当前位置： SCI文献检索 > BIOORGANIC & MEDICINAL CHEMISTRY LETTERS期刊下所有文献 > The design, synthesis and structure-activity relationships associated with C28 amine-based betulinic acid derivatives as inhibitors of HIV-1 maturation.

The design, synthesis and structure-activity relationships associated with C28 amine-based betulinic acid derivatives as inhibitors of HIV-1 maturation.

Abstract：

:The design and synthesis of a series of C28 amine-based betulinic acid derivatives as HIV-1 maturation inhibitors is described. This series represents a continuation of efforts following on from previous studies of C-3 benzoic acid-substituted betulinic acid derivatives as HIV-1 maturation inhibitors (MIs) that were explored in the context of C-28 amide substituents. Compared to the C-28 amide series, the C-28 amine derivatives exhibited further improvements in HIV-1 inhibitory activity toward polymorphisms in the Gag polyprotein as well as improved activity in the presence of human serum. However, plasma exposure of basic amines following oral administration to rats was generally low, leading to a focus on moderating the basicity of the amine moiety distal from the triterpene core. The thiomorpholine dioxide (TMD) 20 emerged from this study as a compound with the optimal antiviral activity and an acceptable pharmacokinetic profile in the C-28 amine series. Compared to the C-28 amide 3, 20 offers a 2- to 4-fold improvement in potency towards the screening viruses, exhibits low shifts in the EC50 values toward the V370A and ΔV370 viruses in the presence of human serum or human serum albumin, and demonstrates improved potency towards the polymorphic T371A and V362I virus variants.

journal_name

Bioorg Med Chem Lett

journal_title

Bioorganic & medicinal chemistry letters

authors

Chen Y,Sit SY,Chen J,Swidorski JJ,Liu Z,Sin N,Venables BL,Parker DD,Nowicka-Sans B,Lin Z,Li Z,Terry BJ,Protack T,Rahematpura S,Hanumegowda U,Jenkins S,Krystal M,Dicker ID,Meanwell NA,Regueiro-Ren A

doi

10.1016/j.bmcl.2018.03.067

subject

Has Abstract

pub_date

2018-05-15 00:00:00

pages

1550-1557

issue

9

eissn

0960-894X

issn

1464-3405

pii

S0960-894X(18)30262-2

journal_volume

28

pub_type

杂志文章

相关文献

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS文献大全
  • Cu2+-labeled dansyl compounds as fluorescent and PET probes for imaging apoptosis.

    abstract：:Compound DNSTT-Cu2+, a novel chelate of Cu2+ with DOTA conjugated to a fluorescent dansyl fragment, is developed for imaging cell apoptosis. Apoptotic U-87MG cells could be selectively visualized by the fluorescence of DNSTT-Cu2+ from cytoplasm of cells, confirmed by the fluorescence of apoptosis cells co-labeled with...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2016.09.057

    authors： Han J,Wang X,Yu M

    更新日期：2016-11-15 00:00:00

  • Gram-scale synthesis of pinusolide and evaluation of its antileukemic potential.

    abstract：:Pinusolide (1), a known platelet-activating factor (PAF) receptor binding antagonist, was synthesized from lambertianic acid (2), a labdane-type diterpene readily accessible in multigram quantities from the Siberian pine tree. It was shown that 1 not only decreases the proliferation activity of tumor cells at relative...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2006.05.077

    authors： Shults EE,Velder J,Schmalz HG,Chernov SV,Rubalova TV,Gatilov YV,Henze G,Tolstikov GA,Prokop A

    更新日期：2006-08-15 00:00:00

  • Analogues and derivatives of ciproxifan, a novel prototype for generating potent histamine H3-receptor antagonists.

    abstract：:Novel derivatives of the highly potent and selective histamine H3-receptor antagonist ciproxifan (3) with different chain lengths as well as with structural variants of the cyclopropyl ketone moiety have been prepared and screened for their antagonist H3-receptor potencies in vitro and in vivo. Some derivatives (2, 6-...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/s0960-894x(00)00473-x

    authors： Stark H,Ligneau X,Sadek B,Ganellin CR,Arrang JM,Schwartz JC,Schunack W

    更新日期：2000-10-16 00:00:00

  • Synthesis and characterization of bis(mu-hydroxo)diiron(III) complex of N-(4-nitro-2-hydroxy)phenylmethyl-N-(2-pyridylethyl)-N-(2-pyridylmethyl)amine and hydroxylation reaction of alkane.

    abstract：:Bis(mu-hydroxo)diiron(III) complex, [Fe2III(mu-OH)2(NE)2](NO3)2 x 3H2O (3) (N-(4-nitro-2-hydroxy)phenylmethyl-N-(2-pyridylethyl)-N-(2-pyridylmethyl)amine = HNE, where H denotes a dissociable proton of the p-nitrophenol group), has been prepared and characterized by X-ray crystallography, electronic and magnetic spectr...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/s0960-894x(01)00070-1

    authors： Kurosaki H,Yoshida H,Ito M,Koike H,Higuchi E,Goto M

    更新日期：2001-03-26 00:00:00

  • Theoretical elucidation on structure-antioxidant activity relationships for indolinonic hydroxylamines.

    abstract：:Indolinonic hydroxylamines (IH), representing a new type of antioxidants, are comparative to alpha-tocopherol to protect lipids from oxidation. To elucidate the structure-activity relationship for IH, B3LYP/6-31G(d, p) method was employed to calculate the O-H bond dissociation enthalpy (BDE), a theoretical parameter t...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/s0960-894x(01)00724-7

    authors： Zhang HY,Wang LF

    更新日期：2002-01-21 00:00:00

  • Selective inhibition of monoamine oxidase A by hispidol.

    abstract：:Hispidol, an aurone, isolated from Glycine max Merrill, was found to potently and selectively inhibit an isoform of recombinant human monoamine oxidase-A (MAO-A), with an IC50 value of 0.26 µM, and to inhibit MAO-B, but with lower potency (IC50 = 2.45 µM). Hispidol reversibly and competitively inhibited MAO-A with a K...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2018.01.049

    authors： Baek SC,Lee HW,Ryu HW,Kang MG,Park D,Kim SH,Cho ML,Oh SR,Kim H

    更新日期：2018-02-15 00:00:00

  • SAR of a series of inhaled A(2A) agonists and comparison of inhaled pharmacokinetics in a preclinical model with clinical pharmacokinetic data.

    abstract：:COPD is a major cause of mortality in the western world. A(2A) agonists are postulated to reduce the lung inflammation that causes COPD. The cardiovascular effects of A(2A) agonists dictate that a compound needs to be delivered by inhalation to be therapeutically useful. The pharmacological and pharmacokinetic SAR of ...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2009.05.027

    authors： Mantell SJ,Stephenson PT,Monaghan SM,Maw GN,Trevethick MA,Yeadon M,Walker DK,Selby MD,Batchelor DV,Rozze S,Chavaroche H,Lemaitre A,Wright KN,Whitlock L,Stuart EF,Wright PA,Macintyre F

    更新日期：2009-08-01 00:00:00

  • Sequential cytotoxicity: a theory examined using a series of 3,5-bis(benzylidene)-1-diethylphosphono-4-oxopiperidines and related phosphonic acids.

    abstract：:The concept of sequential cytotoxicity, which states that successive chemical attacks on cellular constituents can be more deleterious to neoplasms than normal cells, was evaluated using a series of 3,5-bis(benzylidene)-1-diethylphosphono-4-oxopiperidines 1 and related phosphonic acids 2, which were screened against a...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2010.09.051

    authors： Das S,Das U,Sakagami H,Hashimoto K,Kawase M,Gorecki DK,Dimmock JR

    更新日期：2010-11-15 00:00:00

  • LAT1 activity of carboxylic acid bioisosteres: Evaluation of hydroxamic acids as substrates.

    abstract：:Large neutral amino acid transporter 1 (LAT1) is a solute carrier protein located primarily in the blood-brain barrier (BBB) that offers the potential to deliver drugs to the brain. It is also up-regulated in cancer cells, as part of a tumor's increased metabolic demands. Previously, amino acid prodrugs have been show...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2016.09.001

    authors： Zur AA,Chien HC,Augustyn E,Flint A,Heeren N,Finke K,Hernandez C,Hansen L,Miller S,Lin L,Giacomini KM,Colas C,Schlessinger A,Thomas AA

    更新日期：2016-10-15 00:00:00

  • Synthesis, docking, and biological studies of phenanthrene β-diketo acids as novel HIV-1 integrase inhibitors.

    abstract：:In the present study we report the synthesis of halogen-substituted phenanthrene β-diketo acids as new HIV-1 integrase inhibitors. The target phenanthrenes were obtained using both standard thermal- and microwave-assisted synthesis. 4-(6-Chlorophenanthren-2-yl)-2,4-dioxobutanoic acid (18) was the most active compound ...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2013.09.009

    authors： Sharma H,Sanchez TW,Neamati N,Detorio M,Schinazi RF,Cheng X,Buolamwini JK

    更新日期：2013-11-15 00:00:00

  • Optimization and SAR for dual ErbB-1/ErbB-2 tyrosine kinase inhibition in the 6-furanylquinazoline series.

    abstract：:Synthetic modifications on a 6-furanylquinazoline scaffold to optimize the dual ErbB-1/ErbB-2 tyrosine kinase inhibition afforded consistent SAR whereby a 4-(3-fluorobenzyloxy)-3-haloanilino provided the best enzyme potency and cellular selectivity. Changes made to the 6-furanyl group had little impact on the enzyme a...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2006.05.090

    authors： Petrov KG,Zhang YM,Carter M,Cockerill GS,Dickerson S,Gauthier CA,Guo Y,Mook RA Jr,Rusnak DW,Walker AL,Wood ER,Lackey KE

    更新日期：2006-09-01 00:00:00

  • Synthesis and SAR study of tricyclic sulfones as γ-secretase inhibitors: C-6 and C-8 positions.

    abstract：:SAR exploration at C-6 and C-8 positions of the tricyclic sulfone series was carried out. Several functional groups were found to be well tolerated at C-6 and C-8 positions. Selective combination of C-6 and C-8 modification resulted in new tricyclic sulfone analogs with efficacy in in vivo mouse Aβ(40) lowering model....

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2011.03.094

    authors： Su J,Tang H,McKittrick BA,Xu R,Clader JW,Greenlee WJ,Hyde L,Zhang L

    更新日期：2011-06-01 00:00:00

  • 1-Aryl-tetrahydroisoquinoline analogs as active anti-HIV agents in vitro.

    abstract：:A series of 1-aryl-6,7-dihydroxyl(methoxy)-1,2,3,4-tetrahydroisoquinolines (compounds 1-36) were synthesized via Pictet-Spengler cyclization. All the synthesized compounds were assayed for activities against HIV-1(IIIB) in C8166 cell cultures by MTT method for the first time. The results of the anti-HIV screening reve...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2008.02.040

    authors： Cheng P,Huang N,Jiang ZY,Zhang Q,Zheng YT,Chen JJ,Zhang XM,Ma YB

    更新日期：2008-04-01 00:00:00

  • Substituent effect on the preferred DNA binding mode and affinity of a homologous series of naphthalene diimides.

    abstract：:A combination of isothermal titration calorimetry (ITC), topoisomerase I DNA unwinding assays, and ethidium bromide displacement studies were employed to investigate the binding of a homologous series of naphthalene diimides (NDI) to DNA. Our results suggest that the nature of the substituent plays a significant role ...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2011.05.069

    authors： McKnight RE,Reisenauer E,Pintado MV,Polasani SR,Dixon DW

    更新日期：2011-07-15 00:00:00

  • Design of novel CXCR4 antagonists that are potent inhibitors of T-tropic (X4) HIV-1 replication.

    abstract：:A novel series of CXCR4 antagonists were identified based on the substantial redesign of AMD070. These compounds possessed potent anti-HIV-1 activity and showed excellent pharmacokinetics in rat and dog. ...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2011.01.021

    authors： Skerlj R,Bridger G,McEachern E,Harwig C,Smith C,Kaller A,Veale D,Yee H,Skupinska K,Wauthy R,Wang L,Baird I,Zhu Y,Burrage K,Yang W,Sartori M,Huskens D,De Clercq E,Schols D

    更新日期：2011-03-01 00:00:00

  • First hydroxamate inhibitors for carboxypeptidase A. N-acyl-N-hydroxy-beta-phenylalanines.

    abstract：:A series of N-acyl-N-hydroxy-beta-Phe were designed, synthesized, and shown to have potent inhibitory activity for carboxypeptidase A (CPA). They are the first examples of CPA inhibitors having a hydroxamate functionality. ...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/s0960-894x(99)00055-4

    authors： Kim DH,Jin Y

    更新日期：1999-03-08 00:00:00

  • Novel pyrrolidine melanin-concentrating hormone receptor 1 antagonists with reduced hERG inhibition.

    abstract：:We discovered novel pyrrolidine MCHR1 antagonist 1 possessing moderate potency. Profiling of pyrrolidine 1 demonstrated that it was an inhibitor of the hERG channel. Investigation of the structure-activity relationship of this class of pyrrolidines allowed us to optimize the MCHR1 potency and decrease the hERG inhibit...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2011.02.046

    authors： Fox BM,Natero R,Richard K,Connors R,Roveto PM,Beckmann H,Haller K,Golde J,Xiao SH,Kayser F

    更新日期：2011-04-15 00:00:00

  • Syntheses and anti-inflammatory activity of azamollugin derivatives.

    abstract：:Oxomollugin (2) is a degradation product of mollugin (1) and a potent inhibitor of NO-production including nuclear factor kappa B signals. In our endeavor to develop a potent anti-inflammatory compound, we synthesized several aza-derivatives of oxomollugin (2) and evaluated their NO-production inhibitory activity. Aza...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2015.11.081

    authors： Nishino H,Nakajima Y,Kakubari Y,Asami N,Deguchi J,Nugroho AE,Hirasawa Y,Kaneda T,Kawasaki Y,Goda Y,Morita H

    更新日期：2016-01-15 00:00:00

  • Structure-based design of flavone-based inhibitors of wild-type and T315I mutant of ABL.

    abstract：:The existence of drug resistance caused by mutations in the break-point cluster region-Abelson (BCR-ABL) tyrosine kinase domain remains a clinical challenge due to limited treatment options for effective CML therapies. Here, we report a series of flavone-based common inhibitors equipotent for the wild type and the mos...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2013.05.095

    authors： Choe H,Kim J,Hong S

    更新日期：2013-08-01 00:00:00

  • Uncarinic acids: phospholipase Cgamma1 inhibitors from hooks of Uncaria rhynchophylla.

    abstract：:Bioactivity-guided fractionation of the CHCl3 extract from hooks of Uncaria rhynchophylla led to the isolation of two triterpene esters, namely uncarinic acids A (1) and B (2). Their structures were established by spectroscopic and chemical methods. These compounds inhibited phospholipase Cgamma1 with IC50 values of 3...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/s0960-894x(99)00211-5

    authors： Lee JS,Yang MY,Yeo H,Kim J,Lee HS,Ahn JS

    更新日期：1999-05-17 00:00:00

  • Pyrrolidine-carboxamides and oxadiazoles as potent hNK1 antagonists.

    abstract：:The preparation and structure-activity-relationships of novel pyrrolidine-carboxamides and oxadiazoles are described. Compounds in this series were found to be potent hNK(1) antagonists in vitro and efficacious in vivo with minimal interactions with P(450) liver enzymes. Oxadiazole analog 22 was determined to have exc...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2007.08.028

    authors： Young JR,Eid R,Turner C,DeVita RJ,Kurtz MM,Tsao KL,Chicchi GG,Wheeldon A,Carlson E,Mills SG

    更新日期：2007-10-01 00:00:00

  • Pyrido pyrimidinones as selective agonists of the high affinity niacin receptor GPR109A: optimization of in vitro activity.

    abstract：:Pyrido pyrimidinones are selective agonists of the human high affinity niacin receptor GPR109A (HM74A). They show no activity on the highly homologous low affinity receptor GPR109B (HM74). Starting from a high throughput screening hit the in vitro activity of the pyrido pyrimidinones was significantly improved providi...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2010.07.108

    authors： Peters JU,Kühne H,Dehmlow H,Grether U,Conte A,Hainzl D,Hertel C,Kratochwil NA,Otteneder M,Narquizian R,Panousis CG,Ricklin F,Röver S

    更新日期：2010-09-15 00:00:00

  • Design, synthesis and biological evaluation of N-hydroxy-aminobenzyloxyarylamide analogues as novel selective κ opioid receptor antagonists.

    abstract：:Aminobenzyloxyarylamide derivatives 1a-i and 2a-t were designed and synthesized as novel selective κ opioid receptor (KOR) antagonists. The benzoyl amide moiety of LY2456302 was changed into N-hydroxybenzamide and benzisoxazole-3(2H)-one to investigate whether it could increase the binding affinity or selectivity for ...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2020.127236

    authors： He G,Song Q,Wang J,Xu A,Peng K,Zhu Q,Xu Y

    更新日期：2020-07-01 00:00:00

  • Design, synthesis, and cytostatic activity of novel cyclic curcumin analogues.

    abstract：:A series of novel cyclic analogues of curcumin were synthesized and analyzed for in vitro cytostatic activity. Condensation of 2-acetylcycloalkanones with a variety of aromatic aldehydes resulted in the formation of 2-arylidene-6-(3-arylacryoyl)-cycloalkanone derivatives. A number of these analogues were found to have...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2007.07.079

    authors： Youssef D,Nichols CE,Cameron TS,Balzarini J,De Clercq E,Jha A

    更新日期：2007-10-15 00:00:00

  • A stepwise dechlorination/cross-coupling strategy to diversify the vancomycin 'in-chloride'.

    abstract：:In an effort to rapidly access vancomycin analogues bearing diverse functionality at the 6c-Cl (the 'in-chloride') position, a two-step dechlorination/cross-coupling protocol was developed. Conditions for efficient cross-coupling of the relatively unreactive 6c-Cl group were found that ensure high conversion with mini...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2015.12.027

    authors： Wadzinski TJ,Gea KD,Miller SJ

    更新日期：2016-02-01 00:00:00

  • Orally active zwitterionic factor Xa inhibitors with long duration of action.

    abstract：:We have optimized 2-aminomethylphenylamine derivative as a factor Xa inhibitor. Several polar functional groups were introduced in the central phenyl ring, and we focused on zwitter ionic compound showing continuous inhibitory activity in oral administration test. In vitro and oral activities were improved by optimiza...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2011.10.021

    authors： Mochizuki A,Nagata T,Kanno H,Takano D,Kishida M,Suzuki M,Ohta T

    更新日期：2011-12-15 00:00:00

  • Identification of potent and novel small-molecule inhibitors of caspase-3.

    abstract：:The design and synthesis of a series of novel, reversible, small molecule inhibitors of caspase-3 are described. ...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2003.08.024

    authors： Allen DA,Pham P,Choong IC,Fahr B,Burdett MT,Lew W,DeLano WL,Gordon EM,Lam JW,O'Brien T,Lee D

    更新日期：2003-11-03 00:00:00

  • Novel N1-(benzyl)cinnamamidine derived NR2B subtype-selective NMDA receptor antagonists.

    abstract：:Novel (E)-N(1)-(benzyl)cinnamamidines were prepared and evaluated as NR2B subtype NMDA receptor ligands. Excellent affinity was achieved by appropriate substitution of either phenyl ring. The 2-methoxybenzyl compound 1h had approximately 1,000-fold lower IC(50) in NR2B than NR2A-containing cells. Replacement of the st...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/s0960-894x(02)01060-0

    authors： Curtis NR,Diggle HJ,Kulagowski JJ,London C,Grimwood S,Hutson PH,Murray F,Richards P,Macaulay A,Wafford KA

    更新日期：2003-02-24 00:00:00

  • Design of novel alpha7-subtype-preferring nicotinic acetylcholine receptor agonists: application of docking and MM-PBSA computational approaches, synthetic and pharmacological studies.

    abstract：:In the search for nicotinic acetylcholine receptor (nAChRs) agonists with a selective affinity for the homomeric alpha7 channels, we carried out the virtual screening of a test set of potential nicotinic ligands, and adopted a simplified MM-PBSA approach to estimate their relative binding free energy values. By means ...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2009.09.073

    authors： Grazioso G,Pomè DY,Matera C,Frigerio F,Pucci L,Gotti C,Dallanoce C,De Amici M

    更新日期：2009-11-15 00:00:00

  • Nonbenzamidine acylsulfonamide tissue factor-factor VIIa inhibitors.

    abstract：:Aminoisoquinoline and isoquinoline groups have successfully replaced the more basic P1 benzamidine group of an acylsulfonamide factor VIIa inhibitor. Inhibitory activity was optimized by the identification of additional hydrophobic and hydrophilic P' binding interactions. The molecular details of these interactions we...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2013.06.027

    authors： Glunz PW,Zhang X,Zou Y,Delucca I,Nirschl AH,Cheng X,Weigelt CA,Cheney DL,Wei A,Anumula R,Luettgen JM,Rendina AR,Harpel M,Luo G,Knabb R,Wong PC,Wexler RR,Priestley ES

    更新日期：2013-09-15 00:00:00