM, Erxleben A and Ochocki J (2015) Properties and applications of flavonoid metal complexes. RSC Advances 5: 45853–45877.

Kim SM, Kang K, Jho EH, et al. (2011) Hepatoprotective effect of flavonoid glycosides from Lespedeza cuneata against oxidative stress induced by tert‐butyl hyperoxide. Phytotherapy Research 25 (7): 1011–1017.

Kitagawa S, Nabekura T, Takahashi T, et al. (2005) Structure–activity relationships of the inhibitory effects of flavonoids on P‐glycoprotein‐mediated transport in KB‐C2 Cells. Biological and Pharmaceutical Bulletin 28 (12): 2274–2278.

Kostanecki SV, Lampe V and Tambor J (1904a) Synthesis of Quercetin. European Journal of Inorganic Chemistry (Ber. Dtsch. Chem. Ges.) 37 (2): 1402–1405. DOI: 10.1002/cber.19040370234.

Kostanecki SV, Lampe V and Tambor J (1904b) Synthese des Fisetins. European Journal of Inorganic Chemistry (Ber. Dtsch. Chem. Ges) 37: 784–791. DOI: 10.1002/cber.190403701128.

Kumar S and Pandey AK (2013) Chemistry and biological activities of flavonoids: an overview. The Scientific World Journal 2013: 162750.

Labbe D, Provencal M, Lamy S, et al. (2009) The flavonols quercetin, kaempferol, and myricetin inhibit hepatocyte growth factor‐induced medulloblastoma cell migration. Journal of Nutrition 139 (4): 646–652. DOI: 10.3945/jn.108.102616.

Lago JHG, Toledo‐Arruda AC, Mernak M, et al. (2014) Structure‐activity association of flavonoids in lung diseases. Molecules 19 (3): 3570–3595. DOI: 10.3390/molecules19033570.

Lai WW, Hsu SC, Chueh FS, et al. (2013) Quercetin inhibits migration and invasion of SAS human oral cancer cells through inhibition of NF‐kβ and matrix metalloproteinase‐2/‐9 signaling pathways. Anticancer Research 33: 1941–1950.

Lee YJ and Wu TD (2001) Total synthesis of Kaempferol and methylated Kaempferol derivatives. Journal of the Chinese Chemical Society 48: 201–206. DOI: 10.1002/jccs.200100033.

Li Y and Ding Y (2012) Minireview: therapeutic potential of myricetin in diabetes mellitus. Food Science and Human Wellness 1: 19–25.

Liu YF, Gao F, Li XW, et al. (2012) The anticonvulsant and neuroprotective effects of baicalin on pilocarpine‐induced epileptic model in rats. Neurochemical Research 37 (8): 1670–1680. DOI: 10.1007/s11064-012-0771-8.

Miean KH and Mohamed S (2001) Flavonoid (myricetin, quercetin, kaempferol, luteolin, and apigenin) content of edible tropical plants. Journal of Agricultural and Food Chemistry 49 (6): 3106–3112.

Miranda CL, Maier CS and Stevens JF (2012) Flavonoids. Encyclopedia of Life Sciences. DOI: 10.1002/9780470015902.a0003068.pub2.

Mulholland PJ, Ferry DR, Anderson D, et al. (2001) Pre‐clinical and clinical study of QC12, a water‐soluble, pro‐drug of quercetin. Annals of Oncology 12: 245–248. DOI: 10.1023/A:1008372017097.

Odenthal J, Van Heumen BW, Roelofs HM, et al. (2012) The influence of curcumin, quercetin and eicosapentaenoic acid on the expression of phase II, detoxification enzymes in the intestinal cell lines HT‐29, Caco‐2, HuTu 80, and LT97. Nutrition and Cancer 64: 856–863.

Pal HC, Sharma S, Strickland LR, et al. (2014) Fisetin Inhibits Human Melanoma Cell Invasion through Promotion of Mesenchymal to Epithelial Transition and by Targeting MAPK and NFκBSignaling Pathways. PLoS ONE 9 (1): e86338. https://doi.org/10.1371/journal.pone.0086338

Pal HC, Diamond AC, Strickland LR, et al. (2016) Fisetin, a dietary flavonoid, augments the anti‐invasive and anti‐metastatic potential of sorafenib in melanoma. Oncotarget 7 (2): 1227.

Ren MX, Deng XH, Ai F, Yuan GY and Song HY (2015) Effect of quercetin on the proliferation of the human ovarian cancer cell line SKOV‐3 in vitro. Experimental and Therapeutic Medicine 10 (2): 579–583.

Ren R, Shi C, Cao J, et al. (2016) Neuroprotective effects of a standardized flavonoid extract of safflower against neurotoxin induced cellular and animal models of Parkinson's disease. Scientific Reports 6: 22135. DOI: 10.1038/srep22135.

Robert JN, Els van N, Danny EC, et al. (2001) Flavonoids: a review of probable mechanisms of action and potential applications. American Journal of Clinical Nutrition 74: 418–425.

Sharma A, Khare R, Kumar V, et al. (2014) 1‐(Substituted)‐4, 4, 6‐trimethyl‐3, 4‐dihydropyrimidine‐2(1H)‐thione: green synthesis, antibacterial activity and DNA photocleavage activity. International Journal of Pharmacy and Pharmaceutical Sciences 6 (3): 171–175.

Sharma A, Kumar V, Khare R, et al. (2015) Synthesis, docking study, and DNA photocleavage activity of some pyrimidinylhydrazones and 3‐(quinolin‐3‐yl)‐5, 7‐dimethyl‐1, 2, 4‐triazolo [4, 3‐a] pyrimidine derivatives. Medicinal Chemistry Research 24 (5): 1830–1841.

Sharma A and Tuli HS (2017) Natural moieties as promising anti‐cancer drugs. Journal of Biological and Chemical Sciences 4 (1): 301–303.

Slimestad R, Fossen T and Vagen IM (2007) Onions: a source of unique dietary flavonoids. Journal of Agricultural and Food Chemistry 55 (25): 10067–10080.

Stahlhut SG, Siedler S, Malla S, et al. (2015) Assembly of a novel biosynthetic pathway for production of the plant flavonoid fisetin in Escherichia coli. Metabolic Engineering 31: 84–93. DOI: 10.1016/j.ymben.2015.07.002.

Testai L, Martelli A, Cristofaro M, et al. (2013) Cardioprotective effects of different flavonoids against myocardial ischaemia/reperfusion injury in Langendorff‐perfused rat hearts. Journal of Pharmacy & Pharmaceutical Sciences 65 (5): 750–756. DOI: 10.1111/jphp.12032.Epub.

Woo HD and Kim J (2013) Dietary flavonoid intake and smoking‐related cancer risk: a meta‐analysis. PLoS One 8 (9): e75604.

Wu Y, Wang F, Zheng Q, et al. (2006) Hepatoprotective effect of total flavonoids from Laggeraalata against carbon tetrachloride‐induced injury in primary cultured neonatal rat hepatocytes and in rats with hepatic damage. Journal of Biomedical Science 13 (4): 569–578.

Xiao J (2017) Dietary flavonoid aglycones and their glycosides: which show better biological significance? Critical Reviews in Food Science and Nutrition 57 (9): 1874–1905. DOI: 10.1080/10408398.2015.1032400.

Xiuqin LI (2006) Activation of breviscapine to calcium‐activated potassium channels in rat aortic smooth muscle. Journal of Clinical Cardiology 22: 351–353.

Yao LH, Jiang YM, Shi J, et al. (2004) Flavonoids in food and their health benefits. Plant Foods for Human Nutrition 59 (3): 113–122.

Yiming L, Wei H, Aihua L, et al. (2008) Neuroprotective effects of breviscapine against apoptosis induced by transient focal cerebral ischaemia in rats. Journal of Pharmacy & Pharmaceutical Sciences 60 (3): 349–355. DOI: 10.1211/jpp.60.3.0010.

Zhou WH, Cheng GQ, Shao XM, et al. (2010) Selective head cooling with mild systemic hypothermia after neonatal hypoxic‐ischemic encephalopathy: a multicenter randomized controlled trial in China. Journal of Pediatrics 157 (3): 367–372.

Further Reading

Aherne SA and O'Brien NM (2002) Dietary flavonols: chemistry, food content, and metabolism. Nutrition 18: 75–81.

Dangles O and Dufour C (2008) Flavonoid–protein binding processes and their potential impact on human health. In: Daayf F and Lattanzio V (eds) Recent Advances in Polyphenol Research, vol. 1. Oxford, UK: Wiley‐Blackwell. DOI: 10.1002/9781444302400.ch3.

Faggio C, Sureda A, Morabito S, et al. (2017) Flavonoids and platelet aggregation: A brief review. European Journal of Pharmacology 807: 91–101. DOI: 10.1016/j.ejphar.2017.04.009.

Gonçalves CFL, de Freitas ML and Ferreira ACF (2017) Flavonoids, thyroid iodide uptake and thyroid cancer‐a review. International Journal of Molecular Sciences 18 (6. pii:): E1247. DOI: 10.3390/ijms18061247.

Havsteen BH (2002) The biochemistry and medical significance of the flavonoids. Pharmacology and Therapeutics 96: 67–202. DOI: 10.1016/S0163-7258(02)00298-X.

Husain Q (2010) In: Hui HY (ed.) Handbook of Fruit and Vegetable Flavors. New Jersey: John Wiley & Sons.

Ibrahim RK (2001b) Flavonoids. Encyclopedia of Life Sciences. DOI: 10.1038/npg.els.0003068.

Lago JHG, Toledo‐Arruda AC, Mernak M, et al. (2014) Structure‐activity association of flavonoids in lung diseases. Molecules 19 (3): 3570–3595. DOI: 10.3390/molecules19033570.

Pallauf K, Duckstein N and Rimbach G (2017) A literature review of flavonoids and lifespan in model organisms. Proceedings of the Nutrition Society 76 (2): 145–162. DOI: 10.1017/S0029665116000720.

Xiao X, Wang X, Gui X, et al. (2016) Natural flavonoids as promising analgesic candidates: a systematic review. Chemistry and Biodiversity 13 (11): 1427–1440. DOI: 10.1002/cbdv.201600060.

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Sharma, Ajay, Sharma, Pooja, Singh Tuli, Hardeep, and Sharma, Anil K(Jan 2018) Phytochemical and Pharmacological Properties of Flavonols. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0027666]