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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
  • 40 Downloads

Abstract

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.

Keywords

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

Notes

Acknowledgements

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

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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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