当前位置： SCI文献检索 > BIOORGANIC CHEMISTRY期刊下所有文献 > Design and synthesis of newer 1,3,4-oxadiazole and 1,2,4-triazole based Topsentin analogues as anti-proliferative agent targeting tubulin.

Design and synthesis of newer 1,3,4-oxadiazole and 1,2,4-triazole based Topsentin analogues as anti-proliferative agent targeting tubulin.

Abstract：

:A set of two series of 1,3,4-oxadiazole (11a-n) and 1,2,4-Triazole (12a, c, e, g, h, j-n) based topsentin analogues were prepared by replacing imizadole moiety of topsentin through a multistep synthesis starting from indole. All the compounds synthesized were submitted for single dose (10 µM) screening against a NCI panel of 60-human cancer cell lines. Among all cancer cell lines, colon (HCC-2998) and Breast (MCF-7, T-47D) cancer cell lines were found to be more susceptible for this class of compounds. Among the compounds tested, compounds 11a, 11d, 11f, 12e and 12h, were exhibited good anti-proliferative activity against various cancer cell lines. Compounds 11d, 12e and 12h demonstrated better activity with IC50 2.42 µM, 3.06 µM, and 3.30 µM respectively against MCF-7 human cancer cell line than that of the standard drug doxorubicin IC50 6.31 µM. Furthermore, 11d induced cell cycle arrest at G0/G1 phase and also disrupted mitochondrial membrane potential with reducing cell migration potential of MCF-7 cells in dose dependent manner. In vitro microtubule polymerization assays found that compound 11d disrupt tubulin dynamics by inhibiting tubulin polymerization with IC50 3.89 μM compared with standard nocodazole (IC50 2.49 μM). In silico docking studies represented that 11d was binding at colchicine binding site of β-tubulin. Compound 11d emerged as lead molecule from the library of compounds tested and this may serve as a template for further drug discovery.

journal_name

Bioorg Chem

journal_title

Bioorganic chemistry

authors

Naaz F,Ahmad F,Lone BA,Pokharel YR,Fuloria NK,Fuloria S,Ravichandran M,Pattabhiraman L,Shafi S,Shahar Yar M

doi

10.1016/j.bioorg.2019.103519

subject

Has Abstract

pub_date

2020-01-01 00:00:00

pages

103519

eissn

0045-2068

issn

1090-2120

pii

S0045-2068(19)31567-6

journal_volume

95

pub_type

杂志文章

相关文献

BIOORGANIC CHEMISTRY文献大全
  • Advanced glycation end-products (AGE) trapping agents: Design and synthesis of nature inspired indeno[2,1-c]pyridinones.

    abstract：:Advanced glycation end products (AGEs) are implicated to be the key players in most of the diabetic complications. The AGE's interfere with the proteins heterogeneously, thereby rendering denaturation and the consequent loss of function and accumulation. Thus, a novel natural product inspired indeno[2,1-c]pyridinone (...

    journal_title：Bioorganic chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bioorg.2020.104375

    authors： Anaga N,D B,Abraham B,Nisha P,Varughese S,Jayamurthy P,Somappa SB

    更新日期：2020-12-01 00:00:00

  • Development of pyridazine derivatives as potential EGFR inhibitors and apoptosis inducers: Design, synthesis, anticancer evaluation, and molecular modeling studies.

    abstract：:Novel hybrids of pyridazine-pyrazoline were synthesized aiming to develop new antiproliferative candidates. All compounds were submitted to the National Cancer Institute (NCI), USA, and many were proved to have significant antiproliferative activity. In addition, in vitro studies of the epidermal growth factor recepto...

    journal_title：Bioorganic chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bioorg.2020.104473

    authors： Ahmed MF,Santali EY,Mohi El-Deen EM,Naguib IA,El-Haggar R

    更新日期：2021-01-01 00:00:00

  • Design, synthesis and biological evaluation of resveratrol-cinnamoyl derivates as tubulin polymerization inhibitors targeting the colchicine binding site.

    abstract：:A novel series of resveratrol-cinnamoyl hybrids as tubulin polymerization inhibitors were designed and synthesized, and evaluated for their anti-proliferative activities against A549, MCF-7, HepG2, HeLa and MDA-MB-231 five cancer cell lines. Most designed compounds showed better anti-proliferative activities. Particul...

    journal_title：Bioorganic chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bioorg.2019.103319

    authors： Yin Y,Lian BP,Xia YZ,Shao YY,Kong LY

    更新日期：2019-12-01 00:00:00

  • Inula japonica ameliorated bleomycin-induced pulmonary fibrosis via inhibiting soluble epoxide hydrolase.

    abstract：:Pulmonary fibrosis is a progressive, irreversible, and fatal fibrotic lung disease with a high mortality and morbidity, and commonly nonresponsive to conventional therapy. Inula japonica Thunb. is a traditional Chinese medicine, known as "Xuan Fu Hua" in Chinese, and has been widely applied to relieve cough and dyspne...

    journal_title：Bioorganic chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bioorg.2020.104065

    authors： Zhao WY,Luan ZL,Liu TT,Ming WH,Huo XK,Huang HL,Sun CP,Zhang BJ,Ma XC

    更新日期：2020-09-01 00:00:00

  • Natural product-based semisynthesis and biological evaluation of thiol/amino-Michael adducts of xanthatin derived from Xanthium strumarium as potential pesticidal agents.

    abstract：:Xanthatin, a natural sesquiterpene lactone, occurs as one of the major constituents of Xanthium plants (Compositae) and exhibits many important biological properties. To discover natural products-based pesticides, forty-nine Michael-type thiol/amino adducts of xanthatin were synthesized and characterized, while their ...

    journal_title：Bioorganic chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bioorg.2020.103696

    authors： Zhi XY,Jiang LY,Li T,Song LL,Wu LJ,Cao H,Yang C

    更新日期：2020-04-01 00:00:00

  • Design, synthesis, and pharmacological evaluation of novel 1,2,4-triazol-3-amine derivatives as potential agonists of GABAA subtype receptors with anticonvulsant and hypnotic effects.

    abstract：:In the current study, a series of novel 1,2,4-triazol-3-amine derivatives were designed, synthesized, and biologically evaluated in vivo for their anticonvulsant and hypnotic effects in the pentylenetetrazole (PTZ)-induced seizures, maximal electroshock (MES)-induced seizures, and pentobarbital-induced sleeping tests....

    journal_title：Bioorganic chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bioorg.2020.104212

    authors： Jahani R,Reza Abtahi S,Nematpour M,Fasihi Dastjerdi H,Chamanara M,Hami Z,Paknejad B

    更新日期：2020-11-01 00:00:00

  • α-bisabolol β-D-fucopyranoside as a potential modulator of β-amyloid peptide induced neurotoxicity: An in vitro &in silico study.

    abstract：:Alzheimer's disease (AD) is a multifaceted neurodegenerative disorder affecting the elderly people. For the AD treatment, there is inefficiency in the existing medication, as these drugs reduce only the symptoms of the disease. Since multiple pathological proteins are involved in the development of AD, searching for a...

    journal_title：Bioorganic chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bioorg.2019.102935

    authors： Jeyakumar M,Sathya S,Gandhi S,Tharra P,Suryanarayanan V,Singh SK,Baire B,Pandima Devi K

    更新日期：2019-07-01 00:00:00

  • Synthesis and evaluation of antioxidant and antiproliferative activity of 2-arylbenzimidazoles.

    abstract：:Three series of arylbenzimidazole derivatives 3-40, 45 have been simply synthesized and tested for their antioxidant capacity. The 2-arylbenzimidazoles were tested against various radicals by the DPPH, FRAP and ORAC tests and showed different activity profiles. It has been observed that the number and position of the ...

    journal_title：Bioorganic chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bioorg.2019.103396

    authors： Baldisserotto A,Demurtas M,Lampronti I,Tacchini M,Moi D,Balboni G,Pacifico S,Vertuani S,Manfredini S,Onnis V

    更新日期：2020-01-01 00:00:00

  • Novel Linezolid analogues with antiparasitic activity against Hymenolepis nana.

    abstract：:The stereoselective synthesis and anti- Hymenolepis nana activity of six Linezolid-type compounds, obtained by chemical modification of l-Alanine, are reported in this work. The synthetic strategy was to prepare diasteromeric N,N-dibenzylamino oxazolidinones 1 and 2, and coupling with 4-(4-bromophenyl)morpholine (3) t...

    journal_title：Bioorganic chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bioorg.2020.104359

    authors： Alcántar-Zavala E,Hernández-Guevara E,Ochoa-Terán A,Montes-Ávila J,Estrada-Zavala EA,Salazar-Medina AJ,Alday E,Cabrera A,Aguirre G,Miranda-Soto V,Velazquez C,Díaz-Camacho SP,Medina-Franco JL

    更新日期：2020-12-01 00:00:00

  • Synthesis, antioxidant and anticholinesterase activities of novel coumarylthiazole derivatives.

    abstract：:A newly series of coumarylthiazole derivatives containing aryl urea/thiourea groups were synthesized and their inhibitory effects on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) were evaluated. The result showed that all the synthesized compounds exhibited inhibitory activity to both cholinesterases. ...

    journal_title：Bioorganic chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bioorg.2015.02.002

    authors： Kurt BZ,Gazioglu I,Sonmez F,Kucukislamoglu M

    更新日期：2015-04-01 00:00:00

  • Synthesis, in silico and in vitro studies of new 1,4-dihydropiridine derivatives for antitumor and P-glycoprotein inhibitory activity.

    abstract：:P-glycoprotein (P-gp) is one of the cell membrane pumps which mediate the efflux of molecules such as anticancer drugs to the extracellular matrix of tumor cells. P_gp is a member of the ATP-binding cassette (ABC) transporter family that is implicated in cancer multidrug resistance (MDR). Since MDR is a contributor to...

    journal_title：Bioorganic chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bioorg.2019.103156

    authors： Mollazadeh S,Sahebkar A,Kalalinia F,Behravan J,Hadizadeh F

    更新日期：2019-10-01 00:00:00

  • Non-viral vectors for the mediation of RNAi.

    abstract：:Though the delivery of siRNA into cells, tissues or organs remains to be a big obstacle for its applications, recently siRNA therapeutics has developed rapidly and already there are clinical trials ongoing or planned. Some non-viral vectors have attracted much more attention and shown the great potential for combating...

    journal_title：Bioorganic chemistry

    pub_type： 杂志文章,评审

    doi：10.1016/j.bioorg.2011.07.005

    authors： Zhang S,Zhao Y,Zhi D,Zhang S

    更新日期：2012-02-01 00:00:00

  • New bis-thioglycosyl-1,1'-disulfides from Nasturtium officinale R. Br. and their anti-neuroinflammatory effect.

    abstract：:As a part of our continuing search for bioactive constituents from Brassicaceae family, three new bis-thioglycosides (1-3) were isolated from the 80% MeOH extract of Nasturtium officinale, together with 13 known compounds (4-16). The chemical structures of three new bis-thioglycosides (1-3) were elucidated using NMR t...

    journal_title：Bioorganic chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bioorg.2019.01.062

    authors： Lee TH,Khan Z,Subedi L,Kim SY,Lee KR

    更新日期：2019-05-01 00:00:00

  • Design, synthesis, analgesic, anti-inflammatory activity of novel pyrazolones possessing aminosulfonyl pharmacophore as inhibitors of COX-2/5-LOX enzymes: Histopathological and docking studies.

    abstract：:A series of newly synthesized 4-aryl-hydrazonopyrazolones were designed and their structures were confirmed by spectral and elemental analyses. All synthesized compounds were evaluated for their in vitro COXs, 5-LOX inhibition, in vivo analgesic and anti-inflammatory activities. Compounds 5d, 5f and 5i were found to b...

    journal_title：Bioorganic chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bioorg.2018.03.011

    authors： Abdelgawad MA,Labib MB,Ali WAM,Kamel G,Azouz AA,El-Nahass ES

    更新日期：2018-08-01 00:00:00

  • DNA binding studies of novel diazatruxenones analogs as potential anticancer agents: Synthesis, antitumor investigation, DNA binding, SAR and molecular modeling calculation.

    abstract：:A series of polycyclic skeleton of truxene and triazatruxene analogs has been synthesized and evaluated for antitumor and DNA binding activities. The synthesized structures were confirmed by different spectroscopic techniques such as IR, 1HNMR, 13CNMR, and mass spectroscopy. The antitumor screening was performed adopt...

    journal_title：Bioorganic chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bioorg.2020.104323

    authors： El Sayed MT,Shabaan SN,Sarhan AE,El-Messery SM,El-Sayed SM,Hassan GS

    更新日期：2020-11-01 00:00:00

  • Design, synthesis and melatoninergic potency of new N-acyl 8,9-dihydro-4-methoxy-7H-2-benzo[de]quinolinalkanamines.

    abstract：:A series of new N-acyl 8,9-dihydro-4-methoxy-7H-2-benzo[de]quinolinalkanamines have been prepared and tested for their ability to activate pigment granule aggregation in Xenopus laevis melanophores and bind to the recombinant human MT(1) and MT(2) melatonin receptor subtypes expressed in NIH 3T3 cells. Compounds with ...

    journal_title：Bioorganic chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bioorg.2006.11.006

    authors： Tsotinis A,Eleutheriades A,Hough KA,Davidson K,Sugden D

    更新日期：2007-04-01 00:00:00

  • Synthesis, inhibition properties against xanthine oxidase and molecular docking studies of dimethyl N-benzyl-1H-1,2,3-triazole-4,5-dicarboxylate and (N-benzyl-1H-1,2,3-triazole-4,5-diyl)dimethanol derivatives.

    abstract：:This study focused on synthesis various dimethyl N-benzyl-1H-1,2,3-triazole-4,5-dicarboxylate and (N-benzyl-1H-1,2,3-triazole-4,5-diyl)dimethanol derivatives under the conditions of green chemistry without the use of solvent and catalysts. Their inhibition properties were also investigated on xanthine oxidase (XO) act...

    journal_title：Bioorganic chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bioorg.2021.104654

    authors： Yagiz G,Noma SAA,Altundas A,Al-Khafaji K,Taskin-Tok T,Ates B

    更新日期：2021-01-12 00:00:00

  • Probing the active site of rat porphobilinogen synthase using newly developed inhibitors.

    abstract：:The structurally related tetrapyrrolic pigments are a group of natural products that participate in many of the fundamental biosynthetic and catabolic processes of living organisms. Porphobilinogen synthase catalyzes a rate-limiting step for the biosyntheses of tetrapyrrolic natural products. In the present study, a v...

    journal_title：Bioorganic chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bioorg.2008.11.001

    authors： Li N,Chu X,Liu X,Li D

    更新日期：2009-02-01 00:00:00

  • Caffeine-hydrazones as anticancer agents with pronounced selectivity toward T-lymphoblastic leukaemia cells.

    abstract：:We report design and synthesis of set of novel anticancer agents based on caffeine-hydrazones bearing 2-hydroxyaryl- or 2-N-heteroaryl moiety. Anticancer activity evaluation using seven cancer cell lines and two non-malignant cell lines demonstrated that several derivatives display significant anticancer activity and ...

    journal_title：Bioorganic chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bioorg.2015.03.003

    authors： Kaplánek R,Jakubek M,Rak J,Kejík Z,Havlík M,Dolenský B,Frydrych I,Hajdúch M,Kolář M,Bogdanová K,Králová J,Džubák P,Král V

    更新日期：2015-06-01 00:00:00

  • Synthesis, molecular docking and cytotoxicity evaluation of novel 2-(4-amino-benzosulfonyl)-5H-benzo[b]carbazole-6,11-dione derivatives as histone deacetylase (HDAC8) inhibitors.

    abstract：:A new series of 2-(4-aminobenzosulfonyl)-5H-benzo[b]carbazole-6,11-dione derivatives, which has not been reported yet, has been synthesized from 1,4-naphthoquinone and 4-aminophenylsulfone involving an Michael addition, benzoylation and Pd catalyzed coupling. This set of compounds has been evaluated for in vitro cytot...

    journal_title：Bioorganic chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bioorg.2014.01.002

    authors： Ravichandiran P,Jegan A,Premnath D,Periasamy VS,Muthusubramanian S,Vasanthkumar S

    更新日期：2014-04-01 00:00:00

  • First evaluation of organotellurium derivatives as carbonic anhydrase I, II, IV, VII and IX inhibitors.

    abstract：:A series of tellurides was evaluated as carbonic anhydrase (CA, EC 4.2.1.1) inhibitors against the human (h) carbonic anhydrase isoforms hCA I, II, IV, VII and IX, involved in a variety of diseases, including glaucoma, retinitis pigmentosa, epilepsy, arthritis and tumors. These compounds, which are the first tellurium...

    journal_title：Bioorganic chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bioorg.2017.12.010

    authors： Angeli A,Tanini D,Capperucci A,Supuran CT

    更新日期：2018-02-01 00:00:00

  • An alkali tolerant α-l-rhamnosidase from Fusarium moniliforme MTCC-2088 used in de-rhamnosylation of natural glycosides.

    abstract：:Analkali tolerant α-l-rhamnosidase has been purified to homogeneity from the culture filtrate of a new fungal strain, Fusarium moniliforme MTCC-2088, using concentration by ultrafiltration and cation exchange chromatography on CM cellulose column. The molecular mass of the purified enzyme has been found to be 36.0 kDa...

    journal_title：Bioorganic chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bioorg.2018.11.027

    authors： Kumar D,Yadav S,Yadava S,Yadav KDS

    更新日期：2019-03-01 00:00:00

  • Evaluation of guanylhydrazone derivatives as inhibitors of Candida rugosa digestive lipase: Biological, biophysical, theoretical studies and biotechnological application.

    abstract：:This work aimed to evaluate the inhibition of Candida rugosa lipase by five guanylhydrazone derivatives through biological, biophysical and theoretical studies simulating physiologic conditions. The compound LQM11 (IC50 = 14.70 μM) presented the highest inhibition against the enzyme. Therefore, for a better understand...

    journal_title：Bioorganic chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bioorg.2019.03.030

    authors： Santana CC,Silva-Júnior EF,Santos JCN,Rodrigues ÉEDS,da Silva IM,Araújo-Júnior JX,do Nascimento TG,Oliveira Barbosa LA,Dornelas CB,Figueiredo IM,Santos JCC,Grillo LAM

    更新日期：2019-06-01 00:00:00

  • Synthesis and in-vitro anti-leishmanial activity of (4-arylpiperazin-1-yl)(1-(thiophen-2-yl)-9H-pyrido[3,4-b]indol-3-yl)methanone derivatives.

    abstract：:In the present study, we have reported synthesis and biological evaluation of a series of fifteen 1-(thiophen-2-yl)-9H-pyrido[3,4-b]indole derivatives against both promastigotes and amastigotes of Leishmania parasites responsible for visceral (L. donovani) and cutaneous (L. amazonensis) leishmaniasis. Among these repo...

    journal_title：Bioorganic chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bioorg.2016.11.013

    authors： Ashok P,Chander S,Chow LM,Wong IL,Singh RP,Jha PN,Sankaranarayanan M

    更新日期：2017-02-01 00:00:00

  • Radical formation and coupling of hydroxycinnamic acids containing 1,2-dihydroxy substituents.

    abstract：:Hydroxycinnamic acids involved in the deposition and cross-linking of plant cell-wall polymers do not usually contain 1,2-dihydroxy substituents, despite the presence of both 3,4-dihydroxycinnamic acid and 4,5-dihydroxy-3-methoxycinnamic acid as intermediates in the biogenesis of lignin. Since the O-methyl transferase...

    journal_title：Bioorganic chemistry

    pub_type： 杂志文章

    doi：10.1016/s0045-2068(03)00042-7

    authors： Russell WR,Burkitt MJ,Scobbie L,Chesson A

    更新日期：2003-06-01 00:00:00

  • Microwave assisted synthesis of novel hybrid tacrine-sulfonamide derivatives and investigation of their antioxidant and anticholinesterase activities.

    abstract：:A novel series of tacrine derivatives containing sulfonamide group were synthesized and their inhibitory effects on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) were evaluated. The result showed that all the synthesized tacrine-sulfonamides (VIIIa-o) exhibited inhibitory activity on both cholinesteras...

    journal_title：Bioorganic chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bioorg.2017.01.005

    authors： Ulus R,Zengin Kurt B,Gazioğlu I,Kaya M

    更新日期：2017-02-01 00:00:00

  • Imidazole-pyrazole hybrids: Synthesis, characterization and in-vitro bioevaluation against α-glucosidase enzyme with molecular docking studies.

    abstract：:Herein, substituted imidazole-pyrazole hybrids (2a-2n) were prepared via a multi component reaction employing pyrazole-4-carbaldehydes (1a-1d), ammonium acetate, benzil and arylamines as reactants. All the new compounds were characterized through their spectral and elemental analyses. Further these compounds were test...

    journal_title：Bioorganic chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bioorg.2018.10.047

    authors： Chaudhry F,Naureen S,Ashraf M,Al-Rashida M,Jahan B,Munawar MA,Khan MA

    更新日期：2019-02-01 00:00:00

  • Synthesis of Mitomycin C and decarbamoylmitomycin C N6 deoxyadenosine-adducts.

    abstract：:Mitomycin C (MC), an anti-cancer drug, and its analog, decarbamoylmitomycin C (DMC), are DNA-alkylating agents. MC is currently used in the clinics and its cytotoxicity is mainly due to its ability to form Interstrand Crosslinks (ICLs) which impede DNA replication and, thereby, block cancer cells proliferation. Howeve...

    journal_title：Bioorganic chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bioorg.2019.103280

    authors： Zheng M,Hwang S,Snyder T,Aquilina J,Proni G,Paz MM,Pradhan P,Cheng SY,Champeil E

    更新日期：2019-11-01 00:00:00

  • Design and synthesis of new benzoxazole/benzothiazole-phthalimide hybrids as antitumor-apoptotic agents.

    abstract：:Herein, we synthesized a series of twelve benzoxazole and benzothiazole derivatives incorporated with phthalimide core as anticancer agents. The most active compounds were 5a and 5g against HepG2 and MCF7 cell lines with IC50 = 0.011 and 0.006 μM, respectively. They evaluated against EGFR and HER2 enzymes. From cell c...

    journal_title：Bioorganic chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bioorg.2019.102978

    authors： Philoppes JN,Lamie PF

    更新日期：2019-08-01 00:00:00

  • Structural elucidation and anti-neuroinflammatory activities of lignans from the testas of Vernicia montana.

    abstract：:Vernicia montana Lour. (tung tree) is an oil-producing plant with multiple uses, especially with its great potential in biodiesel production, which was a small Asian tree of the spurge family (Euphorbiaceae) with big economic values. However, studies on small molecular compositions of V. montana are limited. As a resu...

    journal_title：Bioorganic chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bioorg.2020.103690

    authors： Zhou D,Li Y,Chen G,Yang Y,Mi Y,Lin B,Li W,Hou Y,Li N

    更新日期：2020-04-01 00:00:00