Selective inhibition of β-N-acetylhexosaminidases by thioglycosyl-naphthalimide hybrid molecules.

Abstract:

:To develop selective inhibitors for β-N-acetylhexosaminidases which are involved in a myriad of physiological processes, a series of novel thioglycosyl-naphthalimide hybrid inhibitors were designed, synthesized and evaluated for inhibition activity against glycosyl hydrolase family 20 and 84 (GH20 and GH84) β-N-acetylhexosaminidases. These compounds which incorporate groups with varied sizes and lengths at the linker region between thioglycosyl moiety and naphthalimide moiety are designed to improve the selectivity and stacking interactions. The GH84 human O-GlcNAcase (hOGA) was sensitive to the subtle changes in the linker region and the optimal choice is a small size linker with six atoms length. And the GH20 insect β-N-acetylhexosaminidase OfHex1 could tolerate compounds with a hydrophobic bulky linker. Especially, the compound 5c (hOGA, Ki = 3.46 μM; OfHex1, Ki > 200 μM) and the compound 6f (hOGA, Ki > 200 μM; OfHex1, Ki = 21.81 μM) displayed high selectivity. The molecular docking results indicated that the inhibition mechanism was different between the two families due to their different structural characteristics beyond the active sites. These results provide some promising clues to improve selectivity of potent molecules against β-N-acetylhexosaminidases.

journal_name

Bioorg Med Chem

authors

Chen W,Shen S,Dong L,Zhang J,Yang Q

doi

10.1016/j.bmc.2017.11.042

subject

Has Abstract

pub_date

2018-01-15 00:00:00

pages

394-400

issue

2

eissn

0968-0896

issn

1464-3391

pii

S0968-0896(17)31801-1

journal_volume

26

pub_type

杂志文章
  • Engineered production of cancer targeting peptide (CTP)-containing C-1027 in Streptomyces globisporus and biological evaluation.

    abstract::Conjugation of cancer targeting peptides (CTPs) with small molecular therapeutics has emerged as a promising strategy to deliver potent (but typically nonspecific) cytotoxic agents selectively to cancer cells. Here we report the engineered production of a CTP (NGR)-containing C-1027 and evaluation of its activity agai...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bmc.2016.04.017

    authors: Li W,Li X,Huang T,Teng Q,Crnovcic I,Rader C,Shen B

    更新日期:2016-09-01 00:00:00

  • Novel hexadentate and pentadentate chelators for ⁶⁴Cu-based targeted PET imaging.

    abstract::A series of new hexadentate and pentadentate chelators were designed and synthesized as chelators of (64)Cu. The new pentadentate and hexadentate chelators contain different types of donor groups and are expected to form neutral complexes with Cu(II). The new chelators were evaluated for complex kinetics and stability...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bmc.2014.02.041

    authors: Sin I,Kang CS,Bandara N,Sun X,Zhong Y,Rogers BE,Chong HS

    更新日期:2014-04-15 00:00:00

  • Anti-inflammatory properties of a heparin-like glycosaminoglycan with reduced anti-coagulant activity isolated from a marine shrimp.

    abstract::The anti-inflammatory properties of a heparin-like compound from the shrimp Litopenaeus vannamei are related. Besides reducing significantly (p<0.001) the influx of inflammatory cells to injury site in a model of acute inflammation, shrimp heparin-like compound was able to reduce the matrix metalloproteinase (MMPs) ac...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bmc.2008.09.020

    authors: Brito AS,Arimatéia DS,Souza LR,Lima MA,Santos VO,Medeiros VP,Ferreira PA,Silva RA,Ferreira CV,Justo GZ,Leite EL,Andrade GP,Oliveira FW,Nader HB,Chavante SF

    更新日期:2008-11-01 00:00:00

  • Structure-activity relationships of amide-phosphonate derivatives as inhibitors of the human soluble epoxide hydrolase.

    abstract::Structure-activity relationships of amide-phosphonate derivatives as inhibitors of the human soluble epoxide hydrolase (sEH) were investigated. First, a series of alkyl or aryl groups were substituted on the carbon alpha to the phosphonate function in amide compounds to see whether substituted phosphonates can act as ...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bmc.2015.10.016

    authors: Kim IH,Park YK,Nishiwaki H,Hammock BD,Nishi K

    更新日期:2015-11-15 00:00:00

  • Synthesis of benzoxazole derivatives as interleukin-6 antagonists.

    abstract::A growing number of studies have demonstrated that interleukin (IL)-6 plays pathological roles in the development of chronic inflammatory disease and autoimmune disease by activating innate immune cells and by stimulating adaptive inflammatory T cells. So, suppression of IL-6 function may be beneficial for prevention ...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bmc.2017.03.072

    authors: Kim D,Won HY,Hwang ES,Kim YK,Choo HP

    更新日期:2017-06-15 00:00:00

  • Identification of novel benzimidazole derivatives as inhibitors of leukotriene biosynthesis by virtual screening targeting 5-lipoxygenase-activating protein (FLAP).

    abstract::Pharmacological suppression of leukotriene biosynthesis by 5-lipoxygenase (5-LO)-activating protein (FLAP) inhibitors is a promising strategy to intervene with inflammatory, allergic and cardiovascular diseases. Virtual screening targeting FLAP based on a combined ligand- and structure-based pharmacophore model led to...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bmc.2012.04.048

    authors: Banoglu E,Çalişkan B,Luderer S,Eren G,Özkan Y,Altenhofen W,Weinigel C,Barz D,Gerstmeier J,Pergola C,Werz O

    更新日期:2012-06-15 00:00:00

  • Design, synthesis, and activity of caffeoyl pyrrolidine derivatives as potential gelatinase inhibitors.

    abstract::The synthesis and biological evaluation of caffonyl pyrrolidine derivatives as MMPs inhibitors are reported in this paper. Inhibiting activities of synthesized compounds on gelatinase (MMP-2 and -9) were tested by using succinylated gelatin as substrate. Structure-activity relationship results from these tested compou...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bmc.2004.07.025

    authors: Li YL,Xu WF

    更新日期:2004-10-01 00:00:00

  • Design and synthesis of labeled analogs of PhTX-56, a potent and selective AMPA receptor antagonist.

    abstract::Polyamines and polyamine toxins are biologically important molecules, having modulatory effects on nucleotides and proteins. The wasp toxin, philanthotoxin-433 (PhTX-433), is a non-selective and uncompetitive antagonist of ionotropic receptors, such as ionotropic glutamate receptors and nicotinic acetylcholine recepto...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bmc.2005.05.023

    authors: Andersen TF,Vogensen SB,Jensen LS,Knapp KM,Strømgaard K

    更新日期:2005-09-01 00:00:00

  • Exogenous fluorescent tracer agents based on pegylated pyrazine dyes for real-time point-of-care measurement of glomerular filtration rate.

    abstract::Novel pyrazine carboxamides bearing hydrophilic poly(ethylene glycol) (PEG) moieties were designed, synthesized, and evaluated for use as fluorescent glomerular filtration rate (GFR) tracer agents. Among these, compounds 4d and 5c that contain about 48 ethylene oxide units in the PEG chain exhibited the most favorable...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bmc.2012.03.015

    authors: Poreddy AR,Neumann WL,Freskos JN,Rajagopalan R,Asmelash B,Gaston KR,Fitch RM,Galen KP,Shieh JJ,Dorshow RB

    更新日期:2012-04-15 00:00:00

  • NO-glibenclamide derivatives: prototypes of a new class of nitric oxide-releasing anti-diabetic drugs.

    abstract::Endothelial dysfunction and consequent reduction of biosynthesis of endogenous nitric oxide (NO) play an important pathogenetic role in the cardiovascular complications associated with type II diabetes. In this work, the hybrid drugs 3a and 3b, nitrooxymethylbenzoate-derivatives of 1 (which is a hydroxylated active me...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bmc.2009.06.049

    authors: Calderone V,Rapposelli S,Martelli A,Digiacomo M,Testai L,Torri S,Marchetti P,Breschi MC,Balsamo A

    更新日期:2009-08-01 00:00:00

  • Prospects of PASylation® for the design of protein and peptide therapeutics with extended half-life and enhanced action.

    abstract::Pharmacokinetic (PK) extension is no longer just a means to create improved second generation biologics (so-called biobetters), but constitutes an accepted strategy in biopharmaceutical drug development today. Although PEGylation has become a widely applied methodology to furnish therapeutic proteins and peptides with...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bmc.2017.09.016

    authors: Gebauer M,Skerra A

    更新日期:2018-06-01 00:00:00

  • Identification and development of the 1,4-benzodiazepin-2-one and quinazoline-2,4-dione scaffolds as submicromolar inhibitors of HAT.

    abstract::A library of 1,4-benzodiazepines has been synthesised and evaluated for activity against Trypanosoma brucei, a causative parasite of Human African Trypanosomiasis (HAT). The most potent of these derivatives has an MIC value of 0.97 μM. Herein we report the design, synthesis and biological evaluation of the abovementio...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bmc.2012.08.049

    authors: Clark RL,Clements CJ,Barrett MP,Mackay SP,Rathnam RP,Owusu-Dapaah G,Spencer J,Huggan JK

    更新日期:2012-10-15 00:00:00

  • Second-generation aryl isonitrile compounds targeting multidrug-resistant Staphylococcus aureus.

    abstract::Antibiotic resistance remains a major global public health threat that requires sustained discovery of novel antibacterial agents with unexploited scaffolds. Structure-activity relationship of the first-generation aryl isonitrile compounds we synthesized led to an initial lead molecule that informed the synthesis of a...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bmc.2019.03.034

    authors: Kyei-Baffour K,Mohammad H,Seleem MN,Dai M

    更新日期:2019-05-01 00:00:00

  • New sensible method to quantize the intestinal absorption of receptor ligands.

    abstract::In recent years, special attention has been paid to the A3 adenosine receptor (A3AR) as a possible pharmacological target to treat intestinal inflammation. In this work, it was set up a novel method to quantify the concentration of a promising anti-inflammatory agent inside and outside of intestinal barrier using the ...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bmc.2019.06.011

    authors: Buccioni M,Dal Ben D,Lambertucci C,Martí Navia A,Ricciutelli M,Spinaci A,Volpini R,Marucci G

    更新日期:2019-08-01 00:00:00

  • Preclinical evaluation of a CXCR4-specific (68)Ga-labelled TN14003 derivative for cancer PET imaging.

    abstract::Molecular imaging is an ideal platform for non-invasive detection and assessment of cancer. In recent years, the targeted imaging of CXCR4, a chemokine receptor that has been associated with tumour metastasis, has become an area of intensive research. In our pursuit of a CXCR4-specific radiotracer, we designed and syn...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bmc.2013.12.012

    authors: George GP,Stevens E,Åberg O,Nguyen QD,Pisaneschi F,Spivey AC,Aboagye EO

    更新日期:2014-01-15 00:00:00

  • Synthesis and insecticidal activity of chromanone and chromone analogues of diacylhydrazines.

    abstract::Diacylhydrazine derivatives have been identified as one of the most important insect growth regulators. A variety of diacylhydrazine derivatives were designed and synthesized in recent years due to their unique action mechanism, simple structure, and environmental benign character. This paper describes the molecular d...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bmc.2007.01.008

    authors: Zhao PL,Li J,Yang GF

    更新日期:2007-03-01 00:00:00

  • Asymmetric reduction of 3-aryl-3-keto esters using Rhizopus species.

    abstract::Ethyl 3-aryl-3-oxopropanoates (aryl: phenyl, 2-fluorophenyl, 3-nitrophenyl, and 4-nitrophenyl) were reduced enantioselectively to the corresponding (S)-alcohols by the fungus Rhizopus arrhizus and other Rhizopus sp. The best results were generally obtained with Rhizopus arrhizus (wild type) and Rhizopus nivius NCIM 95...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bmc.2006.03.025

    authors: Salvi NA,Chattopadhyay S

    更新日期:2006-07-15 00:00:00

  • Structure based drug design and in vitro metabolism study: Discovery of N-(4-methylthiophenyl)-N,2-dimethyl-cyclopenta[d]pyrimidine as a potent microtubule targeting agent.

    abstract::We report a series of tubulin targeting agents, some of which demonstrate potent antiproliferative activities. These analogs were designed to optimize the antiproliferative activity of 1 by varying the heteroatom substituent at the 4'-position, the basicity of the 4-position amino moiety, and conformational restrictio...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bmc.2018.04.010

    authors: Xiang W,Choudhary S,Hamel E,Mooberry SL,Gangjee A

    更新日期:2018-05-15 00:00:00

  • 7alpha- and 17alpha-substituted estrogens containing tridentate tricarbonyl rhenium/technetium complexes: synthesis of estrogen receptor imaging agents and evaluation using microPET with technetium-94m.

    abstract::To develop technetium and rhenium-labeled imaging agents for estrogen receptor (ER) positive breast tumors, we have prepared tridentate metal tricarbonyl chelates substituted at the 7alpha- and 17alpha-positions of estradiol. Some of the Re(CO)(3) conjugates have high binding for the ER in vitro. The in vivo biodistri...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bmc.2003.09.004

    authors: Luyt LG,Bigott HM,Welch MJ,Katzenellenbogen JA

    更新日期:2003-11-17 00:00:00

  • Design, synthesis and evaluation of flavonoid derivatives as potent AChE inhibitors.

    abstract::A new series of flavonoid derivatives have been designed, synthesized and evaluated as potent AChE inhibitors. Most of them showed more potent inhibitory activities to AChE than rivastigmine. The most potent inhibitor isoflavone derivative 10d inhibit AChE with a IC(50) of 4 nM and showed high BChE/AChE inhibition rat...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bmc.2009.07.072

    authors: Sheng R,Lin X,Zhang J,Chol KS,Huang W,Yang B,He Q,Hu Y

    更新日期:2009-09-15 00:00:00

  • Antimicrobial and cytotoxic arylazoenamines. Part III: antiviral activity of selected classes of arylazoenamines.

    abstract::Eighty-five arylazoenamines, characterized by different types of aryl and basic moieties, have been synthesized and evaluated in cell-based assays for cytotoxicity and antiviral activity against a panel of ten RNA and DNA viruses. The most commonly affected viruses were, in decreasing order, CVB-2, RSV, BVDV, YFV, and...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bmc.2008.08.028

    authors: Tonelli M,Boido V,Canu C,Sparatore A,Sparatore F,Paneni MS,Fermeglia M,Pricl S,La Colla P,Casula L,Ibba C,Collu D,Loddo R

    更新日期:2008-09-15 00:00:00

  • Cell-based biological evaluations of 5-(3-bromo-4-phenethoxybenzylidene)thiazolidine-2,4-dione as promising wound healing agent.

    abstract::Recent studies have focused on prostaglandin E₂ (PGE₂) because PGE₂ regulates vertebrate hematopoietic stem cell induction and engraftment. PGE₂ acts through EP2 and EP4 receptors to mediate regeneration and hematopoietic stem cell (HSC) development via the Wnt signaling pathway. Previously we reported that inhibitors...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bmc.2015.03.010

    authors: Piao YL,Ram Song A,Cho H

    更新日期:2015-05-01 00:00:00

  • Novel fluorescent markers for hypoxic cells of naphthalimides with two heterocyclic side chains for bioreductive binding.

    abstract::Novel naphthalimides with two heterocyclic side chains of 2-nitroimidazole for bioreductive binding were designed, synthesized, and used as fluorescent markers for hypoxic cells. Their evaluation for imaging tumor hypoxia was carried out in V79 cells, CHO cells, and 95D cells in vitro by using fluorescence scan ascent...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bmc.2005.12.012

    authors: Liu Y,Xu Y,Qian X,Liu J,Shen L,Li J,Zhang Y

    更新日期:2006-05-01 00:00:00

  • Novel 6-hydroxy-3-morpholinones as cornea permeable calpain inhibitors.

    abstract::A novel series of 6-hydroxy-3-morpholinones, in which the functional aldehyde and the hydroxy group of P(2) site form a cyclic hemiacetal, was identified as calpain inhibitors. The placement of isobutyl group at the 2-position of the 3-morpholinone was the most effective modification for inhibiting micro- and m-calpai...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bmc.2003.09.031

    authors: Nakamura M,Miyashita H,Yamaguchi M,Shirasaki Y,Nakamura Y,Inoue J

    更新日期:2003-12-01 00:00:00

  • Analysis of the binding specificities of oligomannoside-binding proteins using methylated monosaccharides.

    abstract::The binding specificities of the closely related lectins from Canavalia ensiformis and Dioclea grandiflora were examined using specifically O-alkylated mono- and disaccharides. Both lectins accept any substitution at the monosaccharide C2 hydroxyl group. The binding energy of C2-alkylated ligands-concanavalin A comple...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/s0968-0896(96)00178-2

    authors: Chervenak MC,Toone EJ

    更新日期:1996-11-01 00:00:00

  • t-Butyl pyridine and phenyl C-region analogues of 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides as potent TRPV1 antagonists.

    abstract::A series of 2-substituted 6-t-butylpyridine and 4-t-butylphenyl C-region analogues of 2-(3-fluoro-4-methylsulfonamidophenyl)propanamides were investigated for hTRPV1 antagonism. The analysis of structure activity relationships indicated that the pyridine derivatives generally exhibited a little better antagonism than ...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bmc.2017.03.004

    authors: Lee S,Kang DW,Ryu H,Kim C,Ann J,Lee H,Kim E,Hong S,Choi S,Blumberg PM,Frank-Foltyn R,Bahrenberg G,Stockhausen H,Christoph T,Lee J

    更新日期:2017-04-15 00:00:00

  • Solution structure of endothelin B receptor selective antagonist RES-701-1 determined by 1H NMR spectroscopy.

    abstract::The three-dimensional structure of the endothelin B receptor (ETB) selective antagonist RES-701-1 has been determined by 1H NMR in deuterated dimethyl sulphoxide. RES-701-1 consists of 16 amino acid residues with a novel internal linkage between the beta-carboxyl group of Asp9 and the alpha-amino group of Gly1. The st...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/0968-0896(95)00122-w

    authors: Katahira R,Shibata K,Yamasaki M,Matsuda Y,Yoshida M

    更新日期:1995-09-01 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

  • Design, synthesis and antibacterial study of new potent and selective coumarin-chalcone derivatives for the treatment of tenacibaculosis.

    abstract::With the aim of finding new chemical entities selective for fish pathogens to avoid drug resistance in humans, a series of coumarin-chalcone hybrid compounds with different patterns of substitution were designed and synthesized. Their antibacterial activity was evaluated against important types of human bacteria strai...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bmc.2015.09.028

    authors: Vazquez-Rodriguez S,Lama López R,Matos MJ,Armesto-Quintas G,Serra S,Uriarte E,Santana L,Borges F,Muñoz Crego A,Santos Y

    更新日期:2015-11-01 00:00:00

  • Actin-binding doliculide causes premature senescence in p53 wild type cells.

    abstract::Addressing the actin cytoskeleton as future anticancer target can be an innovative chemotherapeutic approach to combat malignancies. Doliculide is a potent stabilizer of actin filaments and can be used as tool and therapeutic lead in cancer research. Though a variety of molecules are known to bind to actin and lead to...

    journal_title:Bioorganic & medicinal chemistry

    pub_type: 杂志文章

    doi:10.1016/j.bmc.2015.11.042

    authors: Foerster F,Chen T,Altmann KH,Vollmar AM

    更新日期:2016-01-15 00:00:00