当前位置： SCI文献检索 > BIOORGANIC & MEDICINAL CHEMISTRY LETTERS期刊下所有文献 > Enhancing the activity of membrane remodeling epsin-peptide by trimerization.

Enhancing the activity of membrane remodeling epsin-peptide by trimerization.

Abstract：

:Modulating the structural dynamics of biomembranes by inducing bilayer curvature and lipid packing defects has been highlighted as a practical tool to modify membrane-dependent cellular processes. Previously, we have reported on an amphipathic helical peptide derived from the N-terminal segment (residues 1-18, EpN18) of epsin-1, which can promote membrane remodeling including lipid packing defects in cell membranes. However, a high concentration is required to exhibit a pronounced effect. In this study, we demonstrate a significant increase in the membrane-remodeling effect of EpN18 by constructing a branched EpN18 homotrimer. Both monomer and trimer could enhance cell internalization of octaarginine (R8), a cell-penetrating peptide. The EpN18 trimer, however, promoted the uptake of R8 at an 80-fold lower concentration than the monomer. Analysis of the generalized polarization of a polarity-sensitive dye (di-4-ANEPPDHQ) revealed a higher efficacy of trimeric EpN18 in loosening the lipid packing in the cell membrane. Circular dichroism measurements in the presence of lipid vesicles showed that the EpN18 trimer has a higher α-helix content compared with the monomer. The stronger ability of the EpN18 trimer to impede negative bilayer curvature is also corroborated by solid-state 31P NMR spectroscopy. Hence, trimerizing peptides can be considered a promising approach for an exponential enhancement of their membrane-remodeling performance.

journal_name

Bioorg Med Chem Lett

journal_title

Bioorganic & medicinal chemistry letters

authors

Hsu WY,Masuda T,Afonin S,Sakai T,Arafiles JVV,Kawano K,Hirose H,Imanishi M,Ulrich AS,Futaki S

doi

10.1016/j.bmcl.2020.127190

subject

Has Abstract

pub_date

2020-06-15 00:00:00

pages

127190

issue

12

eissn

0960-894X

issn

1464-3405

pii

S0960-894X(20)30289-4

journal_volume

30

pub_type

杂志文章

相关文献

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS文献大全
  • Design, synthesis, and biological evaluation of novel, centrally-acting thyrotropin-releasing hormone analogues.

    abstract：:Novel, metabolically stable and centrally acting TRH analogues with substituted pyridinium moieties replacing the [His(2)] residue of the endogenous peptide were prepared by solid-phase Zincke reaction. The 1,4-dihydropyridine prodrugs of these analogues obtained after reducing the pyridinium moiety were able to reach...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/s0960-894x(02)00368-2

    authors： Prokai-Tatrai K,Perjési P,Zharikova AD,Li X,Prokai L

    更新日期：2002-08-19 00:00:00

  • Ureas with histamine H3-antagonist receptor activity--a new scaffold discovered by lead-hopping from cinnamic acid amides.

    abstract：:A group of tri and tetrasubstituted urea derivatives have been found to be hH(3)-antagonists. The most potent compounds were found in the class of (piperazine-1-yl)-(piperidine-1-yl)-methanones which in addition showed negligible hERG inhibition. ...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2006.07.093

    authors： Lau JF,Jeppesen CB,Rimvall K,Hohlweg R

    更新日期：2006-10-15 00:00:00

  • Non-electrophilic modulators of the canonical Keap1/Nrf2 pathway.

    abstract：:Nrf2 is the major transcription factor that regulates many of the cytoprotective enzymes involved in the adaptive stress response. Modulation of Nrf2 could be therapeutically useful in a number of disease states. Activation can occur through either an electrophilic or non-electrophilic mechanism. To date, most of the ...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章,评审

    doi：10.1016/j.bmcl.2015.04.019

    authors： Richardson BG,Jain AD,Speltz TE,Moore TW

    更新日期：2015-06-01 00:00:00

  • In vivo click reaction between Tc-99m-labeled azadibenzocyclooctyne-MAMA and 2-nitroimidazole-azide for tumor hypoxia targeting.

    abstract：:The bioactivity of nitroimidazole in Tc-99m-labeled 2-nitroimidazole, a traditional solid tumor hypoxia-imaging agent for single photon emission computed tomography (SPECT), is reduced by the presence of large ligand and metallic radionuclide, exhibiting lower tumor-to-nontumor ratios. In an effort to solve this gener...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2015.09.004

    authors： Sun W,Chu T

    更新日期：2015-10-15 00:00:00

  • Synthesis and evaluation of N-[(1S,2S)-3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-methyl-2-aminopropanamide as human cannabinoid-1 receptor (CB1R) inverse agonists.

    abstract：:Obesity is a chronic medical condition that is affecting large population throughout the world. CB1 as a target for treatment of obesity has been under intensive studies. Taranabant was discovered and then developed by Merck as the 1st generation CB1R inverse agonist. Reported here is part of our effort on the 2nd gen...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2009.07.046

    authors： Du W,Jewell JP,Lin LS,Colandrea VJ,Xiao JC,Lao J,Shen CP,Bateman TJ,Reddy VB,Ha SN,Shah SK,Fong TM,Hale JJ,Hagmann WK

    更新日期：2009-09-01 00:00:00

  • Synthesis, 3D-structure and stability analyses of NRPa-308, a new promising anti-cancer agent.

    abstract：:We report herein the synthesis of a newly described anti-cancer agent, NRPa-308. This compound antagonizes Neuropilin-1, a multi-partners transmembrane receptor overexpressed in numerous tumors, and thereby validated as promising target in oncology. The preparation of NRPa-308 proved challenging because of the orthogo...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2019.126710

    authors： Brachet E,Dumond A,Liu WQ,Fabre M,Selkti M,Raynaud F,Hermine O,Benhida R,Belmont P,Garbay C,Lepelletier Y,Ronco C,Pagès G,Demange L

    更新日期：2019-12-15 00:00:00

  • 2,5-Diketopiperazines as potent and selective oxytocin antagonists 1: Identification, stereochemistry and initial SAR.

    abstract：:This paper covers efforts to discover orally active potent and selective oxytocin antagonists. Screening pooled libraries identified a novel series of 2,5-diketopiperazine derivatives with antagonist activity at the human oxytocin receptor. We report the initial structure-activity relationship investigations and the d...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2005.03.045

    authors： Wyatt PG,Allen MJ,Borthwick AD,Davies DE,Exall AM,Hatley RJ,Irving WR,Livermore DG,Miller ND,Nerozzi F,Sollis SL,Szardenings AK

    更新日期：2005-05-16 00:00:00

  • Regioselective synthesis and cytotoxicities of camptothecin derivatives modified at the 7-, 10- and 20-positions.

    abstract：:A series of 7-acyloxymethylcamptothecin and 20-O-acyl-7-acyloxymethylcamptothecin derivatives were regioselectively prepared on different solvents. 7-Acyloxymethylcamptothecins possess more efficacy than 20-O-acyl-7-acyloxymethylcamptothecins against six human cancer cell lines in vitro. ...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2003.08.012

    authors： Pan XD,Han R,Sun PY

    更新日期：2003-11-03 00:00:00

  • Synthesis and evaluation of 3-¹²³I-iodo-5-[2-(S)-3-pyrrolinylmethoxy]-pyridine (niodene) as a potential nicotinic α4β2 receptor imaging agent.

    abstract：:Nicotinic acetylcholine receptors (nAChRs) are downregulated in disease conditions such as Alzheimer's and substance abuse. Presently, (123)I-5-IA-85380 is used in human studies and requires over 6h of scanning time, thus increases patient discomfort. We have designed and synthesized 3-iodo-5-[2-(S)-3-pyrrolinylmethox...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2012.10.012

    authors： Pandey SK,Pan S,Kant R,Kuruvilla SA,Pan ML,Mukherjee J

    更新日期：2012-12-15 00:00:00

  • Antioxidant and antiproliferative activities of hydroxyl-substituted Schiff bases.

    abstract：:Eight hydroxyl-substituted Schiff bases with the different number and position of hydroxyl group on the two asymmetric aromatic rings (A and B rings) were prepared by the reaction between the corresponding aromatic aldehyde and aniline. Their antioxidant effects against the stable galvinoxyl radical (GO(.)) in ethyl a...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2010.03.039

    authors： Cheng LX,Tang JJ,Luo H,Jin XL,Dai F,Yang J,Qian YP,Li XZ,Zhou B

    更新日期：2010-04-15 00:00:00

  • Modulating the development of E. coli biofilms with 2-aminoimidazoles.

    abstract：:The synthesis of a 20 member 2-aminoimidazole/triazole pilot library is reported. Each member of the library was screened for its ability to inhibit or promote biofilm development of either Escherichia coli and Acinetobacter baumannii. From this screen, E. coli-selective 2-aminoimidazoles were discovered, with the bes...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2010.08.075

    authors： Reed CS,Huigens RW 3rd,Rogers SA,Melander C

    更新日期：2010-11-01 00:00:00

  • New polyhydroxytriterpenoid derivatives from fruits of Terminalia chebula Retz. and their α-glucosidase and α-amylase inhibitory activity.

    abstract：:Three new polyhydroxytriterpenoid derivatives, 23-O-neochebuloylarjungenin 28-O-β-d-glycopyranosyl ester (1), 23-O-4'-epi-neochebuloylarjungenin (2), and 23-O-galloylpinfaenoic acid 28-O-β-d-glucopyranosyl ester (17) were isolated from the fruits of Terminalia chebula Retz. along with fourteen known ones. Their struct...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2016.11.039

    authors： Lee DY,Yang H,Kim HW,Sung SH

    更新日期：2017-01-01 00:00:00

  • Novel fluorescent oligoDNA probe bearing a multi-conjugated nucleoside with a fluorophore and a non-fluorescent intercalator as a quencher.

    abstract：:A set of 15mer linear oligoDNA probes bearing a modified nucleoside conjugated with a polyamine/fluorescein/anthraquinone reporting moiety were synthesized. In a single-stranded form, the fluorescence generated by the excitation of fluorescein was efficiently quenched, while marked recovery of the fluorescence was obs...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2006.02.016

    authors： Kodama S,Asano S,Moriguchi T,Sawai H,Shinozuka K

    更新日期：2006-05-15 00:00:00

  • Synthesis and preliminary cytotoxicity of nitrogen mustard derivatives of distamycin A.

    abstract：:Distamycin and nitrogen mustard conjugates, in which the nitrogen mustard unit was coupled to the C-terminus of the pyrrole, were synthesized. The switching of the nitrogen mustard unit from the N-terminus to the C-terminus did not compromise the compound's cytotoxicity. Compound 3, bearing three pyrrole units, was hi...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/s0960-894x(02)00986-1

    authors： Wang Y,Wright SC,Larrick JW

    更新日期：2003-02-10 00:00:00

  • Scaffold oriented synthesis. Part 2: Design, synthesis and biological evaluation of pyrimido-diazepines as receptor tyrosine kinase inhibitors.

    abstract：:We report the discovery of the pyrimido-diazepine scaffolds as novel adenine mimics. Structure-based design led to the discovery of analogs with potent inhibitory activity against receptor tyrosine kinases, such as KDR, Flt3 and c-Kit. Compound 14 exhibited low nanomolar KDR enzymatic and cellular potencies (IC(50)=9 ...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2008.03.021

    authors： Gracias V,Ji Z,Akritopoulou-Zanze I,Abad-Zapatero C,Huth JR,Song D,Hajduk PJ,Johnson EF,Glaser KB,Marcotte PA,Pease L,Soni NB,Stewart KD,Davidsen SK,Michaelides MR,Djuric SW

    更新日期：2008-04-15 00:00:00

  • Polycyclic aromatic compounds as anticancer agents: synthesis and biological evaluation of some chrysene derivatives.

    abstract：:Synthesis and biological evaluation of new chrysene derivatives aimed at the development of anticancer agents were carried out. ...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/s0960-894x(98)00520-4

    authors： Becker FF,Banik BK

    更新日期：1998-10-20 00:00:00

  • Design, synthesis and antithrombotic evaluation of novel dabigatran prodrugs containing methyl ferulate.

    abstract：:A novel series of prodrugs containing dabigatran and methyl (E)-3-(4-hydroxy-2-methoxyphenyl)propenoate (methyl ferulate) were synthesized. All of them reveal the effect of thrombin-induced anti-platelet aggregation in vitro. In addition, in vivo experiment shows that one of the target compounds, X-2 (ED50=3.7 ± 1.0 μ...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2013.01.126

    authors： Yang XZ,Diao XJ,Yang WH,Li F,He GW,Gong GQ,Xu YG

    更新日期：2013-04-01 00:00:00

  • Discovery of 'molecular switches' within a GIRK activator scaffold that afford selective GIRK inhibitors.

    abstract：:This letter describes a multi-dimensional SAR campaign based on a potent, efficacious and selective GIRK1/2 activator (~10-fold versus GIRK1/4 and inactive on nonGIRK 1-containing GIRKs, GIRK 2 or GIRK2/3). Further chemical optimization through an iterative parallel synthesis effort identified multiple 'molecular swit...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2013.06.023

    authors： Wen W,Wu W,Romaine IM,Kaufmann K,Du Y,Sulikowski GA,Weaver CD,Lindsley CW

    更新日期：2013-08-15 00:00:00

  • Facile synthesis of a dimeric dipyrrole-polyamide and synergetic DNA-cleaving activity of its Cu(II) complex.

    abstract：:Inspired by the potent DNA-cleaving activity of the Cu(II) complex of monopyrrole-polyamide dimer 1 (i.e., 1@Cu(2+)), we designed a new dimeric dipyrrole-polyamide analog 2 with the aim to optimize the catalytic activities of the metal complexes of this type of polypyrrole-polyamides. Compound 2 was prepared in 50% yi...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2012.07.085

    authors： Zhou CQ,Lin YL,Chen JX,Wang LS,Yang NN,Zeng W,Chen WH

    更新日期：2012-09-15 00:00:00

  • Synthesis and activity of novel tetrazole compounds and their pyrazole-4-carbonitrile precursors against Leishmania spp.

    abstract：:A new series of 5-(1-aryl-3-methyl-1H-pyrazol-4-yl)-1H-tetrazole derivatives (4a-m) and their precursor 1-aryl-3-methyl-1H-pyrazole-4-carbonitriles (3a-m) were synthesized and evaluated as antileishmanials against Leishmania braziliensis and Leishmania amazonensis promastigotes in vitro. In parallel, the cytotoxicity ...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2013.09.062

    authors： Faria JV,dos Santos MS,Bernardino AM,Becker KM,Machado GM,Rodrigues RF,Canto-Cavalheiro MM,Leon LL

    更新日期：2013-12-01 00:00:00

  • Synthesis and biological evaluation of 9-fluorenone derivatives for SPECT imaging of α7-nicotinic acetylcholine receptor.

    abstract：:The α7-nicotinic acetylcholine receptor (α7-nAChR) subtype, is found to have a connection with the pathogenesis of a variety of psychiatric and neurological disorders. Herein, we report the development of radioiodinated 9-fluorenone derivatives as single-photon emission computed tomography (SPECT) imaging tracers for ...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2019.126724

    authors： Gao H,Wang S,Qi Y,He G,Qiang B,Wang S,Zhang H

    更新日期：2019-12-01 00:00:00

  • Evaluation of licorice flavonoids as protein tyrosine phosphatase 1B inhibitors.

    abstract：:Protein tyrosine phosphatase 1B (PTP1B) is a major negative regulator in insulin- and leptin-signaling cascades as well as a positive regulator in tumorigenesis, and much attention has been paid to PTP1B inhibitors as potential therapies for diabetes, obesity, and cancer. In the present study, the screening of a compo...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2013.08.102

    authors： Li W,Li S,Higai K,Sasaki T,Asada Y,Ohshima S,Koike K

    更新日期：2013-11-01 00:00:00

  • Discovery of an exceptionally potent and selective class of fatty acid amide hydrolase inhibitors enlisting proteome-wide selectivity screening: concurrent optimization of enzyme inhibitor potency and selectivity.

    abstract：:The concurrent implementation of a proteome-wide serine hydrolase selectivity screen with traditional efforts to optimize fatty acid amide hydrolase (FAAH) inhibition potency led to the expedited discovery of a new class of exceptionally potent (Ki < 300 pM) and unusually selective (> 100-fold selective) inhibitors. T...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2004.12.085

    authors： Leung D,Du W,Hardouin C,Cheng H,Hwang I,Cravatt BF,Boger DL

    更新日期：2005-03-01 00:00:00

  • Novel 1,3-dipropyl-8-(1-heteroarylmethyl-1H-pyrazol-4-yl)-xanthine derivatives as high affinity and selective A2B adenosine receptor antagonists.

    abstract：:A series of new 1,3-dipropyl-8-(1-heteroarylmethyl-1H-pyrazol-4-yl)-xanthine derivatives as A(2B)-AdoR antagonists have been synthesized and evaluated for their binding affinities for the A(2B), A(1), A(2A), and A(3)-AdoRs. 8-(1-((3-phenyl-1,2,4-oxadiazol-5-yl)methyl)-1H-pyrazol-4-yl)-1,3-dipropyl-1H-purine-2,6(3H,7H)...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2005.10.002

    authors： Elzein E,Kalla R,Li X,Perry T,Parkhill E,Palle V,Varkhedkar V,Gimbel A,Zeng D,Lustig D,Leung K,Zablocki J

    更新日期：2006-01-15 00:00:00

  • New CD1d agonists: synthesis and biological activity of 6″-triazole-substituted α-galactosyl ceramides.

    abstract：:Huisgen [3+2] dipolar cycloaddition of 6″-azido-6″-deoxy-α-galactosyl ceramide 11 with a range of alkynes (or a benzyne precursor) yielded a series of triazole-containing α-galactosyl ceramide (α-GalCer) analogues in high yield. These α-GalCer analogues and the precursor azide 11 were tested for their ability to activ...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2012.05.009

    authors： Jervis PJ,Graham LM,Foster EL,Cox LR,Porcelli SA,Besra GS

    更新日期：2012-07-01 00:00:00

  • Delta agonist hydroxy bioisosteres: the discovery of 3-((1-benzylpiperidin-4-yl){4-[(diethylamino)carbonyl]phenyl}amino)benzamide with improved delta agonist activity and in vitro metabolic stability.

    abstract：:We have investigated phenol replacements in a series of diaryl amino piperidine delta opioid agonists. From this study we have demonstrated that the hydroxy functional group can be replaced with a primary amide group, giving enhanced activity at the delta receptor, increased selectivity versus mu and kappa as well as ...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2009.09.068

    authors： Griffin AM,Brown W,Walpole C,Coupal M,Adam L,Gosselin M,Salois D,Morin PE,Roumi M

    更新日期：2009-11-01 00:00:00

  • Structure activity relationship and optimization of N-(3-(2-aminothiazol-4-yl)aryl)benzenesulfonamides as anti-cancer compounds against sensitive and resistant cells.

    abstract：:We recently described a new family of bioactive molecules with interesting anti-cancer activities: the N-(4-(3-aminophenyl)thiazol-2-yl)acetamides. The lead compound of the series (1) displays significant anti-proliferative and cytotoxic activities against a panel of cancer cell lines, either sensitive or resistant to...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2017.03.054

    authors： Ronco C,Millet A,Plaisant M,Abbe P,Hamouda-Tekaya N,Rocchi S,Benhida R

    更新日期：2017-05-15 00:00:00

  • Effects of positional and geometrical isomerism on the biological activity of some novel oxazolidinones.

    abstract：:Some novel oxazolidinone derivatives with benzotriazole as pendant have been synthesized and tested for antibacterial activity. Linearly attached benzotriazole derivative showed more potency compared to angular one in vitro. Out of E/Z-isomers of angularly attached derivatives E-isomer was found to be more potent than...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2004.10.073

    authors： Das J,Rao CV,Sastry TV,Roshaiah M,Sankar PG,Khadeer A,Kumar MS,Mallik A,Selvakumar N,Iqbal J,Trehan S

    更新日期：2005-01-17 00:00:00

  • Isosteres of ester derived glucose uptake inhibitors.

    abstract：:Glucose transporters (GLUTs) facilitate glucose uptake and are overexpressed in most cancer cells. Inhibition of glucose transport has been shown to be an effective method to slow the growth of cancer cells both in vitro and in vivo. We have previously reported on the anticancer activity of an ester derived glucose up...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/j.bmcl.2020.127406

    authors： Roberts DA,Wang L,Zhang W,Liu Y,Shriwas P,Qian Y,Chen X,Bergmeier SC

    更新日期：2020-09-15 00:00:00

  • Rapid solid-phase synthesis of DNA-binding pyrrole-imidazole polyamides.

    abstract：:Pyrrole-imidazole polyamides can be synthesized to target predetermined sequences of DNA with nanomolar affinity and high specificity, and have been shown to modulate gene transcription both in vitro and in vivo. To make polyamides more readily available to biological laboratories, we have developed a rapid solid-phas...

    journal_title：Bioorganic & medicinal chemistry letters

    pub_type： 杂志文章

    doi：10.1016/s0960-894x(02)00359-1

    authors： Krutzik PO,Chamberlin AR

    更新日期：2002-08-19 00:00:00