Medicinal Chemistry Research

, Volume 28, Issue 10, pp 1755–1765 | Cite as

Quercetin analogs with high fetal hemoglobin-inducing activity

  • Wachirachai Pabuprapap
  • Yanisa Wassanatip
  • Pichit Khetkam
  • Waraluck Chaichompoo
  • Sukanya Kunkaewom
  • Pongpan Senabud
  • Janejira Hata
  • Ratchanaporn Chokchaisiri
  • Saovaros Svasti
  • Apichart SuksamrarnEmail author
Original Research


β-Thalassemia is the major health problems in developing countries, when affected patients and healthy carriers are numerous, resulting a total absence or severe decrease in the production of β-globin chains. The use of chemical agents for increasing the production of fetal hemoglobin (HbF) by reactivating γ-globin gene to balance excess α-globin chains is an alternative therapeutic approach. Therefore, the search for molecules exhibiting the property of inducing γ-globin gene expression is of great interest. In this report, we discovered that quercetin (1), the major flavonoid isolated from the heartwoods of the medicinal plant Anaxagorea luzonensis promoted the expression of γ-globin gene. Chemical modification of 1 to fourteen methyl ether analogs (215) was conducted. The structures of these compounds were established on the basis of their spectroscopic data and by comparison with those of the reported values. The parent flavonoid and its chemically modified analogs were investigated for their γ-globin gene induction for the first time. The parent compound 1 exhibited less induced γ-globin gene expression than cisplatin and hemin, the positive controls. 3,4′-Di-O-methylquercetin (7), the modified analog, significantly enhanced γ-globin gene expression with 2.6-fold change at 8 μM, which was slightly higher than cisplatin and hemin. Moreover, compounds 1 and 7 displayed less cytotoxic activity against K562::ΔGγAγEGFP cells than cisplatin. Structure-activity relationship (SAR) study revealed that the methoxyl groups at the 3- and 4ʹ-positions and the free hydroxyl group at the 7-position are required for strong HbF-inducing activity.


Quercetin Methylated quercetin Structure-activity relationship β-Thalassemia Hemoglobin F 



This work was supported by The Thailand Research Fund (grant nos. DBG5980003 and DBG6180030) and the Center of Excellence for Innovation in Chemistry (PERCH-CIC), Office of the Higher Education Commission (OHEC), Ministry of Education. WP acknowledges a scholarship from Science Achievement Scholarship of Thailand, OHEC, Ministry of Education.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

44_2019_2412_MOESM1_ESM.pdf (4.9 mb)
Supplementary Data


  1. Al-Dabbas MM, Kitahara K, Suganuma T, Hashimoto F, Tadera K (2006) Antioxidant and α-amylase inhibitory compounds from aerial parts of Varthemia iphionoides Boiss. Biosci Biotechnol Biochem 70:2178–2184CrossRefGoogle Scholar
  2. Ballas SK, Singh P, Adams-Graves P, Wordell CJ (2013) Idiosyncratic side effects of hydroxyurea in patients with sickle cell anemia. J Blood Disord Transf 4:1000162Google Scholar
  3. Boots AW, GRMM Haenen, Bast A (2008) Health effects of quercetin: from antioxidant tonutraceutical. Eur J Pharmacol 585:325–337CrossRefGoogle Scholar
  4. Bouktaib M, Lebrun S, Atmani A, Rolando C (2002) Hemisynthesis of all the O-monomethylated analogues of quercetin including the major metabolites, through selective protection of phenolic functions. Tetrahedron 58:10001–10009CrossRefGoogle Scholar
  5. Cao A, Galanello R (2010) Beta-thalassemia. Genet Med 12:67–76CrossRefGoogle Scholar
  6. Chaneiam N, Changtam C, Mungkongdee T, Suthatvoravut U, Winichagoon P, Vadolas J, Suksamrarn A, Fucharoen S, Svasti S (2013) A reduced curcuminoid analog as a novel inducer of fetal hemoglobin. Ann Hematol 92:379–386CrossRefGoogle Scholar
  7. Chokchaisiri R, Chaneiam N, Svasti S, Fucharoen S, Vadolas J, Suksamrarn A (2010) Labdane diterpenes from the aerial parts of Curcuma comosa enhance fetal hemoglobin production in an erythroid cell line. J Nat Prod 73:724–728CrossRefGoogle Scholar
  8. Chu HW, Wu HT, Lee YJ (2004) Regioselective hydroxylation of 2-hydroxychalcones by dimethyldioxirane towards polymethoxylated flavonoids. Tetrahedron 60:2647–2655CrossRefGoogle Scholar
  9. D’Andrea G (2015) Quercetin: a flavonol with multifaceted therapeutic applications? Fitoterapia 106:256–271CrossRefGoogle Scholar
  10. Daker M, Ahmad M, Khoo AS (2012) Quercetin-induced inhibition and synergistic activity with cisplatin—a chemotherapeutic strategy for nasopharyngeal carcinoma cells. Cancer Cell Int 12:34CrossRefGoogle Scholar
  11. Dasari S, Tchounwou PB (2014) Cisplatin in cancer therapy: molecular mechanisms of action. Eur J Pharmacol 740:364–378CrossRefGoogle Scholar
  12. Daskiewicz JB, Depeint F, Viornery L, Bayet C, Comte-Sarrazin G, Comte G, Gee JM, Johnson IT, Ndjoko K, Hostettmann K, Barron D (2005) Effects of flavonoids on cell proliferation and caspase activation in a human colonic cell line HT29: an SAR study. J Med Chem 48:2790–2804CrossRefGoogle Scholar
  13. Dong H, Gou YL, Cao SG, Chen SX, Sim KY, Goh SH, Kini RM (1999) Eicosenones and methylated flavonols from Amomum koenigii. Phytochemistry 50:899–902CrossRefGoogle Scholar
  14. El-Beshlawy A, Hamdy M, El Ghamrawy M (2009) Fetal globin induction in β-thalassemia. Hemoglobin 33:S197–S203CrossRefGoogle Scholar
  15. Fard AD, Hosseini SA, Shahjahani M, Salari F, Jaseb K (2013) Evaluation of novel fetal hemoglobin inducer drugs in treatment of β-hemoglobinopathy disorders. Int J Hematol Oncol Stem Cell Res 7:47–54Google Scholar
  16. Gonda R, Takeda T, Akiyama T (2000) Studies on the constituents of Anaxagorea luzonensis A. Gray. Chem Pharm Bull 48:1219–1222CrossRefGoogle Scholar
  17. Haraguchi H, Hashimoto K, Yagi A (1992) Antioxidative substances in leaves of Polygonum hydropiper. J Agric Food Chem 40:1349–1351CrossRefGoogle Scholar
  18. Jurd L (1958) Plant polyphenols. V. selective alkylation of the 7-hydroxyl group in polyhydroxyflavones. J Am Chem Soc 80:5531–5536CrossRefGoogle Scholar
  19. Jurd L (1962) The selective alkylation of polyphenols. II. methylation of 7-, 4′-, and 3′-hydroxyl groups in flavonols. J Org Chem 27:1294–1297CrossRefGoogle Scholar
  20. Juvale K, Stefan K, Wiese M (2013) Synthesis and biological evaluation of flavones and benzoflavones as inhibitors of BCRP/ABCG2. Eur J Med Chem 67:115–126CrossRefGoogle Scholar
  21. Karimova ER, Baltina LA, Spirikhin LV, Kondratenko RM, Farkhutdinov RR, Petrova IV (2015) Synthesis and antioxidant activity of quercetin ethers. Chem Nat Compd 51:851–855CrossRefGoogle Scholar
  22. Kode A, Rajendrasozhan S, Caito S, Yang SR, Megson IL, Rahman I (2008) Resveratrol induces glutathione synthesis by activation of Nrf2 and protects against cigarette smoke-mediated oxidative stress in human lung epithelial cells. Am J Physiol Lung Cell Mol Physiol 294:L478–L488CrossRefGoogle Scholar
  23. Kwon YS, Kim CM (2003) Antioxidant constituents from the stem of Sorghum bicolor. Arch Pharm Res 26:535–539CrossRefGoogle Scholar
  24. Lampronti I, Bianchi N, Borgatti M, Fibach E, Prus E, Gambari R (2003) Accumulation of gamma-globin mRNA in human erythroid cells treated with angelicin. Eur J Haematol 71:189–195CrossRefGoogle Scholar
  25. Lee EH, Kim HJ, Song YS, Jin C, Lee KT, Cho J, Lee YS (2003) Constituents of the stems and fruits of Opuntia ficus-indica var. saboten. Arch Pharm Res 26:1018–1023CrossRefGoogle Scholar
  26. Li NG, Shi ZH, Tang YP, Yang JP, Duan JA (2009b) An efficient partial synthesis of 4-O-methylquercetin via regioselective protection and alkylation of quercetin. Beilstein J Org Chem 5:1–5CrossRefGoogle Scholar
  27. Li NG, Shi ZH, Tang YP, Yang JP, Lu TL, Zhang F, Huang YW, Wang ZJ, Duan JA (2011) Synthetic studies on the construction of 7-O-methylquercetin through regioselective protection and alkylation of quercetin. Chin Chem Lett 22:5–8CrossRefGoogle Scholar
  28. Li YQ, Zhou FC, Gao F, Bian JS, Shan F (2009a) Comparative evaluation of quercetin, isoquercetin and rutin as inhibitors of α-glucosidase. J Agric Food Chem 57:11463–11468CrossRefGoogle Scholar
  29. Li Y, Yao J, Han C, Yang J, Chaudhry MT, Wang S, Liu H, Yin Y (2016) Quercetin, inflammation and immunity. Nutrients 8:167CrossRefGoogle Scholar
  30. Liu S, McConnell SC, Ryan TM (2013) Erythropoiesis in the absence of adult hemoglobin. Mol Cell Biol 33:2241–2251CrossRefGoogle Scholar
  31. Macari ER, Lowrey CH (2011) Induction of human fetal hemoglobin via the NRF2 antioxidant response signaling pathway. Blood 117:5987–5997CrossRefGoogle Scholar
  32. McMahon M, Itoh K, Yamamoto M, Chanas SA, Henderson CJ, McLellan LI, Wolf CR, Cavin C, Hayes JD (2001) The Cap’n’Collar basic leucine zipper transcription factor Nrf2 (NF-E2 p45-related factor 2) controls both constitutive and inducible expression of intestinal detoxification and glutathione biosynthetic enzymes. Cancer Res 61:3299–3307Google Scholar
  33. Mouffok S, Haba H, Lavaud C, Long C, Benkhaled M (2012) Chemical constituents of Centaurea omphalotricha Coss. & Durieu ex Batt. & Trab. Rec Nat Prod 6:292–295Google Scholar
  34. Rauf A, Imran M, Khan IA, Ur-Rehman M, Gilani SA, Mehmood Z, Mubarak MS (2018) Anticancer potential of quercetin: a comprehensive review. Phytother Res 32:2109–2130CrossRefGoogle Scholar
  35. Rodrigue CM, Arous N, Bachir D, Smith‐Ravin J, Romeo PH, Galacteros F, Garel MC (2001) Resveratrol, a natural dietary phytoalexin, possesses similar properties to hydroxyurea toward erythroid differentiation. Br J Haematol 113:500–507CrossRefGoogle Scholar
  36. Rund D, Rachmilewitz E (2005) β-Thalassemia. N Engl J Med 353:1135–1146CrossRefGoogle Scholar
  37. Saewan N, Koysomboon S, Chantrapromma K (2011) Anti-tyrosinase and anti-cancer activities of flavonoids from Blumea balsamifera DC. J Med Plant Res 5:1018–1025Google Scholar
  38. Shi S, Zhao Y, Zhou H, Zhang Y, Jiang X, Huang K (2008) Identification of antioxidants from Taraxacum mongolicum by high-performance liquid chromatography-diode array detection-radical-scavenging detection-electrospray ionization mass spectrometry and nuclear magnetic resonance experiments. J Chromatogr A 1209:145–152CrossRefGoogle Scholar
  39. Sutthanut K, Sripanidkulchai B, Yenjai C, Jay M (2007) Simultaneous identification and quantitation of 11 flavonoid constituents in Kaempferia parviflora by gas chromatography. J Chromatogr A 1143:227–233CrossRefGoogle Scholar
  40. Tanigawa S, Fujii M, Hou DX (2007) Action of Nrf2 and Keap1 in ARE-mediated NQO1 expression by quercetin. Free Radic Biol Med 42:1690–1703CrossRefGoogle Scholar
  41. Vadolas J, Wardan H, Orford M, Williamson R, Ioannou PA (2004) Cellular genomic reporter assays for screening and evaluation of inducers of fetal hemoglobin. Hum Mol Genet 13:223–233CrossRefGoogle Scholar
  42. Valesi AG, Rodriguez E, Vander Velde G, Mabry TJ (1972) Methylated flavonols in Larrea cuneifolia. Phytochemistry 11:2821–2826CrossRefGoogle Scholar
  43. Wang Y, Hamburger M, Gueho J, Hostettmann K (1989) Antimicrobial flavonoids from Psiadia trinervia and their methylated and acetylated derivatives. Phytochemistry 28:2323–2327CrossRefGoogle Scholar
  44. Zhang DD (2006) Mechanistic studies of the Nrf2-Keap1 signaling pathway. Drug Metab Rev 38:769–789CrossRefGoogle Scholar
  45. Zhang X, Guo Q, Chen J, Chen Z (2015) Quercetin enhances cisplatin sensitivity of human osteosarcoma cells by modulating microRNA-217-KRAS axis. Mol Cells 38:638–642CrossRefGoogle Scholar
  46. Zheng SY, Li Y, Jiang D, Zhao J, Ge JF (2012) Anticancer effect and apoptosis induction by quercetin in the human lung cancer cell line A-549. Mol Med Rep 5:822–826Google Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Wachirachai Pabuprapap
    • 1
  • Yanisa Wassanatip
    • 2
  • Pichit Khetkam
    • 1
  • Waraluck Chaichompoo
    • 1
  • Sukanya Kunkaewom
    • 1
  • Pongpan Senabud
    • 1
  • Janejira Hata
    • 1
  • Ratchanaporn Chokchaisiri
    • 3
  • Saovaros Svasti
    • 2
  • Apichart Suksamrarn
    • 1
    Email author
  1. 1.Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of ScienceRamkhamhaeng UniversityBangkokThailand
  2. 2.Thalassemia Research Center, Institute of Molecular Biosciences and Department of Biochemistry, Faculty of ScienceMahidol UniversityBangkokThailand
  3. 3.Department of Chemistry, School of ScienceUniversity of PhayaoPhayaoThailand

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