Quercetin analogs with high fetal hemoglobin-inducing activity
- 40 Downloads
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.
KeywordsQuercetin 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.
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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