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To explore whether and how glucuronidation affects pyrogallol-type phytophenols, scutellarein and scutellarin (scutellarein-7- O -glucuronide) were comparatively investigated using a set of antioxidant analyses, including spectrophotometric analysis, UV-vis spectra analysis, and ultra-performance liquid chromatography coupled with electrospray ionization-quadrupole time-of-flight tandem mass spectrometry (UPLC-ESI-Q-TOF-MS/MS) analysis. In spectrophotometric analyses of the scavenging of 1,1-diphenyl-2-picrylhydrazyl (DPPH • ), 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS +• ), and 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl 3-oxide radicals (PTIO • ) and the reduction of Cu 2+ ions, scutellarein showed lower IC 50 values than scutellarin. However, in • O₂ - -scavenging spectrophotometric analysis, scutellarein showed higher IC 50 value than scutellarin. The analysis of UV-Vis spectra obtained after the Fe 2+ -chelating reaction of scutellarin showed a typical UV-Vis peak (λ max = 611 nm), while scutellarein showed no typical peak. In UPLC-ESI-Q-TOF-MS/MS analysis, mixing of scutellarein with DPPH • yielded MS peaks ( m / z 678, 632, 615, 450, 420, 381, 329, 300, 288, 227, 196, 182, 161, and 117) corresponding to the scutellarein-DPPH adduct and an MS peak ( m / z 570) corresponding to the scutellarein-scutellarein dimer. Scutellarin, however, generated no MS peak. On the basis of these findings, it can be concluded that glucuronidation of pyrogallol-type phytophenol antioxidants has a dual effect. On the one hand, glucuronidation can decrease the antioxidant potentials (except for • O₂ - scavenging) and further lower the possibility of radical adduct formation (RAF), while on the other hand, it can enhance the • O₂ - -scavenging and Fe 2+ -chelating potentials.

Erigeron breviscapus , a traditional Chinese medicine, is clinically used for the treatment of occlusive cerebral vascular diseases. We developed a sensitive and reliable ultra-performance liquid chromatography-electrospray-tandem mass spectrometry (UPLC-ESI-MS/MS) method for simultaneous quantitation of chlorogenic acid, scutellarin, and scutellarein, the main active constituents in Erigeron breviscapus , and compared the pharmacokinetics of these active ingredients in sham-operated and middle cerebral artery occlusion (MCAO) rats orally administrated with Erigeron breviscapus extract. Plasma samples were collected at 15 time points after oral administration of the Erigeron breviscapus extract. The levels of chlorogenic acid, scutellarin, and scutellarein in rat plasma at various time points were determined by a UPLC-ESI-MS/MS method, and the drug concentration versus time plots were constructed to estimate pharmacokinetic parameters. The concentration of chlorogenic acid in the plasma reached the maximum plasma drug concentration in about 15 min and was below the limit of detection after 4 h. Scutellarin and scutellarein showed the phenomenon of multiple absorption peaks in sham-operated and MCAO rats, respectively. Compared with the sham-operated rats, the terminal elimination half-life of scutellarein in the MCAO rats was prolonged by more than two times and the area under the curve of each component in the MCAO rats was significantly increased. The results showed chlorogenic acid, scutellarin, and scutellarein in MCAO rats had higher drug exposure than that in sham-operated rats, which provided a reference for the development of innovative drugs, optimal dosing regimens, and clinical rational drug use.

Scutellarin is the major active flavonoid extracted from the traditional Chinese herbal medicine Erigeron breviscapus (Vant.) Hand-Mazz., which is widely used in China. Recently, accumulating evidence has highlighted the potential role of scutellarin and its main metabolite scutellarein in the treatment of cancer. To explore novel anticancer agents with high efficiency, a series of new scutellarein derivatives with a long aliphatic chain were synthesized, and the antiproliferative activities against Jurkat, HCT-116 and MDA-MB-231 cancer cell lines were assessed. Among them, compound 6a exhibited the strongest antiproliferative effects on Jurkat (IC 50 = 1.80 μM), HCT-116 (IC 50 = 11.50 μM) and MDA-MB-231 (IC 50 = 53.91 μM). In particular, 6a even showed stronger antiproliferative effects than the positive control NaAsO₂ on Jurkat and HCT-116 cell lines. The results showed that a proper long aliphatic chain enhanced the antiproliferative activity of scutellarein., Competing Interests: The authors declare no conflict of interest.

Scutellarin ( 1 ) has been widely used to treat acute cerebral infarction in clinic, but poor aqueous solubility decreases its bioavailability. Interestingly, scutellarin ( 1 ) could be metabolized into scutellarein ( 2 ) in vivo. In this study, a sulfonic group was introduced at position C-8 of scutellarein ( 2 ) to enhance the aqueous solubility of the obtained derivative ( 3 ). DPPH (1,1-diphenyl-2-picrylhydrazyl)-radical scavenging ability and antithrombic activity were also conducted to determine its bioactivity. The result showed that scutellarein derivate ( 3 ) could be a better agent for ischemic cerebrovascular disease treatment., Competing Interests: All authors declare no financial/commercial conflict of interests.

Scutellarein (2), which is an important in vivo metabolite of scutellarin (1), was synthesized from 3,4,5-trimethoxyphenol (3) in high yield in four steps. This strategy relies on acetylation, aldolization, cyclization and hydrolysis reactions, respectively.

In this paper, a new and efficient synthesis of 6-O-methylscutellarein (3), the major metabolite of the natural medicine scutellarin, is reported. Two hydroxyl groups at C-4' and C-7 in 2 were selectively protected by chloromethyl methyl ether after the reaction conditions were optimized, then 6-O-methyl-scutellarein (3) was produced in high yield after methylation of the hydroxyl group at C-6 and subsequent deprotection of the two methyl ether groups.