Glucuronidation of Methylated Quercetin Derivatives: Chemical and Biochemical Approaches

Abstract

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.

The beauty of biocatalysis: sustainable synthesis of ingredients in cosmetics

“…Due to its abundance in many plants the majority of formulations obtain glycosides of flavonoids from natural sources, with production of flavonoids from plants being investigated extensively and external growing conditions optimised to improve yields, however in vitro formation is possible and has been achieved both chemically and biosynthetically. 190–193 Successful efforts into the formation of quercetin by cell cultures have also been achieved. 194…”

Utilization of carbon catabolite repression for efficiently biotransformation of anthraquinone O-glucuronides by Streptomyces coeruleorubidus DM

“…Glucuronidation is typically a phase II metabolic process, considered a detoxification step in the mammalian system ( Stachulski and Meng, 2013 ). However, glucuronide metabolites often possess enhanced water solubility and polarity compared to their corresponding aglycones, indicating their potent pharmacological activities ( Docampo-Palacios et al, 2020 ). For instance, morphine-6-O-glucuronide demonstrates a 100-fold stronger anesthetic effect than morphine, as evidenced by clinical trials ( Kilpatrick and Smith, 2005 ).…”

Anti-Inflammatory, Antioxidant, Moisturizing, and Antimelanogenesis Effects of Quercetin 3-O-β-D-Glucuronide in Human Keratinocytes and Melanoma Cells via Activation of NF-κB and AP-1 Pathways

“…3′-methyl-quercetin-3-glucuronide, quercetin-3-glucuronide, and quercetin-3’-sulfate have been identified as major plasma metabolites after 1.5 h from the consumption of fried onions [ 30 , 32 ]. These quercetin metabolites are formed in the small intestine and liver by biotransformation enzymes including UDP-glucuronyltransferases as a result of phase II metabolism [ 29 , 39 , 40 ]. It was also reported that conjugated metabolites of quercetin accumulate in human plasma in the concentration range of 10 −7 to 10 −6 M after the periodic ingestion of onions with meals for 1 week [ 41 ].…”

“…Since these compounds have been observed as the main forms of conjugated quercetin metabolites, studies focusing on the biological activity of flavonols using these conjugated metabolites would be essential, which prompted us to study the biological activity of one of the conjugated quercetin metabolites. One of the most abundant glucuronide metabolites found mainly in plasma and tissues including the liver, kidney, and brain is quercetin 3-O-β-D-glucuronide (Q-3-G) ( Figure 1 ) [ 31 , 35 , 40 , 42 , 43 ], which may generate similar, stronger, or weaker activities compared with parent compounds in different models. Q-3-G is transported to target tissues via plasma to exert its biological activity [ 39 ].…”