Anticancer evaluation and molecular modeling of multi-targeted kinase inhibitors based pyrido[2,3-d]pyrimidine scaffold

Abstract

An efficient synthesis of substituted pyrido[2,3-d]pyrimidines was carried out and evaluated for in vitro anticancer activity against five cancer cell lines, namely hepatic cancer (HepG-2), prostate cancer (PC-3), colon cancer (HCT-116), breast cancer (MCF-7), and lung cancer (A-549) cell lines. Regarding HepG-2, PC-3, HCT-116 cancer cell lines, 7-(4-chlorophenyl)-2-(3-methyl-5-oxo-2,3-dihydro-1H-pyrazol-1-yl)-5-(p-tolyl)- pyrido[2,3-d]pyrimidin-4(3H)-one (5a) exhibited strong, more potent anticancer (IC50: 0.3, 6.6 and 7 µM) relative to the standard doxorubicin (IC50: 0.6, 6.8 and 12.8 µM), respectively. Kinase inhibitory assessment of 5a showed promising inhibitory activity against three kinases namely PDGFR β, EGFR, and CDK4/cyclin D1 at two concentrations 50 and 100 µM in single measurements. Further, a molecular docking study for compound 5a was performed to verify the binding mode towards the EGFR and CDK4/cyclin D1 kinases.

Kinase Inhibitors of Novel Pyridopyrimidinone Candidates: Synthesis and In Vitro Anticancer Properties

“…Among them, pyrido [2,3-d] pyrimidin-4-ones (A-C) were found to lower cell proliferation in various cancer cell lines through inhibition of various kinases, e.g., TKs, PI3K, and CDK4/6 ( Figure 1) [17][18][19]. In continuation of our earlier studies that involved synthesis of different other substituted pyridopyrimidine compounds [20][21][22] and based on the structural features of pyrido [2,3-d]pyrimidine, this study is designed to synthesize various groups containing different substituents in the phenyl ring at position 5 of the parent compound pyrido [2,3-d] pyrimidinone to further improve the SAR-relationship for their cytotoxicity and also for their inhibitory activity against TKs, CDK4/6, and PI3K enzymes.…”

Synthesis and Biological Evaluation of New Pyridothienopyrimidine Derivatives as Antibacterial Agents and Escherichia coli Topoisomerase II Inhibitors

“…To explore the binding modes of the newly synthesized pyridothienopyrimidines ( 2a , b ; 3a , b ; 4a , b ; and 5a , b ) with the active site of E. coli DNA gyrase B, a molecular docking simulation was accomplished using MOE. Firstly, novobiocin (the original co-crystallized ligand) was re-docked in the active site of E. coli DNA gyrase B kinase ((PDB code: 1AJ6) [ 46 , 47 ] ( Figure 3 ) and revealed a score energy of −80 kcal/mol at a root mean square deviation (RMDS) value equal to 0.81 Å. As reported in docking of novobiocin, having a coumarin core linked to oxan-4-yl moiety, the protons of the hydroxyl group of oxan-4-yl and NH 2 of the carbamate group formed hydrogen bonds within the active site of DNA gyrase B kinase via the backbone of Asp46 and the side chain of Asp73 .…”

“…The molecular docking simulation study was done using Molecular Operating Environment (MOE ® ) 2008.10 software [ 51 ]. The crystal structures of E. coli DNA gyrase B complexed with their ligand novobiocin (PDB codes: 1AJ6 and 1S14) [ 46 , 47 ] were retrieved from the Protein Data Bank. At the beginning, the co-crystallized ligand was re-docked into the assigned active E. coli DNA gyrase B enzyme to evaluate the root mean square deviation value.…”

Chiral Pyridine-3,5-bis- (L-phenylalaninyl-L-leucinyl) Schiff Base Peptides as Potential Anticancer Agents: Design, Synthesis, and Molecular Docking Studies Targeting Lactate Dehydrogenase-A

“…In order to further understand and illustrate the interaction of compounds 4-6 with the LDHA active site, the docking modeling studies were done in an open loop conformation of the enzyme. The docking studies were developed using Molecular Operating Environment software, MOE 10.2008 software [51,52] with X-ray crystallographic structure of LDHA (PDB ID: 4ZVV) [53]. The root mean square deviation (RMSD) value of 8.93 was calculated via redocking of the co-crystallized ligand, GNE-140, into the pocket site of LDH-A with docking score energy of −9.73 kcal/mol.…”

“…The three-dimensional X-ray structure of LDHA (PDB code: 4ZVV) [53] was chosen as the template for the modeling study of the screened compounds 4-6. The crystal structure was derived from the RCSB Protein Data Bank and the molecular docking procedure was performed using MOE, 10.2008 software following the reported procedure [51,52].…”