Junxia Zheng

New 3',8''-linked biflavonoids from Selaginella uncinata displaying protective effect against anoxia.

Seven 3′,8′′-linked bioflavonoids, including one new compound, (2′′S)-2′′, 3′′-dihydroamentoflavone-4′-methyl ether (1) and six known compounds: (2S)-2,3- dihydroamentoflavone-4′-methyl ether (2), (2S,2′′S)-2,3,2′′,3′′-tetrahydroamento- flavone-4′-methyl ether (3), (2S,2′′S)-tetrahydroamentoflavone (4), (2S)-2,3-dihydro- amentoflavone (5) and (2′′S)-2′′,3′′-dihydroamentoflavone (6) and amentoflavone (7), were isolated from the 60% ethanolic extract of Selaginella uncinata (Desv.) Spring. The structures of these compounds were elucidated mainly by analysis of their 1D and 2D NMR spectroscopic data, and their absolute configurations were determined by circular-dichroism (CD) spectroscopy. All the seven compounds showed protective effect against anoxia in the anoxic PC12 cells assay, in which compound 6 displayed particularly potent activity.

Exploring QSARs for 5-Lipoxygenase (5-LO) Inhibitory Activity of 2-Substituted 5-Hydroxyindole-3-Carboxylates by CoMFA and CoMSIA

A series of indole and related benzo[g]indole compounds displaying potent activities against 5‐lipoxygenase were selected to establish three‐dimensional quantitative structure–activity relationships using comparative molecular field analysis and comparative molecular similarity indices analysis methods. A training set of 37 active compounds was used to develop the models, which were then valuated by a series of internal and external cross‐validation techniques. A test set of seven compounds was used for the external validation. Models with greater than 70% predictive ability, as determined by external validation, and high internal validity (cross‐validated q2 > 0.5) have been developed. The satisfactory comparative molecular field analysis model predicted a q2 value of 0.779 and an r2 value of 0.957 and revealed that electrostatic and steric properties play a significant role in potency. The best comparative molecular similarity indices analysis model, based on a combination of steric, hydrophobic, and H‐bond donor effects, predicted a q2 value of 0.816 and an r2 value of 0.953. The models were graphically interpreted using comparative molecular field analysis and comparative molecular similarity indices analysis contour plots that provided insight into the structural requirements for increasing the activity of a compound. The results obtained from this study provide a solid basis for future rational design of more active 5‐lipoxygenase inhibitors.

Two new steroidal saponins from Selaginella uncinata (Desv.) Spring and their protective effect against anoxia

Four steroidal saponins were isolated from the anti-anoxic fraction of the 60% EtOH extract of Selaginella uncinata, including two new compounds, (3β, 7β, 12β, 25R)-spirost-5-ene-3, 7, 12-triol-3-O-α-L-rhamnopyranosyl-(1→2)-O-[α-L-rhamnopyranosyl-(1→4)]-O-β-D-glucopyranoside (1), (2α, 3β, 12β, 25R)-spirost-5-ene-2, 3, 12-triol-3-O-α-L-rhamnopyranosyl-(1→2)-O-[α-L-rhamnopyranosyl-(1→4)]-O-β-D-glucopyranoside (2) and two known compounds, (3β, 12β, 25R)-spirost-5-ene-3,12-diol-3-O-α-L-rhamnopyranosyl-(1→2)-O-[α-L-rhamnopyranosyl-(1→4)]-O-β-D-glucopyranoside, (3), (1α, 3β, 25R)-spirost-5-ene-2-diol-3-O-α-L-rhamnopyranosyl-(1→2)-O-[α-L-rhamnopyranosyl(1→4)]-O-β-D-glucopyranoside (4). The four compounds showed potent protective effect against anoxia in the anoxic PC12 cells assay, among which compounds 1 and 2 were the most active. To our knowledge, this is the first study to report the steroidal saponins in the plant S. uncinata and demonstrate their protective effect against anoxia in PC12 cell assay.

Insight into the Interactions between Novel Isoquinolin-1,3-Dione Derivatives and Cyclin-Dependent Kinase 4 Combining QSAR and Molecular Docking

Several small-molecule CDK inhibitors have been identified, but none have been approved for clinical use in the past few years. A new series of 4-[(3-hydroxybenzylamino)-methylene]-4H-isoquinoline-1,3-diones were reported as highly potent and selective CDK4 inhibitors. In order to find more potent CDK4 inhibitors, the interactions between these novel isoquinoline-1,3-diones and cyclin-dependent kinase 4 was explored via in silico methodologies such as 3D-QSAR and docking on eighty-one compounds displaying potent selective activities against cyclin-dependent kinase 4. Internal and external cross-validation techniques were investigated as well as region focusing, bootstraping and leave-group-out. A training set of 66 compounds gave the satisfactory CoMFA model (q 2 = 0.695, r 2 = 0.947) and CoMSIA model (q 2 = 0.641, r 2 = 0.933). The remaining 15 compounds as a test set also gave good external predictive abilities with r 2 pred values of 0.875 and 0.769 for CoMFA and CoMSIA, respectively. The 3D-QSAR models generated here predicted that all five parameters are important for activity toward CDK4. Surflex-dock results, coincident with CoMFA/CoMSIA contour maps, gave the path for binding mode exploration between the inhibitors and CDK4 protein. Based on the QSAR and docking models, twenty new potent molecules have been designed and predicted better than the most active compound 12 in the literatures. The QSAR, docking and interactions analysis expand the structure-activity relationships of constrained isoquinoline-1,3-diones and contribute towards the development of more active CDK4 subtype-selective inhibitors.

New molecular insights into the tyrosyl-tRNA synthase inhibitors: CoMFA, CoMSIA analyses and molecular docking studies

Drug resistance caused by excessive and indiscriminate antibiotic usage has become a serious public health problem. The need of finding new antibacterial drugs is more urgent than ever before. Tyrosyl-tRNA synthase was proved to be a potent target in combating drug-resistant bacteria. In silico methodologies including molecular docking and 3D-QSAR were employed to investigate a series of newly reported tyrosyl-tRNA synthase inhibitors of furanone derivatives. Both internal and external cross-validation were conducted to obtain high predictive and satisfactory CoMFA model (q2 = 0.611, r2pred = 0.933, r2m = 0.954) and CoMSIA model (q2 = 0.546, r2pred = 0.959, r2m = 0.923). Docking results, which correspond with CoMFA/CoMSIA contour maps, gave the information for interactive mode exploration. Ten new molecules designed on the basis of QSAR and docking models have been predicted more potent than the most active compound 3-(4-hydroxyphenyl)-4-(2-morpholinoethoxy)furan-2(5H)-one (15) in the literatures. The results expand our understanding of furanones as inhibitors of tyrosyl-tRNA synthase and could be helpful in rationally designing of new analogs with more potent inhibitory activities.

Three-dimensional quantitative structure-activity relationships of pyrrolopyridinone as cell division cycle kinase inhibitors by CoMFA and CoMSIA

Seventy-five 1,5,6,7-tetrahydro-pyrrolo[3,2-C]pyridinone derivatives displaying potent activities against Cdc7 kinase were selected to establish 3D-QSAR models using CoMFA and CoMSIA methods. Internal and external cross-validation techniques were investigated as well as some measures including region focusing, progressive scrambling, bootstraping and leave-group-out. The satisfactory CoMFA model predicted a q2 value of 0.836 and an r2 value of 0.950, indicating that electrostatic and steric properties play a significant role in potency. The best CoMSIA model, based on a combination of steric, electrostatic and H-bond acceptor effects, predicted a q2 value of 0.636 and an r2 value of 0.907. The models were graphically interpreted using contour plots which provided insight into the structural requirements for increasing the activity of a compound. The final 3D-QSAR results could be used for rational design of potent inhibitors against Cdc7 kinase.

Flavone Di-C-Glycosides from Selaginella uncinata and Their Antioxidative Activities

Selaginella uncinata (Desv.) Spring is used for the treatment of jaundice, dysentery, edema, and rheumatism in traditional Chinese medicine. It is widely distributed in southwest China [1]. Although biflavonoids are the main chemical constituents in Selaginella genus [2, 3], few reports have revealed the existence of flavone-di-C-glycoside constituents until now [4]. In our previous papers, we have reported biflavonoids, steroidal saponins, -lactone derivatives, terpenoids, and phenolic compounds from Selaginella uncinata [5–9]. In our continuous research work, five flavone di-C-glycosides, schaftoside (1), isoschaftoside (2), 6,8-di-C-L-arabinopyranoside-apigenin (3), 6-C-L-arabinopyranosyl-8-C-L-arabinopyranosylapigenin (4), and 6-C-L-arabinopyranosyl-8-C-L-arabinopyranosyl-apigenin (5), have been isolated from the n-butanol fraction of the 60% ethanolic extract of Selaginella uncinata. Compounds 1–5 were isolated from the Selaginella genus for the first time. The antioxidative activities of the five compounds were evaluated in the oxygen radical absorbance capacity (ORAC) assay. All the five compounds showed potent antioxidative activities. Compound 1, yellow amorphous powder. UV (MeOH, max, nm) (log ): 333 (4.25), 273 (4.23). ESI-MS m/z: 587 [M + Na]+, 563 [M – H]–. 1H NMR (400 MHz, DMSO-d6, , ppm, J/Hz): 8.09 (2H, d, J = 8.7, H-2 , 6 ), 6.90 (2H, d, J = 8.7, H-3 , 5 ), 6.72 (1H, s, H-3), 4.76 (1H, d, J = 9.5, H-1 ), 4.69 (1H, d, J = 9.7, H-1 ), 4.09–3.23 (18H, m). 13C NMR (100 MHz, DMSO-d6, , ppm): 181.8 (C-4), 163.4 (C-2), 161.1 2 (C-5, 7), 159.7 (C-4 ), 154.7 (C-9), 129.0 2 (C-2 , 6 ), 121.4 (C-1 ), 116.0 2 (C-3 , 5 ), 108.7 (C-6), 104.5 (C-8), 102.1 2 (C-3, 10), 81.3 (C-5 ), 78.8 (C-3 ), 75.2 (C-1 ), 74.7 (C-2 ), 73.8 (C-1 ), 70.9 (C-3 ), 70.7 (C-2 ), 70.1 (C-4 ), 69.2 (C-4 ), 68.9 (C-5 ), 60.9 (C-6 ). The spectral data presented are in a good agreement with published data on schaftoside [10]. Compound 2, yellow amorphous powder. UV (MeOH, max, nm) (log ): 332 (4.36), 273 (4.35). ESI-MS m/z: 587 [M + Na]+, 563 [M – H]–. 1H NMR (400 MHz, DMSO-d6, , ppm, J/Hz): 13.66 (1H, br.s, 5-OH), 8.00 (2H, d, J = 8.1, H-2 , 6 ), 6.90 (2H, d, J = 8.1, H-3 , 5 ), 6.76 (1H, s, H-3), 4.99–4.57 (7H, m), 3.91–3.51 (13H, m). 13C NMR (100 MHz, DMSO-d6, , ppm): 182.0 (C-4), 163.7 (C-7), 161.1 2 (C-2, 5), 158.4 (C-4 ), 155.1 (C-9), 128.9 2 (C-2 , 6 ), 121.6 (C-1 ), 115.9 2 (C-3 , 5 ), 108.2 (C-6), 105.1 (C-8), 102.5 2 (C-3, 10), 81.8 (C-5 ), 78.9 (C-3 ), 74.3 (C-1 ), 74.0 (C-2 ), 73.4 (C-1 ), 71.1 (C-3 ), 70.6 (C-2 ), 70.1 (C-4 ), 69.5 (C-4 ), 68.6 (C-5 ), 61.3 (C-6 ). The spectral data presented are in a good agreement with published data on isoschaftoside [10].

γ-Lactone Derivatives and Terpenoids from Selaginella uncinata and Their Protective Effect Against Anoxia

Selaginella uncinata (Desv. ex Poir.) Spring, a common and important species of Selaginella genus, is widely distributed in southwest China. As a traditional plant medicine, it is used for the treatment of jaundice, dysentery, edema, and rheumatism [1]. In our previous papers, we reported on the anti-anoxic effects of the 60% ethanolic extract of Selaginella uncinata and the anti-anoxic biflavonoids isolated from the EtOAc-soluble fraction of the 60% EtOH extract [2, 3]. In our continuous research work on the isolation of the anti-anoxic compounds, two -lactone derivatives, viburnolide A (1) and viburnolide B (2), and four terpenoids, isololiolide (3), dehydrololiolide (4), cis, trans-abscisic acid (5), and trans, trans-abscisic acid (6), have been isolated from the EtOAc-soluble and n-butanol-soluble fractions. Although the biflavonoids, flavonoids, chromone glycosides, and phenolic compounds are common in Selaginella genus [4–9], few reports have revealed the existence of -lactone derivatives and terpenoids constituents until now, and the six compounds 1–6 were isolated from this genus for the first time. Compound 1. Brown yellow, amorphous powder. UV (MeOH, max, nm) (log ): 356 (2.38), 276 (3.48), 227 (4.28). ESI-MS m/z: 507 [M + Na]+, 483 [M – H]– and 967 [2M – H]–1. 1H NMR (400 MHz, DMSO-d6, , ppm, J/Hz): 2.90 (1H, dd, J = 17.4, 9.2, H-3A), 3.04 (1H, dd, J = 17.4, 12.2, H-3B), 3.07 (1H, m, H-5 ), 3.20 (1H, m, H-2 ), 3.22 (1H, m, H-3 ), 3.28 (1H, m, H-4 ), 3.51 (2H, m, H-6 ), 3.94 (1H, s, H-8), 3.96 (1H, dd, J = 9.1, 5.3, H-11B), 4.21 (1H, dd, J = 7.0, 5.3, H-12), 4.31 (1H, dd, J = 9.1, 7.0, H-11A), 4.70 (1H, d, J = 7.5, H-1 ), 4.80 (1H, dd, J = 12.2, 9.2, H-4), 6.76 (2H, d, J = 8.5, H-15, 17), 7.16 (2H, d, J = 8.5, H-14, 18). 13C NMR (100 MHz, DMSO-d6, , ppm): 174.2 (C-2), 170.8 (C-6), 157.7 (C-16), 122.8 (C-13), 130.0 2 (C-14, 18), 115.6 2 (C-15, 17), 107.2 (C-9), 89.1 (C-5), 96.1 (C-1 ), 88.2 (C-8), 77.1 (C-5 ), 76.7 (C-3 ), 73.4 (C-2 ), 73.2 (C-12), 69.1 (C-4 ), 75.0 (C-11), 59.9 (C-6 ), 43.0 (C-4), 32.5 (C-3). The spectral data presented are in a good agreement with published data on viburnolide A [10].

Date on identification of flavonoids in Plumula nelumbinis by UPLC-ESI-QTOF-MS and antioxidant activity from 13 habitats in China

Plumula nelumbinis is a well-known health food and a traditional Chinese medicine, is used in many countries around the world. For its pharmacological properties are related to its chemical composition, a ultra-performance liquid chromatography electrospray ionization quadrupole time-of-flight mass spectrometry (UPLC-ESI-QTOF-MS) method was used to identify the flavonoids in P. nelumbinis. The first set of data shows the MS-MS Spectrograms of 12 flavonoid standards and 38 flavonoids detected in the P. nelumbinis from Xiangtan, Hunan province. The second set of data shows the total flavonoids content and the antioxidant activity of total flavonoid in P. nelumbinis from 13 habitats. The antioxidant activity were accomplished with 1,1-diphenyl-2-picrylhydrazyl (DPPH), oxygen radical absorbance capacity (ORAC) and ferric reducing ability of plasma (FRAP) assays.