•Scutellarin had a wide range of benefits to brain injury.•Eight methylated scutellarein derivatives were synthesized based on metabolism in vivo.•The thrombin inhibition activity, antioxidant activity and physicochemical properties of these derivatives were evaluated.•Preliminary SARs of these derivatives were analyzed.•6-O-methyl-scutellarein (5) showed good biological activity.Scutellarin (1) could be hydrolyzed into scutellarein (2) in vivo and then converted into methylated, sulfated and glucuronidated forms. In order to investigate the biological activities of these methylated metabolites, eight methylated analogs of scutellarein (2) were synthesized via semi-synthetic methods. The antithrombotic activities of these compounds were evaluated through the analyzation of prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT) and fibrinogen (FIB). Their antioxidant activities were assessed by measuring their scavenging capacities toward 1,1-diphenyl-2-picrylhydrazyl radical (DPPH) and the ability to protect PC12 cells against H2O2-induced cytotoxicity. Furthermore, the physicochemical properties of these compounds including aqueous solubility and lipophilicity were also investigated. The results showed that 6-O-methylscutellarein (5) demonstrated potent antithrombotic activity, stronger antioxidant activity and balanced solubility and permeability compared with scutellarin (1), which warrants further development of 5 as a promising lead for the treatment of ischemic cerebrovascular disease.6-O-methyl-scutellarein (5) demonstrated potent antithrombotic activity, stronger antioxidant activity and balanced solubility and permeability compared with scutellarin (1), which warrants further development for the treatment of ischemic cerebrovascular disease.

In order to improve the biological activity and water solubility of scutellarin (1), some derivatives of its main metabolite (scutellarein) were designed and synthesized. All the compounds were tested for their thrombin inhibition activity through the analyzation of thrombin time (TT), activated partial thromboplastin time (APTT), prothrombin time (PT) and fibrinogen (FIB). Their antioxidant activities were assessed by measuring their scavenging capacities toward 1,1-diphenyl-2-picrylhydrazyl radical (DPPH) and the ability to protect PC12 cells against H2O2-induced cytotoxicity, their water solubility were also assessed by ultraviolet (UV) spectrophotometer. The results showed that compound 8b demonstrated stronger anticoagulant and antioxidant activity, better water solubility compared with scutellarein (2), which warrants it as a promising agent for the treatment of ischemic cerebrovascular disease.

O-Alkylated quercetin analogs were synthesized and their anticancer activities were assessed by a high-throughout screening (HTS) method. The structure–activity relationships (SAR) showed that introduction of long alkyl chain such as propyl group at the C-3 OH position or short alkyl chain such as ethyl group at the C-4′ OH position were very important for keeping inhibitory activities against the 16 cancer cell lines. Furthermore, when the two n-butyl groups were introduced into the C-3, C-7 or C-4′, C-7 positions, the anticancer activity was enhanced.

Scutellarein, which is the main metabolite of scutellarin in vivo, has better neuroprotective effects than scutellarin against brain ischemia. However, there are few studies on the metabolic profile of scutellarein in vivo. In this study, a method based on ultra performance liquid chromatography/quadrupole-time-of-flight mass spectrometry was applied to identify the scutellarein and its metabolites in rat plasma, urine and feces after oral administration of scutellarein. Using MSE and mass defect filter techniques, scutellarein (M1), the glucuronide conjugate of scutellarein (M2, M3), scutellarin (M4), 6,7-di-O-β-D-glucuronide scutellarein (M5), the glucuronide conjugate of apigenin (M6), 4′-O-sulfate scutellarein (M7), the methylated conjugate of scutellarein (M8), the methylated and glucuronide conjugate of scutellarein (M9), and the acetylated conjugate of scutellarein (M10) were detected in rat urine. M1, M2, M4, and M10 were detected in rat plasma and only M10 was found in feces. Our studies indicated that scutellarein can be metabolised by glucuronide conjugation, dehydroxylation, sulfation, methylation and acetylation in vivo after oral administration.

Four series of acid amides were synthesized, and through measurement using a fluorogenic substrate assay with human recombinant MMP-1, MMP-2 and MMP-9, compound 3f showed considerable inhibitory activities against MMP-2, MMP-9 and the best selectivity over MMP-1. Preliminary structure–activity relationship analysis indicated that caffeic acid amides with electron-donating groups at para-position of amino phenyl group showed better inhibitory activities and selectivity than those with electron-withdrawing groups, and the presence of adjacent dihydroxy in the caffeoyl group was very important for the MMP-2 and MMP-9 inhibitory activities.Four series of acid amides were synthesized, preliminary structure–activity relationship analysis indicated that caffeic acid amides with electron-donating groups at para-position of amino phenyl group showed better inhibitory activities and selectivity than those with electron-withdrawing groups, and the presence of adjacent dihydroxy in the caffeoyl group was very important for the MMP-2 and MMP-9 inhibitory activities.

In blood, quercetin is mainly found in metabolized forms. In order to study the activities of these quercetin metabolites in cardiovascular disease, 17 methylquercetin derivatives were synthesized based on metabolism in vivo, their thrombin inhibition activity were evaluated through the analyzation of prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT) and fibrinogen (FIB). The results showed that 6 methylquercetin derivatives had stronger inhibitory activities than that of quercetin. Preliminary SARs analysis showed that hydroxyl groups at C-3′ and C-4′ position in the B-ring and hydroxyl group at C-3 position in the C-ring played key roles in the thrombin inhibitory activity. The findings of this study would provide information for the exploitation and utilization of quercetin as thrombin inhibitor for thrombotic disease treatment.Graphical abstract17 methylquercetin derivatives were synthesized based on metabolism in vivo, their thrombin inhibition activity were evaluated and preliminary SARs of these derivatives as thrombin inhibitors were analyzed.Highlights► Flavonoids maybe promising lead compounds as thrombin inhibitors. ► 17 methylquercetin derivatives were synthesized based on metabolism in vivo. ► The thrombin inhibition activity of 17 methylquercetin derivatives were evaluated. ► Preliminary SARs of these derivatives as thrombin inhibitors were analyzed.

Scutellarein, which is the main metabolite of scutellarin in vivo, has better neuroprotective effects than scutellarin against brain ischemia. However, there are few studies on the metabolic profile of scutellarein in vivo. In this study, a method based on ultra performance liquid chromatography/quadrupole-time-of-flight mass spectrometry was applied to identify the scutellarein and its metabolites in rat plasma, urine and feces after oral administration of scutellarein. Using MSE and mass defect filter techniques, scutellarein (M1), the glucuronide conjugate of scutellarein (M2, M3), scutellarin (M4), 6,7-di-O-β-D-glucuronide scutellarein (M5), the glucuronide conjugate of apigenin (M6), 4′-O-sulfate scutellarein (M7), the methylated conjugate of scutellarein (M8), the methylated and glucuronide conjugate of scutellarein (M9), and the acetylated conjugate of scutellarein (M10) were detected in rat urine. M1, M2, M4, and M10 were detected in rat plasma and only M10 was found in feces. Our studies indicated that scutellarein can be metabolised by glucuronide conjugation, dehydroxylation, sulfation, methylation and acetylation in vivo after oral administration.