Detail
Article
Online article
FT
Medvik - BMC
  • Something wrong with this record ?

2-Acetamido-2-deoxy-d-glucono-1,5-lactone Sulfonylhydrazones: Synthesis and Evaluation as Inhibitors of Human OGA and HexB Enzymes

M. Kiss, I. Timári, T. Barna, Z. Mészáros, K. Slámová, P. Bojarová, V. Křen, JM. Hayes, L. Somsák

. 2022 ; 23 (3) : . [pub] 20220118

Language English Country Switzerland

Document type Journal Article

Persistent link   https://www.medvik.cz/link/bmc22011301

Grant support
K 109450, FK-125067, PD 135034 National Research, Development and Innovation Office of Hungary
GINOP-2.3.2-15-2016-00008, GINOP-2.3.3-15-2016-00004 European Union
21-01948L Czech Science Foundation
CA18132 GlycoNanoBio European Cooperation in Science and Technology
BO/00372/20/7 Hungarian Academy of Sciences
ÚNKP-21-5-DE-471 New National Excellence Program of the Ministry for Innovation and Technology in Hungary

Inhibition of the human O-linked β-N-acetylglucosaminidase (hOGA, GH84) enzyme is pharmacologically relevant in several diseases such as neurodegenerative and cardiovascular disorders, type 2 diabetes, and cancer. Human lysosomal hexosaminidases (hHexA and hHexB, GH20) are mechanistically related enzymes; therefore, selective inhibition of these enzymes is crucial in terms of potential applications. In order to extend the structure-activity relationships of OGA inhibitors, a series of 2-acetamido-2-deoxy-d-glucono-1,5-lactone sulfonylhydrazones was prepared from d-glucosamine. The synthetic sequence involved condensation of N-acetyl-3,4,6-tri-O-acetyl-d-glucosamine with arenesulfonylhydrazines, followed by MnO2 oxidation to the corresponding glucono-1,5-lactone sulfonylhydrazones. Removal of the O-acetyl protecting groups by NH3/MeOH furnished the test compounds. Evaluation of these compounds by enzyme kinetic methods against hOGA and hHexB revealed potent nanomolar competitive inhibition of both enzymes, with no significant selectivity towards either. The most efficient inhibitor of hOGA was 2-acetamido-2-deoxy-d-glucono-1,5-lactone 1-naphthalenesulfonylhydrazone (5f, Ki = 27 nM). This compound had a Ki of 6.8 nM towards hHexB. To assess the binding mode of these inhibitors to hOGA, computational studies (Prime protein-ligand refinement and QM/MM optimizations) were performed, which suggested the binding preference of the glucono-1,5-lactone sulfonylhydrazones in an s-cis conformation for all test compounds.

References provided by Crossref.org

000      
00000naa a2200000 a 4500
001      
bmc22011301
003      
CZ-PrNML
005      
20220506130933.0
007      
ta
008      
220425s2022 sz f 000 0|eng||
009      
AR
024    7_
$a 10.3390/ijms23031037 $2 doi
035    __
$a (PubMed)35162960
040    __
$a ABA008 $b cze $d ABA008 $e AACR2
041    0_
$a eng
044    __
$a sz
100    1_
$a Kiss, Mariann $u Department of Organic Chemistry, University of Debrecen, POB 400, H-4002 Debrecen, Hungary
245    10
$a 2-Acetamido-2-deoxy-d-glucono-1,5-lactone Sulfonylhydrazones: Synthesis and Evaluation as Inhibitors of Human OGA and HexB Enzymes / $c M. Kiss, I. Timári, T. Barna, Z. Mészáros, K. Slámová, P. Bojarová, V. Křen, JM. Hayes, L. Somsák
520    9_
$a Inhibition of the human O-linked β-N-acetylglucosaminidase (hOGA, GH84) enzyme is pharmacologically relevant in several diseases such as neurodegenerative and cardiovascular disorders, type 2 diabetes, and cancer. Human lysosomal hexosaminidases (hHexA and hHexB, GH20) are mechanistically related enzymes; therefore, selective inhibition of these enzymes is crucial in terms of potential applications. In order to extend the structure-activity relationships of OGA inhibitors, a series of 2-acetamido-2-deoxy-d-glucono-1,5-lactone sulfonylhydrazones was prepared from d-glucosamine. The synthetic sequence involved condensation of N-acetyl-3,4,6-tri-O-acetyl-d-glucosamine with arenesulfonylhydrazines, followed by MnO2 oxidation to the corresponding glucono-1,5-lactone sulfonylhydrazones. Removal of the O-acetyl protecting groups by NH3/MeOH furnished the test compounds. Evaluation of these compounds by enzyme kinetic methods against hOGA and hHexB revealed potent nanomolar competitive inhibition of both enzymes, with no significant selectivity towards either. The most efficient inhibitor of hOGA was 2-acetamido-2-deoxy-d-glucono-1,5-lactone 1-naphthalenesulfonylhydrazone (5f, Ki = 27 nM). This compound had a Ki of 6.8 nM towards hHexB. To assess the binding mode of these inhibitors to hOGA, computational studies (Prime protein-ligand refinement and QM/MM optimizations) were performed, which suggested the binding preference of the glucono-1,5-lactone sulfonylhydrazones in an s-cis conformation for all test compounds.
650    _2
$a antigeny nádorové $x chemie $x metabolismus $7 D000951
650    _2
$a inhibitory enzymů $x chemická syntéza $x chemie $x farmakologie $7 D004791
650    _2
$a histonacetyltransferasy $x chemie $x metabolismus $7 D051548
650    _2
$a lidé $7 D006801
650    _2
$a hyaluronoglukosaminidasa $x chemie $x metabolismus $7 D006821
650    _2
$a hydrazony $x chemická syntéza $x chemie $x farmakologie $7 D006835
650    _2
$a laktony $x chemie $7 D007783
650    _2
$a sloučeniny manganu $x chemie $7 D017895
650    _2
$a molekulární modely $7 D008958
650    _2
$a molekulární konformace $7 D008968
650    _2
$a oxidy $x chemie $7 D010087
650    _2
$a vztahy mezi strukturou a aktivitou $7 D013329
650    _2
$a beta-hexosaminidasa, beta řetězec $x chemie $x metabolismus $7 D054821
655    _2
$a časopisecké články $7 D016428
700    1_
$a Timári, István $u Department of Organic Chemistry, University of Debrecen, POB 400, H-4002 Debrecen, Hungary
700    1_
$a Barna, Teréz $u Department of Genetics and Applied Microbiology, University of Debrecen, POB 400, H-4002 Debrecen, Hungary
700    1_
$a Mészáros, Zuzana $u Laboratory of Biotransformation, Institute of Microbiology of the Czech Academy of Sciences, Vídeňská 1083, CZ-14220 Praha 4, Czech Republic $u Faculty of Food and Biochemical Technology, University of Chemistry and Technology Prague, Technická 1903/3, CZ-16628 Praha 6, Czech Republic
700    1_
$a Slámová, Kristýna $u Laboratory of Biotransformation, Institute of Microbiology of the Czech Academy of Sciences, Vídeňská 1083, CZ-14220 Praha 4, Czech Republic
700    1_
$a Bojarová, Pavla $u Laboratory of Biotransformation, Institute of Microbiology of the Czech Academy of Sciences, Vídeňská 1083, CZ-14220 Praha 4, Czech Republic $1 https://orcid.org/0000000170690973 $7 xx0122667
700    1_
$a Křen, Vladimír $u Laboratory of Biotransformation, Institute of Microbiology of the Czech Academy of Sciences, Vídeňská 1083, CZ-14220 Praha 4, Czech Republic $1 https://orcid.org/0000000210914020 $7 xx0070803
700    1_
$a Hayes, Joseph M $u School of Pharmacy & Biomedical Sciences, University of Central Lancashire, Preston PR1 2HE, UK $1 https://orcid.org/0000000277459616
700    1_
$a Somsák, László $u Department of Organic Chemistry, University of Debrecen, POB 400, H-4002 Debrecen, Hungary $1 https://orcid.org/0000000291039845
773    0_
$w MED00176142 $t International journal of molecular sciences $x 1422-0067 $g Roč. 23, č. 3 (2022)
856    41
$u https://pubmed.ncbi.nlm.nih.gov/35162960 $y Pubmed
910    __
$a ABA008 $b sig $c sign $y p $z 0
990    __
$a 20220425 $b ABA008
991    __
$a 20220506130926 $b ABA008
999    __
$a ok $b bmc $g 1789072 $s 1162499
BAS    __
$a 3
BAS    __
$a PreBMC
BMC    __
$a 2022 $b 23 $c 3 $e 20220118 $i 1422-0067 $m International journal of molecular sciences $n Int J Mol Sci $x MED00176142
GRA    __
$a K 109450, FK-125067, PD 135034 $p National Research, Development and Innovation Office of Hungary
GRA    __
$a GINOP-2.3.2-15-2016-00008, GINOP-2.3.3-15-2016-00004 $p European Union
GRA    __
$a 21-01948L $p Czech Science Foundation
GRA    __
$a CA18132 GlycoNanoBio $p European Cooperation in Science and Technology
GRA    __
$a BO/00372/20/7 $p Hungarian Academy of Sciences
GRA    __
$a ÚNKP-21-5-DE-471 $p New National Excellence Program of the Ministry for Innovation and Technology in Hungary
LZP    __
$a Pubmed-20220425

Find record

Citation metrics

Archiving options