Molecular modeling based approach, synthesis, and cytotoxic activity of novel benzoin derivatives targeting phosphoinostide 3-kinase (PI3Kα)

Sabbah, Dima A.; Saada, Musaab; Khalaf, Reema Abu; Bardaweel, Sanaa K.; Sweidan, Kamal; Al-Qirim, Tariq; Al-Zughier, Amani; Halim, Heba Abdel; Sheikha, Ghassan Abu

doi:10.1016/j.bmcl.2015.06.011

Cited by 27 publications

(16 citation statements)

References 51 publications

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“…The difference in activity between 12 and 27 might be due to the H bond supplied by the O atom. It is worth noting that the series exhibited distinct antiproliferative activity in both cell lines, suggesting differences in the binding sites of WT PI3Kα and MUT (H1047R) PI3Kα, which accords with our previous data on PI3Kα [13,14,[16][17][18][19]23,24].…”

Section: Biological Evaluation Of the Synthesized Compoundssupporting

confidence: 91%

“…The backbones of the synthesized molecules form H-bonds with S773, S774, A775, K776, W780, K802, D810, Y836, E849, V851, N853, S854, Q859, D915, H917, S919, N920, and D933 (Table 3, Figure 5). Furthermore, other computational [14,16,17,19,20,34] and experimental studies [4] have assigned the contribution of these key binding amino acids in the PI3Kα/ligand binding interaction. Interestingly, 5, 7-27 displayed comparable affinity toward both WT (2RD0) and MUT (H1047R) (3HHM) PI3Kα.…”

Section: Molecular Dockingmentioning

confidence: 99%

“…Lately, we released a series of N-substituted 4-hydroxy-2-quinolone-3-carboxamides that suppressed human colon carcinoma (HCT116) cell line proliferation and enhanced apoptosis through inducing caspase-3 activity and destructing cellular DNA illustrated by 3 [18]. Our ceaseless research has uncovered diverse scaffolds [19][20][21][22][23][24] targeting PI3Kα.…”

Section: Introductionmentioning

confidence: 99%

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Molecular Modeling, Synthesis and Biological Evaluation of N-Phenyl-4-Hydroxy-6-Methyl-2-Quinolone-3-CarboxAmides as Anticancer Agents

et al. 2020

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The emergence of phosphatidylinositol 3-kinase (PI3Kα) in cancer development has accentuated its significance as a potential target for anticancer drug design. Twenty one derivatives of N-phenyl-4-hydroxy-6-methyl-2-quinolone-3-carboxamide were synthesized and characterized using NMR (1H and 13C) and HRMS. The derivatives displayed inhibitory activity against human epithelial colorectal adenocarcinoma (Caco-2) and human colon cancer (HCT-116) cell lines: compounds 8 (IC50 Caco-2 = 98 µM, IC50 HCT-116 = 337 µM) and 16 (IC50 Caco-2 = 13 µM, IC50 HCT-116 = 240.2 µM). Results showed that compound 16 significantly affected the gene encoding AKT, BAD, and PI3K. The induced-fit docking (IFD) studies against PI3Kα demonstrated that the scaffold accommodates the kinase domains and forms H-bonds with significant binding residues.

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Section: Biological Evaluation Of the Synthesized Compoundssupporting

confidence: 91%

Section: Molecular Dockingmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Molecular Modeling, Synthesis and Biological Evaluation of N-Phenyl-4-Hydroxy-6-Methyl-2-Quinolone-3-CarboxAmides as Anticancer Agents

et al. 2020

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“…In order to identify the structural-basis of PI3Kα/ligand interaction of the verified compounds in the catalytic kinase domain of PI3Kα, we employed QPLD docking [40, 41] against the kinase cleft of 2RD0. Our QPLD docking data show that some of the synthesized molecules 2 – 9 bind to the kinase domain of PI3Kα (Fig.…”

Section: Resultsmentioning

confidence: 99%

Novel amphiphilic pyridinium ionic liquids-supported Schiff bases: ultrasound assisted synthesis, molecular docking and anticancer evaluation

Al-blewi

Rezki

Al‐Sodies

et al. 2018

Chemistry Central Journal

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BackgroundPyridinium Schiff bases and ionic liquids have attracted increasing interest in medicinal chemistry.ResultsA library of 32 cationic fluorinated pyridinium hydrazone-based amphiphiles tethering fluorinated counteranions was synthesized by alkylation of 4-fluoropyridine hydrazone with various long alkyl iodide exploiting lead quaternization and metathesis strategies. All compounds were assessed for their anticancer inhibition activity towards different cancer cell lines and the results revealed that increasing the length of the hydrophobic chain of the synthesized analogues appears to significantly enhance their anticancer activities. Substantial increase in caspase-3 activity was demonstrated upon treatment with the most potent compounds, namely 8, 28, 29 and 32 suggesting an apoptotic cellular death pathway.ConclusionsQuantum-polarized ligand docking studies against phosphoinositide 3-kinase α displayed that compounds 2–6 bind to the kinase site and form H-bond with S774, K802, H917 and D933. Electronic supplementary materialThe online version of this article (10.1186/s13065-018-0489-z) contains supplementary material, which is available to authorized users.

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“…Therefore, a detailed understanding of interactions between small molecules and proteins may form the basis for a rational drug design strategy. 45 – 48 This approach was widely considered in order to design molecules addressing a broad range of major pathologies such as cancers 49 , 50 or cardiovascular diseases. 51 – 53 …”

Section: Modeling Ligand–protein Interactions In Drug Designmentioning

confidence: 99%

Molecular docking as a popular tool in drug design, an in silico travel

Ruyck¹,

Brysbaert²,

Blossey³

et al. 2016

AABC

221

121

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New molecular modeling approaches, driven by rapidly improving computational platforms, have allowed many success stories for the use of computer-assisted drug design in the discovery of new mechanism-or structure-based drugs. In this overview, we highlight three aspects of the use of molecular docking. First, we discuss the combination of molecular and quantum mechanics to investigate an unusual enzymatic mechanism of a flavoprotein. Second, we present recent advances in anti-infectious agents’ synthesis driven by structural insights. At the end, we focus on larger biological complexes made by protein–protein interactions and discuss their relevance in drug design. This review provides information on how these large systems, even in the presence of the solvent, can be investigated with the outlook of drug discovery.

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Molecular modeling based approach, synthesis, and cytotoxic activity of novel benzoin derivatives targeting phosphoinostide 3-kinase (PI3Kα)

Cited by 27 publications

References 51 publications

Molecular Modeling, Synthesis and Biological Evaluation of N-Phenyl-4-Hydroxy-6-Methyl-2-Quinolone-3-CarboxAmides as Anticancer Agents

Molecular Modeling, Synthesis and Biological Evaluation of N-Phenyl-4-Hydroxy-6-Methyl-2-Quinolone-3-CarboxAmides as Anticancer Agents

Novel amphiphilic pyridinium ionic liquids-supported Schiff bases: ultrasound assisted synthesis, molecular docking and anticancer evaluation

Molecular docking as a popular tool in drug design, an in silico travel

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