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 new series of benzamide derivatives as glucokinase activators （GKAs） were designed and synthesized, and their activation for glucokinase were evaluated by the preliminary glucokinase activity assay. The structure-activity relationship （SAR） is discussed. The result shows that compound 12d and 12h have potent activity reference drug RO-28-1675.

摘要：Thirteen thiomorpholine-bearing compounds were designed and synthesized as dipeptidyl peptidase IV（DPP-IV） inhibitors, with natural and non-natural L-amino acids as the starting *** structures were characterized by ~1H NMR,^（13）C NMR and *** target compounds were screened for the DPP-IV inhibition,and the preliminary SAR result was ***, compounds 4c,4d and 4f with good DPP-IV inhibition in vitro were further evaluated through a mouse oral glucose tolerance test （OGTT）.The preliminary result showed the potential value for further studies on those thiomorpholine-bearing compounds as DPP-IV inhibitors.

摘要：A series of novel 3-（（4-（t-buty-）-2-（2-benzylidenehydrazinyl）thiazol-5-yl）methyl）quinolin-2（1H）-ones （7a--7z） were designed, synthesized and evaluated for their ability of inhibiting neuraminidase （NA） of influenza H1N1 virus. Some compounds displayed moderate influenza NA inhibitory activity. Compound 71 with the scaffold of 2-（2-（2-methoxybenzylidene）hydrazinyl）thiazole was the best one, exhibiting moderate NA inhibitory activity with ICs0 of 44.66 ~tmol/L. Structure-activity relationship showed that compounds with methoxy or hydroxy groups at the ortho position, fluorine and nitro groups at the meta position and chlorine and bromine groups at the para posi- tion of phenyl ring were more active. Docking study indicated that compound 71 has important interactions with some key residues （including Asp151, Glu119, Arg292, Tyr406, and Asn347） and binds to 430-cavity adjacent to NA active site.

摘要：In order to develop novel LpxC inhibitors with good activities and metabolic stability, two series of compounds with hydrophilic terminus have been synthesized and their in vitro antibacterial activities against Escherichial coil and Pseudomonas aemginosa were evaluated. Especially, compounds 22b and c exhibited comparable antibacterial activities to CHIR-090 and better metabolic stability than CHIR-090 and LPC-011 in liver microsomes （rat and mouse）, which indicated the terminal methylsulfone may be a preferred structure in the design of LpxC inhibitors and worthy of further investigations.

摘要：In order to investigate the effect of different C4 linkage moieties on the cytotoxicity of podophyllotoxin derivatives, novel 4-N- and 4-C-substituted 4＇-O-demethylepipodophyllotoxin derivatives were designed and synthesized. All the compounds were tested against A549 and MCF-7 tumor cells in vitro, and six compounds showed significant cytotoxicity. The most active compound 9f was superior to GL-331, and exhibited potent cytotoxicity with IC50 value at 10^-7 mol/L level.

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：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：Summary of main observation and conclusion To combat multidrug-resistant Gram-positive bacteria,new antimicrobials particularly those with novel mechanism of action are badly *** with conventional antibiotics which are typical inhibitors,small-molecule activators of bacterial CIpP represent a new class of *** ClpP activator has been developed for clinical ***,we conducted a screening on our library of benga-mide-like ring opened analogues and found that L472-2 possesses a low minimum inhibitory concentration(MIC)against *** and shows no activity for ClpP activation in vitro,but it displayed reduced antibacterial activity against *** with clpP *** order to obtain bengamide analogues that activate ClpP in vitro as well as possess antibacterial activity,we perform further structural modifications starting from *** 37 re-mains the antimicrobial activity and activation of ClpP protein in vitro,which could be viewed as a new chemical scaffold for ClpP activators and worthy of further investigation.

摘要：In the present study, ultrasonic extraction technique （UET） is used to improve the yield of polysaccharides from Lami- naria japonica （LJPs）. And their antioxidative as well as glycosidase inhibitory activities are investigated. Box-Behnken design （BBD） combined with response surface methodology （RSM） is applied to optimize ultrasonic extraction for polysaccharides. The optimized conditions are obtained as extraction time at 54 min, ultrasonic power at 1050 W, extraction temperature at 80℃ and ratio of material to solvent at 1：50 （g mL-1）. Under these optimal ultrasonic extraction conditions, an actual experimental yield （5.75% ＋ 0.3%） is close to the predicted result （5.67%） with no significant difference （P〉0.05）. Vitro antioxidative and glycosidase inhibitory activities tests indicate that the crude polysaccharides （LJP） and two major ethanol precipitated fractions （LJP1 and LJP2） are in a concentration-dependent manner. LJP2 （30%-60% ethanol precipitated polysaccharides） possesses the strongest α-glucosidase in- hibitory activity and moderate scavenging activity against hydroxyl radicals （66.09% ±2.19%, 3.0 mg mL-l）. Also, the inhibitory activity against a-glucosidase （59.08% ± 3.79%, 5.0 mg mL-1） is close to that of acarbose （63.99% ± 3.27%, 5.0 mg mL-l）. LJP 1 （30% ethanol precipitated polysaccharides） exhibits the strongest scavenging activity against hydroxyl radicals （99.80%q-0.00%, 3.0mg mL-1） and moderate a-glucosidase inhibitory activity （47.76%± 1.92%, 5.0 mgmL-1）. LJP shows the most remarkable DPPH scav- enging activity （66.20%±0.11%, 5.0mgmL-1） but weakest a-glucosidase inhibitory activity （37.77%±1.30%, 5.0mgmL-1）. How- ever, all these LJPs exert weak inhibitory effects against a-amylase. These results show that UET is an effective method for extract- ing bioactive polysaccharides from seaweed materials. LJP 1 and LJP2 can be developed as a potential ingredient in hypoglycemic agents or functional food for the management of diabetes. This study provi