1486-70-0Relevant articles and documents
Glucuronidation of Methylated Quercetin Derivatives: Chemical and Biochemical Approaches
Docampo-Palacios, Maite L.,Alvarez-Hernández, Anislay,Adiji, Olubu,Gamiotea-Turro, Daylin,Valerino-Diaz, Alexander B.,Viegas, Luís P.,Ndukwe, Ikenna E.,De Fátima, ?ngelo,Heiss, Christian,Azadi, Parastoo,Pasinetti, Giulio M.,Dixon, Richard A.
, p. 14790 - 14807 (2020/12/23)
Botanical supplements derived from grapes are functional in animal model systems for the amelioration of neurological conditions, including cognitive impairment. Rats fed with grape extracts accumulate 3′-O-methyl-quercetin-3-O-β-d-glucuronide (3) in their brains, suggesting 3 as a potential therapeutic agent. To develop methods for the synthesis of 3 and the related 4′-O-methyl-quercetin-7-O-β-d-glucuronide (4), 3-O-methyl-quercetin-3′-O-β-d-glucuronide (5), and 4′-O-methyl-quercetin-3′-O-β-d-glucuronide (6), which are not found in the brain, we have evaluated both enzymatic semisynthesis and full chemical synthetic approaches. Biocatalysis by mammalian UDP-glucuronosyltransferases generated multiple glucuronidated products from 4′-O-methylquercetin, and is not cost-effective. Chemical synthetic methods, on the other hand, provided good results; 3, 5, and 6 were obtained in six steps at 12, 18, and 30% overall yield, respectively, while 4 was synthesized in five steps at 34% overall yield. A mechanistic study on the unexpected regioselectivity observed in the quercetin glucuronide synthetic steps is also presented.
Quercetin analogs with high fetal hemoglobin-inducing activity
Pabuprapap, Wachirachai,Wassanatip, Yanisa,Khetkam, Pichit,Chaichompoo, Waraluck,Kunkaewom, Sukanya,Senabud, Pongpan,Hata, Janejira,Chokchaisiri, Ratchanaporn,Svasti, Saovaros,Suksamrarn, Apichart
, p. 1755 - 1765 (2019/08/02)
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 4?-positions and the free hydroxyl group at the 7-position are required for strong HbF-inducing activity.
Natural and Synthetic Flavonoids as Potent Mycobacterium tuberculosis UGM Inhibitors
Villaume, Sydney A.,Fu, Jian,N'Go, Inès,Liang, Hui,Lou, Huayong,Kremer, Laurent,Pan, Weidong,Vincent, Stéphane P.
, p. 10423 - 10429 (2017/08/07)
This study reports a novel class of inhibitors of uridine 5′-diphosphate (UDP) galactopyranose mutase (UGM) derived from a screening of natural products. This enzyme is an essential biocatalyst involved in the cell wall biosynthesis of Mycobacterium tuberculosis. Flavonoids are potent inhibitors of UGM. The synthesis of novel methylated flavonoids allowed a structure–activity relationship analysis to be performed and which functional groups and structural elements were required for UGM inhibition could be determined. The binding mode of one of the best inhibitors was found to be noncompetitive. Docking simulations indicated that this molecule was likely to bind UGM in its open conformation, in a cavity recently identified as a “druggable” pocket. Importantly, two of the best inhibitors of the M. tuberculosis UGM displayed moderate activity against whole M. tuberculosis cells. This study reports the first natural products that act as inhibitor of UGM. Given the importance of natural products in medicinal chemistry, these results create new opportunities for the discovery of new antitubercular agents.
