Abstract:A practical two-photon fluorescent probe was developed for highly sensitive and selective sensing of the activities of catechol-O-methyltransferase (COMT) in complex biological samples. To this end, a series of 3-substituted 7,8-dihydroxycoumarins were designed and synthesized. Among them, 3-BTD displayed the best combination of selectivity, sensitivity, reactivity, and fluorescence response following COMT-catalyzed 8-O-methylation. The newly developed two-photon fluorescent probe 3-BTD can be used for determi… Show more
“…Based on the substrate specificities of both CES1 and CES2, some optical probe substrates have been recently developed for assessing the real activities of CES1 or CES2 in complex biological systems ( Supplementary Information Table S2 ) 49 , 51 , 58 , 59 , 60 , 61 , 62 , 63 , 64 . These optical probes provide practical and efficient tools for high-throughput screening (HTS) of CES modulators in cell/tissue preparations or even in living cells, due to the inherent advantages including non-destructive, highly sensitive, easily managed, and applicable to HTS assay 49 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 . Figure 3 Substrate specificity of CES1.…”
Section: Tissue Distribution and Substrate Specificity Of Cesmentioning
Mammalian carboxylesterases (CEs) are key enzymes from the serine hydrolase superfamily. In the human body, two predominant carboxylesterases (CES1 and CES2) have been identified and extensively studied over the past decade. These two enzymes play crucial roles in the metabolism of a wide variety of endogenous esters, ester-containing drugs and environmental toxicants. The key roles of CES in both human health and xenobiotic metabolism arouse great interest in the discovery of potent CES modulators to regulate endobiotic metabolism or to improve the efficacy of ester drugs. This review covers the structural and catalytic features of CES, tissue distributions, biological functions, genetic polymorphisms, substrate specificities and inhibitor properties of CES1 and CES2, as well as the significance and recent progress on the discovery of CES modulators. The information presented here will help pharmacologists explore the relevance of CES to human diseases or to assign the contribution of certain CES in xenobiotic metabolism. It will also facilitate medicinal chemistry efforts to design prodrugs activated by a given CES isoform, or to develop potent and selective modulators of CES for potential biomedical applications.
“…Based on the substrate specificities of both CES1 and CES2, some optical probe substrates have been recently developed for assessing the real activities of CES1 or CES2 in complex biological systems ( Supplementary Information Table S2 ) 49 , 51 , 58 , 59 , 60 , 61 , 62 , 63 , 64 . These optical probes provide practical and efficient tools for high-throughput screening (HTS) of CES modulators in cell/tissue preparations or even in living cells, due to the inherent advantages including non-destructive, highly sensitive, easily managed, and applicable to HTS assay 49 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 . Figure 3 Substrate specificity of CES1.…”
Section: Tissue Distribution and Substrate Specificity Of Cesmentioning
Mammalian carboxylesterases (CEs) are key enzymes from the serine hydrolase superfamily. In the human body, two predominant carboxylesterases (CES1 and CES2) have been identified and extensively studied over the past decade. These two enzymes play crucial roles in the metabolism of a wide variety of endogenous esters, ester-containing drugs and environmental toxicants. The key roles of CES in both human health and xenobiotic metabolism arouse great interest in the discovery of potent CES modulators to regulate endobiotic metabolism or to improve the efficacy of ester drugs. This review covers the structural and catalytic features of CES, tissue distributions, biological functions, genetic polymorphisms, substrate specificities and inhibitor properties of CES1 and CES2, as well as the significance and recent progress on the discovery of CES modulators. The information presented here will help pharmacologists explore the relevance of CES to human diseases or to assign the contribution of certain CES in xenobiotic metabolism. It will also facilitate medicinal chemistry efforts to design prodrugs activated by a given CES isoform, or to develop potent and selective modulators of CES for potential biomedical applications.
“…In contrast to non-fluorescent probes, fluorescent substrates for target enzyme(s) have inherent advantages, such as high sensitivity and applicability to HTS 32. , 33. , 34.…”
Section: Introductionmentioning
confidence: 99%
“…In contrast to non-fluorescent probes, fluorescent substrates for target enzyme(s) have inherent advantages, such as high sensitivity and applicability to HTS32., 33., 34., 35., 36., 37., 38., 39., 40., 41., 42., 43.. Recently, significant breakthroughs have been made in the development of fluorescent probes for UGT1A1, and several fluorescent probes that are highly selective for UGT1A1 activities in complex biological samples have been successfully developed (Fig.…”
Uridine-diphosphate glucuronosyltransferase 1A1 (UGT1A1) is an important conjugative enzyme in mammals that is responsible for the conjugation and detoxification of both endogenous and xenobiotic compounds. Strong inhibition of UGT1A1 may trigger adverse drug/herb–drug interactions, or result in metabolic disorders of endobiotic metabolism. Therefore, both the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have recommended assaying the inhibitory potential of drugs under development on the human UGT1A1 prior to approval. This review focuses on the significance, progress and challenges in discovery and characterization of UGT1A1 inhibitors. Recent advances in the development of UGT1A1 probes and their application for screening UGT1A1 inhibitors are summarized and discussed in this review for the first time. Furthermore, a long list of UGT1A1 inhibitors, including information on their inhibition potency, inhibition mode, and affinity, has been prepared and analyzed. Challenges and future directions in this field are highlighted in the final section. The information and knowledge that are presented in this review provide guidance for rational use of drugs/herbs in order to avoid the occurrence of adverse effects
via
UGT1A1 inhibition, as well as presenting methods for rapid screening and characterization of UGT1A1 inhibitors and for facilitating investigations on UGT1A1—ligand interactions.
“…Ultimately a series of different property groups, including phenyl, cyano, carbonyl, carboxyl, carboxylic ester and benzothiazole, were introduced to the C-3 site of daphnetin. All these compounds were prepared from 2,3,4-trihydroxybenzaldehyde through Knoevenagel condensation ( Scheme 2 ) [ 18 ]. The detailed experimental procedures are described in the Supporting Information .…”
Section: Resultsmentioning
confidence: 99%
“…The synthetic routes of daphnetin derivatives 13 – 19 are illustrated in Scheme 2 , and the details in the synthetic procedure of the compounds are described in the Supporting Information based on our previous study [ 18 ].…”
In this study, daphnetin 1 was chosen as the lead compound, and C-3 or C-4-substituted daphnetins were designed and synthesized to explore the potential relationship between the antioxidant activities and the chemical structures of daphnetin derivatives. The antioxidant activities of the generated compounds were evaluated utilizing the free radical scavenging effect on 2,2′-diphenyl-1-picrylhydrazyl, 2,2′-azinobis-(3-ethylbenzthiazoline-6-sulfonate) cation, and the ferric reducing power assays, and were then compared with those of the standard antioxidant Trolox. The results showed that the catechol group was the key pharmacophore for the antioxidant activity of the daphnetins. The introduction of an electron-withdrawing hydrophilic group at the C-4 position of daphnetin enhanced the antioxidative capacity, but this trend was not observed for C-3 substitution. In addition, introduction of a a hydrophobic phenyl group exerted negative effects on the antioxidant activity in both the C-3 and C-4 substitutions. Among all of the derivatives tested, the most powerful antioxidant was 4-carboxymethyl daphnetin (compound 9), for which the strongest antioxidant activity was observed in all of the assays. In addition, compound 9 also displayed strong pharmaceutical properties in the form of metabolic stability. To summarize, compound 9 holds great potential to be developed as an antioxidant agent with excellent antioxidant activity and proper pharmacokinetic behavior.
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