当前位置： SCI文献检索 > BIOORGANIC & MEDICINAL CHEMISTRY期刊下所有文献 > Development of a novel class of peroxisome proliferator-activated receptor (PPAR) gamma ligands as an anticancer agent with a unique binding mode based on a non-thiazolidinedione scaffold.

Development of a novel class of peroxisome proliferator-activated receptor (PPAR) gamma ligands as an anticancer agent with a unique binding mode based on a non-thiazolidinedione scaffold.

Abstract：

:We previously identified dibenzooxepine derivative 1 as a potent PPARγ ligand with a unique binding mode owing to its non-thiazolidinedione scaffold. However, while 1 showed remarkably potent MKN-45 gastric cancer cell aggregation activity, an indicator of cancer differentiation-inducing activity induced by PPARγ activation, we recognized that 1 was metabolically unstable. In the present study, we identified a metabolically soft spot, and successfully discovered 3-fluoro dibenzooxepine derivative 9 with better metabolic stability. Further optimization provided imidazo[1,2-a]pyridine derivative 17, which showed potent MKN-45 gastric cancer cell aggregation activity and excellent PK profiles compared with 9. Compound 17 exerted a growth inhibitory effect on AsPC-1/AG1 pancreatic tumor in mice. Furthermore, the decrease in the hematocrit (an indicator of localized edema, a serious adverse effect of PPARγ ligands) was tolerable even with oral administration at 200 mg/kg in healthy mice.

journal_name

Bioorg Med Chem

journal_title

Bioorganic & medicinal chemistry

authors

Yamamoto K,Tamura T,Nakamura R,Hosoe S,Matsubara M,Nagata K,Kodaira H,Uemori T,Takahashi Y,Suzuki M,Saito JI,Ueno K,Shuto S

doi

10.1016/j.bmc.2019.115122

subject

Has Abstract

pub_date

2019-11-15 00:00:00

pages

115122

issue

22

eissn

0968-0896

issn

1464-3391

pii

S0968-0896(19)31039-9

journal_volume

27

pub_type

杂志文章

相关文献

BIOORGANIC & MEDICINAL CHEMISTRY文献大全
  • Phenyl substituted 3-hydroxypyridin-2(1H)-ones: inhibitors of influenza A endonuclease.

    abstract：:Inhibition of the endonuclease activity of influenza RNA-dependent RNA polymerase is recognized as an attractive target for the development of new agents for the treatment of influenza infection. Our earlier study employing small molecule fragment screening using a high-resolution crystal form of pandemic 2009 H1N1 in...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2013.08.053

    authors： Parhi AK,Xiang A,Bauman JD,Patel D,Vijayan RS,Das K,Arnold E,Lavoie EJ

    更新日期：2013-11-01 00:00:00

  • Broad-spectrum antimicrobial activity of hemoglobin.

    abstract：:While hemoglobin is one of the most well characterized proteins due to its function in oxygen transport, few additional properties of hemoglobin have been described. While screening serum samples for novel antimicrobial factors, it was found that intact hemoglobin tetramers, including that from human, exhibited consid...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/s0968-0896(00)00263-7

    authors： Parish CA,Jiang H,Tokiwa Y,Berova N,Nakanishi K,McCabe D,Zuckerman W,Xia MM,Gabay JE

    更新日期：2001-02-01 00:00:00

  • Synthesis and evaluation of 4- and 5-pyridazin-3-one phenoxypropylamine analogues as histamine-3 receptor antagonists.

    abstract：:A novel series of 4-pyridazin-3-one and 5-pyridazin-3-one analogues were designed and synthesized as H(3)R antagonists. Structure-activity relationship revealed the 5-pyridazin-3-ones 8a and S-methyl 8b had excellent human and rat H(3)R affinities, and acceptable pharmacokinetic properties. In vivo evaluation of 8a sh...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2012.04.028

    authors： Becknell NC,Lyons JA,Aimone LD,Huang Z,Gruner JA,Raddatz R,Hudkins RL

    更新日期：2012-06-15 00:00:00

  • Characterization of novel furan compounds on the basis of their radical scavenging activity and cytoprotective effects against glutamate- and lipopolysaccharide-induced insults.

    abstract：:There is increasing evidence indicating that free radicals and oxygenases such as cyclooxygenase (COX) and lipoxygenase (LOX) are related to the onset and development of neurodegenerative diseases. In order to prevent and/or delay these diseases, the use of radical-scavenging antioxidants and inhibitors against oxygen...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2008.10.038

    authors： Nishio K,Fukuhara A,Omata Y,Saito Y,Yamaguchi S,Kato H,Yoshida Y,Niki E

    更新日期：2008-12-15 00:00:00

  • Structure-activity relationship study of pyrimido[1,2-c][1,3]benzothiazin-6-imine derivatives for potent anti-HIV agents.

    abstract：:3,4-Dihydro-2H,6H-pyrimido[1,2-c][1,3]benzothiazin-6-imine (PD 404182) is an antiretroviral agent with submicromolar inhibitory activity against human immunodeficiency virus-1 (HIV-1) and HIV-2 infection. In the current study, the structure-activity relationships of accessory groups at the 3- and 9-positions of pyrimi...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2012.08.030

    authors： Mizuhara T,Oishi S,Ohno H,Shimura K,Matsuoka M,Fujii N

    更新日期：2012-11-01 00:00:00

  • Inactivation of the human papillomavirus-16 E6 oncoprotein by organic disulfides.

    abstract：:We are investigating compounds that could be useful in the treatment of neoplastic lesions of the cervix by acting on the oncoprotein E6 of human papillomavirus-16. The E6 protein contains two potential zinc-binding domains that are required for most of its functions. We have published tests that measure (i) the relea...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/s0968-0896(00)00193-0

    authors： Beerheide W,Sim MM,Tan YJ,Bernard HU,Ting AE

    更新日期：2000-11-01 00:00:00

  • Novel tricyclic indeno[2,1-d]pyrimidines with dual antiangiogenic and cytotoxic activities as potent antitumor agents.

    abstract：:We designed, synthesized and evaluated 13 novel tricyclic indeno[2,1-d]pyrimidines as RTK inhibitors. These analogues were synthesized via a Dieckmann condensation of 1,2-phenylenediacetonitrile followed by cyclocondensation with guanidine carbonate to afford the 2-amino-3,9-dihydro-indeno[2,1-d]pyrimidin-4-one. Sulfo...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2012.05.068

    authors： Gangjee A,Zhao Y,Ihnat MA,Thorpe JE,Bailey-Downs LC,Kisliuk RL

    更新日期：2012-07-15 00:00:00

  • Phenylhydrazides as inhibitors of Leishmania amazonensis arginase and antileishmanial activity.

    abstract：:Searching for new substances with antileishmanial activity, we synthesized and evaluated a series of α,α-difluorohydrazide and α,α-difluoramides against Leishmania amazonensis arginase (LaArg). Four α,α-difluorohydrazide derivatives showed activity against LaArg with Ki in the range of 1.3-26 μM. The study of the kine...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2019.07.022

    authors： Crizanto de Lima E,Castelo-Branco FS,Maquiaveli CC,Farias AB,Rennó MN,Boechat N,Silva ER

    更新日期：2019-09-01 00:00:00

  • Deoxyiminoalditols from aldonolactones--V. Preparation of the four stereoisomers of 1,5-dideoxy-1,5-iminopentitols. Evaluation of these iminopentitols and three 1,5-dideoxy-1,5-iminoheptitols as glycosidase inhibitors.

    abstract：:The four stereoisomeric 1,5-dideoxy-1,5-iminopentitols with D-arabino-(D-lyxo-) (3), ribo- (9), L-lyxo (L-arabino-) (13) and xylo-(18) configurations were synthesized. The corresponding aldonolactones (1, 7 and 11) or aldonic acid ester (15b) having a leaving group at C-5 gave by reaction with aqueous ammonia, the 5-a...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/s0968-0896(96)00167-8

    authors： Godskesen M,Lundt I,Madsen R,Winchester B

    更新日期：1996-11-01 00:00:00

  • Synthesis and biological evaluation of novel phthalazinone derivatives as topically active phosphodiesterase 4 inhibitors.

    abstract：:Inhibitors of phosphodiesterase 4 (PDE4) are an important class of anti-inflammatory drug that act by inhibiting the production of proinflammatory cytokines, including tumor necrosis factor-alpha (TNF-alpha). We have synthesized and evaluated a series of 2-substituted phthalazinone derivatives as PDE4 inhibitors. Stru...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2009.08.014

    authors： Kagayama K,Morimoto T,Nagata S,Katoh F,Zhang X,Inoue N,Hashino A,Kageyama K,Shikaura J,Niwa T

    更新日期：2009-10-01 00:00:00

  • Synthesis and physical characterization of a P1 arginine combinatorial library, and its application to the determination of the substrate specificity of serine peptidases.

    abstract：:Serine peptidases are a large, well-studied, and medically important class of peptidases. Despite the attention these enzymes have received, details concerning the substrate specificity of even some of the best known enzymes in this class are lacking. One approach to rapidly characterizing substrate specificity for pe...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/s0968-0896(02)00174-8

    authors： Furlong ST,Mauger RC,Strimpler AM,Liu YP,Morris FX,Edwards PD

    更新日期：2002-11-01 00:00:00

  • 3-Amino-2(5H)furanones as inhibitors of subgenomic hepatitis C virus RNA replication.

    abstract：:A new class of compounds able to block the replication of subgenomic HCV RNA in liver cells is described. 3-Amino-2(5H)furanones 4 may be regarded as diketoacid analogues and were obtained by basic rearrangement of the isoxazolidine nucleus. ...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2008.09.006

    authors： Iannazzo D,Piperno A,Romeo G,Romeo R,Chiacchio U,Rescifina A,Balestrieri E,Macchi B,Mastino A,Cortese R

    更新日期：2008-11-01 00:00:00

  • Discovery of novel phenoxazinone derivatives as DKK1/LRP6 interaction inhibitors: Synthesis, biological evaluation and structure-activity relationships.

    abstract：:Amino derivatives of NCI8642 were synthesized and evaluated as inhibitors of DKK1/LRP6 interactions. The new inhibitors were able to activate the Wnt signaling pathway as indicated by the increased levels of β-catenin, and decrease the DKK1-induced Tau phosphorylation at serine 396. ...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2016.01.025

    authors： Thysiadis S,Mpousis S,Avramidis N,Katsamakas S,Balomenos A,Remelli R,Efthimiopoulos S,Sarli V

    更新日期：2016-03-01 00:00:00

  • Chemical and enzymatic synthesis of fructose analogues as probes for import studies by the hexose transporter in parasites.

    abstract：:Various D-fructose analogues modified at C-1 or C-6 positions were synthesized from D-glucose by taking advantage of the Amadori rearrangement or using the aldol condensation between dihydroxyacetone phosphate and appropriate aldehyde catalyzed by fructose 1,6-diphosphate aldolase from rabbit muscle. The affinities of...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/s0968-0896(00)00018-3

    authors： Azéma L,Bringaud F,Blonski C,Périé J

    更新日期：2000-04-01 00:00:00

  • General synthesis and biological evaluation of alpha-1-C-substituted derivatives of fagomine (2-deoxynojirimycin-alpha-C-glycosides).

    abstract：:A general synthesis of alpha-1-C-substituted derivatives of fagomine (2-deoxynojirimycin-alpha-C-glycosides) by ring-opening reactions of an aziridine with various heteroatomic nucleophiles, including thiol, amine, alcohol, carboxylate and phosphate, is described. The nine-step reaction sequence proceeded in an overal...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2004.12.043

    authors： Goujon JY,Gueyrard D,Compain P,Martin OR,Ikeda K,Kato A,Asano N

    更新日期：2005-03-15 00:00:00

  • Studies on anti-HIV quinolones: new insights on the C-6 position.

    abstract：:The 6-desfluoroquinolones which have been developed by our group represent a promising class of compounds for the treatment of HIV infection since they act on transcriptional regulation, a crucial step in the replication cycle that has not been clinically exploited, yet. Focussing attention on the N-1 and C-6 position...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2008.11.056

    authors： Massari S,Daelemans D,Manfroni G,Sabatini S,Tabarrini O,Pannecouque C,Cecchetti V

    更新日期：2009-01-15 00:00:00

  • Synthesis of 4-substituted nipecotic acid derivatives and their evaluation as potential GABA uptake inhibitors.

    abstract：:In this study, we disclose the design and synthesis of novel 4-susbtituted nipecotic acid derivatives as inhibitors of the GABA transporter mGAT1. Based on molecular modeling studies the compounds are assumed to adopt a binding pose similar to that of the potent mGAT1 inhibitor nipecotic acid. As substitution in 4-pos...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2016.03.038

    authors： Hellenbrand T,Höfner G,Wein T,Wanner KT

    更新日期：2016-05-01 00:00:00

  • No carrier added synthesis of O-(2'-[18F]fluoroethyl)-L-tyrosine via a novel type of chiral enantiomerically pure precursor, NiII complex of a (S)-tyrosine Schiff base.

    abstract：:O-(2'-[(18)F]fluoroethyl)-l-tyrosine ([(18)F]FET) has gained much attention as a promising amino acid radiotracer for tumor imaging with positron emission tomography (PET) due to favorable imaging characteristics and relatively long half-life of (18)F (110min) allowing remote-site application. Here we present a novel ...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2008.03.040

    authors： Krasikova RN,Kuznetsova OF,Fedorova OS,Maleev VI,Saveleva TF,Belokon YN

    更新日期：2008-05-01 00:00:00

  • Synthesis, tuberculosis inhibitory activity, and SAR study of N-substituted-phenyl-1,2,3-triazole derivatives.

    abstract：:The aim of this work was to describe the synthesis, the in vitro anti-Mycobacterium tuberculosis profile, and the structure-activity relationship (SAR) study of new N-substituted-phenyl-1,2,3-triazole-4-carbaldehydes (3a-l). The reactions of aromatic amine hydrochlorides with diazomalonaldehyde (1) produced several N-...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2006.08.019

    authors： Costa MS,Boechat N,Rangel EA,da Silva Fde C,de Souza AM,Rodrigues CR,Castro HC,Junior IN,Lourenço MC,Wardell SM,Ferreira VF

    更新日期：2006-12-15 00:00:00

  • Screening helix-threading peptides for RNA binding using a thiazole orange displacement assay.

    abstract：:The fluorescent intercalator displacement assay using thiazole orange has been adapted to the study of RNA-binding helix-threading peptides (HTPs). This assay is highly sensitive with HTP-binding RNAs and provides binding affinity data in good agreement with quantitative ribonuclease footprinting without the need for ...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2008.08.066

    authors： Krishnamurthy M,Schirle NT,Beal PA

    更新日期：2008-10-01 00:00:00

  • Characterization and in vitro activity of a branched peptide boronic acid that interacts with HIV-1 RRE RNA.

    abstract：:A branched peptide containing multiple boronic acids was found to bind RRE IIB selectively and inhibit HIV-1 p24 capsid production in a dose-dependent manner. Structure-activity relationship studies revealed that branching in the peptide is crucial for the low micromolar binding towards RRE IIB, and the peptide demons...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2016.04.009

    authors： Wynn JE,Zhang W,Tebit DM,Gray LR,Hammarskjold ML,Rekosh D,Santos WL

    更新日期：2016-09-01 00:00:00

  • Design and synthesis of silicon-containing tubulin polymerization inhibitors: replacement of the ethylene moiety of combretastatin A-4 with a silicon linker.

    abstract：:Silicon-containing combretastatin analogs were designed, synthesized and evaluated for stability and biological activities. Among them, compound 31 exhibited strong tubulin polymerization-inhibitory activity and very potent tumor cell growth-inhibitory activity (IC50=0.007 μM) in MCF-7 cell proliferation assay. This c...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2013.09.046

    authors： Nakamura M,Kajita D,Matsumoto Y,Hashimoto Y

    更新日期：2013-12-01 00:00:00

  • Isolation of antiplasmodial anthraquinones from Kniphofia ensifolia, and synthesis and structure-activity relationships of related compounds.

    abstract：:Bioassay-guided separation of the South African plant Kniphofia ensifolia for antiplasmodial activity led to the isolation of two new anthraquinones, named kniphofiones A and B (3 and 4), together with three known bioactive anthraquinone monomers (1, 2 and 5), and four known bisanthraquinones (6-9). The structures of ...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2013.11.032

    authors： Dai Y,Harinantenaina L,Bowman JD,Da Fonseca IO,Brodie PJ,Goetz M,Cassera MB,Kingston DG

    更新日期：2014-01-01 00:00:00

  • Structural optimization of a retrograde trafficking inhibitor that protects cells from infections by human polyoma- and papillomaviruses.

    abstract：:Human polyoma- and papillomaviruses are non-enveloped DNA viruses that cause severe pathologies and mortalities. Under circumstances of immunosuppression, JC polyomavirus causes a fatal demyelinating disease called progressive multifocal leukoencephalopathy (PML) and the BK polyomavirus is the etiological agent of pol...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2014.06.053

    authors： Carney DW,Nelson CD,Ferris BD,Stevens JP,Lipovsky A,Kazakov T,DiMaio D,Atwood WJ,Sello JK

    更新日期：2014-09-01 00:00:00

  • Kinetic controlled affinity labeling of target enzyme with thioester chemistry.

    abstract：:High specificity has been an important feature in affinity labeling for target profiling. Especially, to label targets via rapidly progressing reactions with consumption of ligand (probe), high specificity of reaction with common functional groups of target protein should be achieved without reactions with similar gro...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2016.05.059

    authors： Tomohiro T,Nakabayashi M,Sugita Y,Morimoto S

    更新日期：2016-08-01 00:00:00

  • Bromo-deaza-SAH: a potent and selective DOT1L inhibitor.

    abstract：:Chemical inhibition of proteins involved in chromatin-mediated signaling is an emerging strategy to control chromatin compaction with the aim to reprogram expression networks to alter disease states. Protein methyltransferases constitute one of the protein families that participate in epigenetic control of gene expres...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2013.01.049

    authors： Yu W,Smil D,Li F,Tempel W,Fedorov O,Nguyen KT,Bolshan Y,Al-Awar R,Knapp S,Arrowsmith CH,Vedadi M,Brown PJ,Schapira M

    更新日期：2013-04-01 00:00:00

  • Design, synthesis and biological evaluation of novel hydroxamic acid based histone deacetylase 6 selective inhibitors bearing phenylpyrazol scaffold as surface recognition motif.

    abstract：:In recent years, inhibition of HDAC6 became a promising therapeutic strategy for the treatment of cancer and HDAC6 inhibitors were considered to be potent anti-cancer agents. In this work, celecoxib showed moderate degree of HDAC6 inhibition activity and selectivity in preliminary enzyme inhibition activity assay. A s...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2017.08.029

    authors： Yang J,Cheng G,Xu Q,Luan S,Wang S,Liu D,Zhao L

    更新日期：2018-05-01 00:00:00

  • Synthesis of both enantiomers of hydroxypipecolic acid derivatives equivalent to 5-azapyranuronic acids and evaluation of their inhibitory activities against glycosidases.

    abstract：:We have synthesized 3-hydroxy- and 3,4,5-trihydroxypipecolic acid derivatives corresponding to 5-aza derivatives of uronic acids and evaluated their inhibitory activities against various glycosidases including beta-glucuronidase. Compounds 4 and 5 were chosen as common intermediates for the synthesis of 3,4,5-trihydro...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2008.06.016

    authors： Yoshimura Y,Ohara C,Imahori T,Saito Y,Kato A,Miyauchi S,Adachi I,Takahata H

    更新日期：2008-09-01 00:00:00

  • ORL1 and opioid receptor preferences of nociceptin and dynorphin A analogues with Dmp substituted for N-terminal aromatic residues.

    abstract：:Nociceptin (NOC) and dynorphin A (DYN) analogues containing 2',6'-dimethylphenylalanine (Dmp) in place of Phe or Tyr in position 1 and/or 4 were synthesized and their metabolic stability and receptor-binding properties were investigated. [Dmp1]NOC(1-13)-NH2 (1) possessed high ORL1 receptor affinity comparable to that ...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2005.11.021

    authors： Sasaki Y,Kawano S,Kohara H,Watanabe H,Ambo A

    更新日期：2006-04-01 00:00:00

  • Binding ability of a thymine-functionalized oligolysine towards nucleic acids.

    abstract：:In this Letter, we investigated the binding properties towards nucleic acids of a thymine-functionalized oligolysine, composed of nucleobase-bearing amino acid moieties and underivatized l-lysine residues alternate in the backbone. The basic nucleopeptide proved to be well soluble in water and able to interact with bo...

    journal_title：Bioorganic & medicinal chemistry

    pub_type： 杂志文章

    doi：10.1016/j.bmc.2013.12.053

    authors： Roviello GN,Musumeci D,D'Alessandro C,Pedone C

    更新日期：2014-02-01 00:00:00