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

Synthesis, Molecular Docking and Biological Characterization of Pyrazine Linked 2-Aminobenzamides as New Class I Selective Histone Deacetylase (HDAC) Inhibitors with Anti-Leukemic Activity

HS. Ibrahim, M. Abdelsalam, Y. Zeyn, M. Zessin, AM. Mustafa, MA. Fischer, P. Zeyen, P. Sun, EF. Bülbül, A. Vecchio, F. Erdmann, M. Schmidt, D. Robaa, C. Barinka, C. Romier, M. Schutkowski, OH. Krämer, W. Sippl

. 2021 ; 23 (1) : . [pub] 20211229

Language English Country Switzerland

Document type Journal Article

Persistent link   https://www.medvik.cz/link/bmc22011621

Grant support
KR2291/12-1, KR2291/8-1, KR2291/9-1, Project-ID 393547839 Deutsche Forschungsgemeinschaft
Project No 65 Brigitte und Dr. Konstanze Wegener-Stiftung
Grant Nr. 2019.086.1 Wilhelm-Sander Foundation

Class I histone deacetylases (HDACs) are key regulators of cell proliferation and they are frequently dysregulated in cancer cells. We report here the synthesis of a novel series of class-I selective HDAC inhibitors (HDACi) containing a 2-aminobenzamide moiety as a zinc-binding group connected with a central (piperazin-1-yl)pyrazine or (piperazin-1-yl)pyrimidine moiety. Some of the compounds were additionally substituted with an aromatic capping group. Compounds were tested in vitro against human HDAC1, 2, 3, and 8 enzymes and compared to reference class I HDACi (Entinostat (MS-275), Mocetinostat, CI994 and RGFP-966). The most promising compounds were found to be highly selective against HDAC1, 2 and 3 over the remaining HDAC subtypes from other classes. Molecular docking studies and MD simulations were performed to rationalize the in vitro data and to deduce a complete structure activity relationship (SAR) analysis of this novel series of class-I HDACi. The most potent compounds, including 19f, which blocks HDAC1, HDAC2, and HDAC3, as well as the selective HDAC1/HDAC2 inhibitors 21a and 29b, were selected for further cellular testing against human acute myeloid leukemia (AML) and erythroleukemic cancer (HEL) cells, taking into consideration their low toxicity against human embryonic HEK293 cells. We found that 19f is superior to the clinically tested class-I HDACi Entinostat (MS-275). Thus, 19f is a new and specific HDACi with the potential to eliminate blood cancer cells of various origins.

References provided by Crossref.org

000      
00000naa a2200000 a 4500
001      
bmc22011621
003      
CZ-PrNML
005      
20220506130924.0
007      
ta
008      
220425s2021 sz f 000 0|eng||
009      
AR
024    7_
$a 10.3390/ijms23010369 $2 doi
035    __
$a (PubMed)35008795
040    __
$a ABA008 $b cze $d ABA008 $e AACR2
041    0_
$a eng
044    __
$a sz
100    1_
$a Ibrahim, Hany S $u Department of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther-University of Halle-Wittenberg, 06120 Halle (Saale), Germany $u Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Egyptian Russian University, Badr City, Cairo 11829, Egypt $1 https://orcid.org/0000000210484059
245    10
$a Synthesis, Molecular Docking and Biological Characterization of Pyrazine Linked 2-Aminobenzamides as New Class I Selective Histone Deacetylase (HDAC) Inhibitors with Anti-Leukemic Activity / $c HS. Ibrahim, M. Abdelsalam, Y. Zeyn, M. Zessin, AM. Mustafa, MA. Fischer, P. Zeyen, P. Sun, EF. Bülbül, A. Vecchio, F. Erdmann, M. Schmidt, D. Robaa, C. Barinka, C. Romier, M. Schutkowski, OH. Krämer, W. Sippl
520    9_
$a Class I histone deacetylases (HDACs) are key regulators of cell proliferation and they are frequently dysregulated in cancer cells. We report here the synthesis of a novel series of class-I selective HDAC inhibitors (HDACi) containing a 2-aminobenzamide moiety as a zinc-binding group connected with a central (piperazin-1-yl)pyrazine or (piperazin-1-yl)pyrimidine moiety. Some of the compounds were additionally substituted with an aromatic capping group. Compounds were tested in vitro against human HDAC1, 2, 3, and 8 enzymes and compared to reference class I HDACi (Entinostat (MS-275), Mocetinostat, CI994 and RGFP-966). The most promising compounds were found to be highly selective against HDAC1, 2 and 3 over the remaining HDAC subtypes from other classes. Molecular docking studies and MD simulations were performed to rationalize the in vitro data and to deduce a complete structure activity relationship (SAR) analysis of this novel series of class-I HDACi. The most potent compounds, including 19f, which blocks HDAC1, HDAC2, and HDAC3, as well as the selective HDAC1/HDAC2 inhibitors 21a and 29b, were selected for further cellular testing against human acute myeloid leukemia (AML) and erythroleukemic cancer (HEL) cells, taking into consideration their low toxicity against human embryonic HEK293 cells. We found that 19f is superior to the clinically tested class-I HDACi Entinostat (MS-275). Thus, 19f is a new and specific HDACi with the potential to eliminate blood cancer cells of various origins.
650    _2
$a protinádorové látky $x chemická syntéza $x chemie $x farmakokinetika $x farmakologie $7 D000970
650    _2
$a benzamidy $x chemická syntéza $x chemie $x farmakologie $7 D001549
650    _2
$a nádorové buněčné linie $7 D045744
650    _2
$a HEK293 buňky $7 D057809
650    _2
$a inhibitory histondeacetylas $x chemická syntéza $x chemie $x farmakokinetika $x farmakologie $7 D056572
650    _2
$a lidé $7 D006801
650    12
$a simulace molekulového dockingu $7 D062105
650    _2
$a protonová magnetická rezonanční spektroskopie $7 D066244
650    _2
$a pyraziny $x chemie $7 D011719
650    _2
$a pyridiny $x chemická syntéza $x chemie $x farmakologie $7 D011725
650    _2
$a ortoaminobenzoáty $x chemická syntéza $x chemie $7 D062367
655    _2
$a časopisecké články $7 D016428
700    1_
$a Abdelsalam, Mohamed $u Department of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther-University of Halle-Wittenberg, 06120 Halle (Saale), Germany $u Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt
700    1_
$a Zeyn, Yanira $u Department of Toxicology, University Medical Center, 55131 Mainz, Germany
700    1_
$a Zessin, Matthes $u Department of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther-University of Halle-Wittenberg, 06120 Halle (Saale), Germany $u Department of Enzymology, Institute of Biochemistry, Martin-Luther-University of Halle-Wittenberg, 06120 Halle (Saale), Germany
700    1_
$a Mustafa, Al-Hassan M $u Department of Toxicology, University Medical Center, 55131 Mainz, Germany $u Department of Zoology, Faculty of Science, Aswan University, Aswan 81528, Egypt $1 https://orcid.org/0000000244532573
700    1_
$a Fischer, Marten A $u Department of Toxicology, University Medical Center, 55131 Mainz, Germany
700    1_
$a Zeyen, Patrik $u Department of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther-University of Halle-Wittenberg, 06120 Halle (Saale), Germany
700    1_
$a Sun, Ping $u Department of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther-University of Halle-Wittenberg, 06120 Halle (Saale), Germany
700    1_
$a Bülbül, Emre F $u Department of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther-University of Halle-Wittenberg, 06120 Halle (Saale), Germany $1 https://orcid.org/0000000299012022
700    1_
$a Vecchio, Anita $u Department of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther-University of Halle-Wittenberg, 06120 Halle (Saale), Germany
700    1_
$a Erdmann, Frank $u Department of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther-University of Halle-Wittenberg, 06120 Halle (Saale), Germany $1 https://orcid.org/0000000152610984
700    1_
$a Schmidt, Matthias $u Department of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther-University of Halle-Wittenberg, 06120 Halle (Saale), Germany $1 https://orcid.org/0000000338762695
700    1_
$a Robaa, Dina $u Department of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther-University of Halle-Wittenberg, 06120 Halle (Saale), Germany
700    1_
$a Barinka, Cyril $u Institute of Biotechnology of the Czech Academy of Sciences, BIOCEV, Prumyslova 595, 25250 Vestec, Czech Republic $1 https://orcid.org/0000000327513060 $7 xx0126049
700    1_
$a Romier, Christophe $u Département de Biologie Structurale Intégrative, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), CNRS, INSERM, Université de Strasbourg, CEDEX, 67404 Illkirch, France
700    1_
$a Schutkowski, Mike $u Department of Enzymology, Institute of Biochemistry, Martin-Luther-University of Halle-Wittenberg, 06120 Halle (Saale), Germany
700    1_
$a Krämer, Oliver H $u Department of Toxicology, University Medical Center, 55131 Mainz, Germany $1 https://orcid.org/000000033973045X
700    1_
$a Sippl, Wolfgang $u Department of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther-University of Halle-Wittenberg, 06120 Halle (Saale), Germany $1 https://orcid.org/0000000259859261
773    0_
$w MED00176142 $t International journal of molecular sciences $x 1422-0067 $g Roč. 23, č. 1 (2021)
856    41
$u https://pubmed.ncbi.nlm.nih.gov/35008795 $y Pubmed
910    __
$a ABA008 $b sig $c sign $y p $z 0
990    __
$a 20220425 $b ABA008
991    __
$a 20220506130916 $b ABA008
999    __
$a ok $b bmc $g 1789298 $s 1162819
BAS    __
$a 3
BAS    __
$a PreBMC
BMC    __
$a 2021 $b 23 $c 1 $e 20211229 $i 1422-0067 $m International journal of molecular sciences $n Int J Mol Sci $x MED00176142
GRA    __
$a KR2291/12-1, KR2291/8-1, KR2291/9-1, Project-ID 393547839 $p Deutsche Forschungsgemeinschaft
GRA    __
$a Project No 65 $p Brigitte und Dr. Konstanze Wegener-Stiftung
GRA    __
$a Grant Nr. 2019.086.1 $p Wilhelm-Sander Foundation
LZP    __
$a Pubmed-20220425
Back

Find record

Citation metrics

Archiving options