• Something wrong with this record ?

2,4-Diaryl-pyrimido[1,2-a]benzimidazole derivatives as novel anticancer agents endowed with potent anti-leukemia activity: Synthesis, biological evaluation and kinase profiling

MA. Shaldam, D. Hendrychová, R. El-Haggar, V. Vojáčková, TA. Majrashi, EB. Elkaeed, N. Masurier, V. Kryštof, HO. Tawfik, WM. Eldehna

. 2023 ; 258 (-) : 115610. [pub] 20230627

Language English Country France

Document type Journal Article

Persistent link   https://www.medvik.cz/link/bmc23016085

Acute myeloid leukemia (AML) stands as one of the most aggressive type of human cancer that can develop rapidly and thus requires immediate management. In the current study, the development of novel derivatives of pyrimido[1,2-a]benzimidazole (5a-p) as potential anti-AML agents is reported. The prepared compounds 5a-p were inspected for their in vitro anti-tumor activity at NCI-DTP and subsequently 5h was selected for full panel five-dose screening to assess its TGI, LC50 and GI50 values. Compound 5h showed effective anti-tumor activity at low micromolar concentration on all tested human cancer cell lines with GI50 range from 0.35 to 9.43 μM with superior sub-micromolar activity towards leukemia. Furthermore, pyrimido[1,2-a]benzimidazoles 5e-l were tested on a panel ofhuman acute leukemia cell lines, namely HL60, MOLM-13, MV4-11, CCRF-CEM and THP-1, where 5e-h reached single-digit micromolar GI50 values for all the tested cell lines. All prepared compounds were first tested for inhibitory action against the leukemia-associated mutant FLT3-ITD, as well as against ABL, CDK2, and GSK3 kinases, in order to identify the kinase target for the herein described pyrimido[1,2-a]benzimidazoles. However, the examined molecules disclosed non-significant activity against these kinases. Thereafter, a kinase profiling on a panel of 338 human kinases was then used to discover the potential target. Interestingly, pyrimido[1,2-a]benzimidazoles 5e and 5h significantly inhibited BMX kinase. Further investigation for the effect on cell cycle of HL60 and MV4-11 cells and caspase 3/7 activity was also performed. In addition, the changes in selected proteins (PARP-1, Mcl-1, pH3-Ser10) associated with cell death and viability were analyzed in HL60 and MV4-11 cells by immunoblotting.

References provided by Crossref.org

000      
00000naa a2200000 a 4500
001      
bmc23016085
003      
CZ-PrNML
005      
20231026110500.0
007      
ta
008      
231013s2023 fr f 000 0|eng||
009      
AR
024    7_
$a 10.1016/j.ejmech.2023.115610 $2 doi
035    __
$a (PubMed)37437350
040    __
$a ABA008 $b cze $d ABA008 $e AACR2
041    0_
$a eng
044    __
$a fr
100    1_
$a Shaldam, Moataz A $u Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, 33516, Egypt
245    10
$a 2,4-Diaryl-pyrimido[1,2-a]benzimidazole derivatives as novel anticancer agents endowed with potent anti-leukemia activity: Synthesis, biological evaluation and kinase profiling / $c MA. Shaldam, D. Hendrychová, R. El-Haggar, V. Vojáčková, TA. Majrashi, EB. Elkaeed, N. Masurier, V. Kryštof, HO. Tawfik, WM. Eldehna
520    9_
$a Acute myeloid leukemia (AML) stands as one of the most aggressive type of human cancer that can develop rapidly and thus requires immediate management. In the current study, the development of novel derivatives of pyrimido[1,2-a]benzimidazole (5a-p) as potential anti-AML agents is reported. The prepared compounds 5a-p were inspected for their in vitro anti-tumor activity at NCI-DTP and subsequently 5h was selected for full panel five-dose screening to assess its TGI, LC50 and GI50 values. Compound 5h showed effective anti-tumor activity at low micromolar concentration on all tested human cancer cell lines with GI50 range from 0.35 to 9.43 μM with superior sub-micromolar activity towards leukemia. Furthermore, pyrimido[1,2-a]benzimidazoles 5e-l were tested on a panel ofhuman acute leukemia cell lines, namely HL60, MOLM-13, MV4-11, CCRF-CEM and THP-1, where 5e-h reached single-digit micromolar GI50 values for all the tested cell lines. All prepared compounds were first tested for inhibitory action against the leukemia-associated mutant FLT3-ITD, as well as against ABL, CDK2, and GSK3 kinases, in order to identify the kinase target for the herein described pyrimido[1,2-a]benzimidazoles. However, the examined molecules disclosed non-significant activity against these kinases. Thereafter, a kinase profiling on a panel of 338 human kinases was then used to discover the potential target. Interestingly, pyrimido[1,2-a]benzimidazoles 5e and 5h significantly inhibited BMX kinase. Further investigation for the effect on cell cycle of HL60 and MV4-11 cells and caspase 3/7 activity was also performed. In addition, the changes in selected proteins (PARP-1, Mcl-1, pH3-Ser10) associated with cell death and viability were analyzed in HL60 and MV4-11 cells by immunoblotting.
650    _2
$a lidé $7 D006801
650    _2
$a nádorové buněčné linie $7 D045744
650    _2
$a kinasa 3 glykogensynthasy $7 D038362
650    _2
$a inhibitory proteinkinas $7 D047428
650    12
$a protinádorové látky $7 D000970
650    12
$a akutní myeloidní leukemie $x farmakoterapie $x patologie $7 D015470
650    _2
$a benzimidazoly $x farmakologie $x terapeutické užití $7 D001562
650    _2
$a tyrosinkinasa 3 podobná fms $7 D051941
650    _2
$a proliferace buněk $7 D049109
650    _2
$a apoptóza $7 D017209
655    _2
$a časopisecké články $7 D016428
700    1_
$a Hendrychová, Denisa $u Department of Experimental Biology, Faculty of Science, Palacký University Olomouc, Šlechtitelů 27, 78371, Olomouc, Czech Republic
700    1_
$a El-Haggar, Radwan $u Pharmaceutical Chemistry Department, Faculty of Pharmacy, Helwan University, 11795, Ain Helwan, Cairo, Egypt
700    1_
$a Vojáčková, Veronika $u Department of Experimental Biology, Faculty of Science, Palacký University Olomouc, Šlechtitelů 27, 78371, Olomouc, Czech Republic
700    1_
$a Majrashi, Taghreed A $u Department of Pharmacognosy, College of Pharmacy, King Khalid University, Asir, 61421, Saudi Arabia
700    1_
$a Elkaeed, Eslam B $u Department of Pharmaceutical Sciences, College of Pharmacy, AlMaarefa University, Riyadh, 13713, Saudi Arabia
700    1_
$a Masurier, Nicolas $u IBMM, Univ Montpellier, CNRS, ENSCM, Montpellier, France
700    1_
$a Kryštof, Vladimír $u Department of Experimental Biology, Faculty of Science, Palacký University Olomouc, Šlechtitelů 27, 78371, Olomouc, Czech Republic; Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacký University Olomouc, Hněvotínská 5, 77900, Olomouc, Czech Republic
700    1_
$a Tawfik, Haytham O $u Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Tanta University, Tanta, 31527, Egypt
700    1_
$a Eldehna, Wagdy M $u Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, 33516, Egypt. Electronic address: wagdy2000@gmail.com
773    0_
$w MED00001628 $t European journal of medicinal chemistry $x 1768-3254 $g Roč. 258, č. - (2023), s. 115610
856    41
$u https://pubmed.ncbi.nlm.nih.gov/37437350 $y Pubmed
910    __
$a ABA008 $b sig $c sign $y - $z 0
990    __
$a 20231013 $b ABA008
991    __
$a 20231026110453 $b ABA008
999    __
$a ok $b bmc $g 1999916 $s 1202447
BAS    __
$a 3
BAS    __
$a PreBMC-MEDLINE
BMC    __
$a 2023 $b 258 $c - $d 115610 $e 20230627 $i 1768-3254 $m European journal of medicinal chemistry $n Eur J Med Chem $x MED00001628
LZP    __
$a Pubmed-20231013

Find record

Citation metrics

Archiving options