摘要：Sarcaglarols A-D(1-4),two pairs of lindenane-monoterpene heterodimers fused by a 1,2-dioxane moiety,were discovered and isolated from the leaves of Sarcandra glabra guided by MS/MS molecular networking-based *** planar structures,absolute configurations of basic skeleton and flexible polyhydric side chain were established by analysis of HRESIMS,NMR spectroscopic data,ECD spectrum,and the X-ray diffraction study of isopropylidene *** intermolecular[2+2+2]cycloaddition may play a key role in the biosynthesis pathway of the 1,2-dioxane moiety fused lindenane-monoterpene heterodimer skeleton,which can be recognized as the biogenetic precursors of our previous reported lindenane-normonoterpene *** addition,compounds 1,3 and 4 exhibited moderate inhibitory effects of lipid accumulation in free fatty acid-exposed L02 cells.

摘要：To search for potent anti-ischemic stroke agents,a series of tetramethylpyrazine(TMP)/resveratrol(RES)hybrids 6 a-t were designed and *** hybrids inhibited adenosine diphosphate(ADP)-or arachidonic acid(AA)-induced platelet aggregation,among them,6 d,6 g-i,6 o and 6 q were more active than *** most active compound 6 h exhibited more potent antiplatelet aggregation activity than TMP,RES,as well as positive control ticlopidine(Ticlid)and aspirin(ASP).Furthermore,6 h exerted strong antioxidative activity in a dose-dependent manner in rat pheochromocytoma PC12 cells which were treated with hydrogen peroxide(H2 O2)or hydroxyl radical(·OH).Importantly,6 h significantly protected primary neuronal cells suffered from oxygen-glucose deprivation/reoxygenation(OGD/R)injury,comparable to an anti-ischemic drug edaravone(Eda).Together,our findings suggest that 6 h may be a promising candidate warranting further investigation for the intervention of ischemic stroke.

摘要：Taxol is a 'blockbuster' antitumor drug produced by Taxus species with extremely low amount, while its analogue 7-β-xylosyl-10-deacetyltaxol is generally much higher in the plants. Both the fungal enzymes LXYL-P1à1 and LXYL-P1à2 can convert 7-β-xylosyl-10-deacetyltaxol into10-deacetyltaxol for Taxol semi-synthesis. Of them, LXYL-P1à2 is twice more active than LXYLP1à1, but there are only 11 significantly different amino acids in terms of the polarity and acidic-basic properties between them. In this study, single and multiple site-directed mutations at the 11 sites from LXYL-P1à1 to LXYL-P1à2 were performed to define the amino acids with upward bias in activities and to acquire variants with improved catalytic properties. Among all the 17 mutants, E12(A72 T/V91 S) was the most active and even displayed 2.8-and 3-fold higher than LXYL-P1à2 on β-xylosidase andβ-glucosidase activities. The possible mechanism for such improvement was proposed by homology modeling and molecular docking between E12 and 7-β-xylosyl-10-deacetyltaxol. The recombinant yeast GS115-P1 E12-7 was constructed by introducing variant E12, the molecular chaperone gene pdi and the bacterial hemoglobin gene vhb. This engineered yeast rendered 4 times higher biomass enzyme activity than GS115-3.5 K-P1à2 that had been used for demo-scale fermentation. Thus, GS115-P1 E12-7 becomes a promising candidate to replace GS115-3.5 K-P1à2 for industrial purpose.

摘要：To improve aqueous solubility and anti-ischemic activity of 3-n-butylphthalide(NBP),we designed and synthesized the ring-opened derivative of NBP-ferulic acid-glucose trihybrids(S1-S8).These hybrids inhibited adenosine diphosphate(ADP)-or arachidonic acid(AA)-induced platelet aggregation,among them,S2 was 30-fold more water-soluble,and over 10-fold more potent in inhibition of platelet aggregation,as well as reduced ROS generation and protected primary neuronal cells from OGD/Rinduced damage,in comparison with NB ***,S2 was more active than its three moieties alone or in combination,suggesting that the activity of S2 may be attributed to the synergistic effects of these ***,in vivo studies indicated that S2 not only possessed good pharmacokinetic profile,but also improved NBP distribution in rodent brain,suggesting that the glucose moiety in S2 may be recognized by glucose transporter 1(GLUT1)on blood-brain barrier(BBB),promoting it to penetrate through *** findings suggest that S2 may be a promising candidate for the intervention of ischemic stroke,warranting further study.

摘要：The imaging mass spectrometry（IMS） technology has experienced a rapid development in recent years.A new IMS technology which is based on air flow assisted ionization（AFAI） was *** allows for the convenient pretreatment of the samples and can image a large area of sample in a single measurement with high *** AFAI in DESI mode was used as the ion source in this *** new IMS method is named *** adoption of assisted air flow makes the sample pretreatment easy and *** optimization of the distance between the ion transport tube and MS orifice increases the sensitivity of the *** data processing,a program based on MATLAB with the function of numerical analysis was developed.A theoretical imaging resolution of a few hundred microns can be *** composite AFAI-IMS images of different target analytes were imaged with high sensitivity.A typical AFAI-IMS image of the whole-body section of a rat was obtained in a single analytical *** ability to image a large area for relevant samples in a single measurement with high sensitivity and repeatability is a significant *** method has enormous potentials in the MS imaging of large and complicated samples.

摘要：A series of benzoxepin-5-ones were designed and synthesized by the cyclization of chalcones which were previously found as FXR antagonists. The cellular FXR antagonism of benzoxepines was investigated,among which the most potent compound 10 l was able to reduce the plasma and hepatic triglyceride and plasma ALT levels in mice.

摘要：A series of new hybrids of dehydroandrographolide(TAD),a biologically active natural product,bearing nitric oxide(NO)-releasing moieties were synthesized and designated as NO-donor *** biological activities of target compounds were studied in human erythroleukemia K562 cells and breast cancer MCF-7 *** evaluation indicated that the most active compound I-5 produced high levels of NO and inhibited the proliferation of K562(IC_(50) 1.55μmol?L^(–1))and MCF-7(IC_(50)2.91μmol?L^(–1))cells,which were more potent than the lead compound TAD and attenuated by an NO *** conclusion,I-5 is a novel hybrid with potent antitumor activity and may become a promising candidate for future intensive study.

摘要：FTY720 and IMMH002,prodrugs for sphingosine-1-phosphate receptor 1(S1P1)agonists,show inadequate and inconsistent levels of phosphorylation in humans compared to that in *** this study,FTY720 or IMMH002 analogues(21-24)were designed and synthesized with modified head pieces to improve the biotransformation of the prodrugs to the active phosphorylated *** compounds were synthesized via a convergent route using the key and optically pure building block 9,which was first synthesized via asymmetrically catalyzed *** phosphorylation rates of these analogues in rat or human blood were *** new methyl-substituted analogue compound 21 showed higher phosphorylation rates in both rats and humans than the parent compound,whereas compound 23 showed improvements in rats,but not in *** pharmacokinetics studies of rats,compounds 21 and 23 both had higher levels of phosphorylation than FTY720 and ***,our study not only yielded new compounds with therapeutic potential,but also showed species differences between rats and humans in response to the structural modifications,which might be useful for predicting the biotransformation behavior and efficacy of this class of prodrugs in the clinic.

摘要：A series of novel indole derivatives were designed and synthesized and their inhibitory activity against B-Raf and HepG2 cell were also described. Among them, compounds 7a and 7b exhibited excellent potency, which showed the potential for further research as lead compounds.

摘要：To develop fusion protein of a GnRH Fc fragment and the integrin targeting AP25 antitumor peptide for GnRH receptor-expressing cancer *** LMRAP fusion protein was constructed.A transwell invasion assay was *** gene mRNA and protein levels of GnRHR-I,α5β1,andαvβ3 in different cancer cell lines were *** proliferation was measured using a cell counting *** antagonist assay was performed on GnRH ***-tumor activity was evaluated with a mouse xenograft tumor ***(IHC)was applied to detect CD31 and CD34 *** characteristics were determined with an indirect competition *** developed bifunctional fusion protein LMRAP not only inhibited HUVEC invasion,but also inhibited proliferation of GnRHR-I,α5β1,and high expression cancer *** IC50 for LMRAP in the GnRH receptor was 6.235 x 10-4 mol/*** significantly inhibited human prostate cancer cell line22 RV1 proliferation in vivo and in *** significantly inhibited CD31 and CD34 *** elimination half-life of the fusion protein LMRAP was 33 h in *** fusion protein made of a GnRH Fc fragment and the integrin targeting AP25 peptide retained the bifunctional biological activity of GnRHR blocking,angiogenesis inhibition,prolonged half-life and good tolerance.