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Title: Quercetin analogs with high fetal hemoglobin-inducing activity
Authors: Wachirachai Pabuprapap
Yanisa Wassanatip
Pichit Khetkam
Waraluck Chaichompoo
Sukanya Kunkaewom
Pongpan Senabud
Janejira Hata
Ratchanaporn Chokchaisiri
Saovaros Svasti
Apichart Suksamrarn
University of Phayao
Ramkhamhaeng University
Mahidol University
Keywords: Chemistry
Issue Date: 1-Oct-2019
Citation: Medicinal Chemistry Research. Vol.28, No.10 (2019), 1755-1765
Abstract: © 2019, Springer Science+Business Media, LLC, part of Springer Nature. 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 (2−15) 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.
ISSN: 15548120
Appears in Collections:Scopus 2019

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