Design and molecular modeling of novel P38α MAPK inhibitors targeting breast cancer, synthesized from oxygen heterocyclic natural compounds

Abdelhafez, Omaima M.; Ahmed, Eman Y.; Latif, N.; Arafa, Reem K.; Elmageed, Zakaria Y. Abd; Ali, Hamed I.

doi:10.1016/j.bmc.2019.02.027

Cited by 23 publications

(11 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Many of these H-bonds were formed with particular residues such as Gly 170 (NH), Leu 171 (NH), Gly 110 (NH), Lys 53 (NH), and Val 158 (NH and C=O). These observations are in agreement with the study conducted by Abdelhafez et al [20], where the interactions of furocromone and benzofuran derivatives against the same enzyme were studied. The lowest docking score was observed for the derivative 5 with −8.5 kcal/mol.…”

Section: Binding Mode Analysis After Molecular Docking Studiessupporting

confidence: 93%

Prostaglandins Isolated from the Octocoral Plexaura homomalla: In Silico and In Vitro Studies Against Different Enzymes of Cancer

et al. 2020

View full text Add to dashboard Cite

Prostaglandin A2-AcMe (1) and Prostaglandin A2 (2) were isolated from the octocoral Plexaura homomalla and three semisynthetic derivatives (3–5) were then obtained using a reduction protocol. All compounds were identified through one- and two-dimensional (1D and 2D) nuclear magnetic resonance (NMR) experiments. Additionally, evaluation of in vitro cytotoxic activity against the breast (MDA-MB-213) and lung (A549) cancer cell lines, in combination with enzymatic activity and molecular docking studies with the enzymes p38α-kinase, Src-kinase, and topoisomerase IIα, were carried out for compounds 1–5 in order to explore their potential as inhibitors of cancer-related molecular targets. Results showed that prostaglandin A2 (2) was the most potent compound with an IC50 of 16.46 and 25.20 μg/mL against MDA-MB-213 and A549 cell lines, respectively. In addition, this compound also inhibited p38α-kinase in 49% and Src-kinase in 59% at 2.5 μM, whereas topoisomerase IIα was inhibited in 64% at 10 μM. Enzymatic activity was found to be consistent with molecular docking simulations, since compound 2 also showed the lowest docking scores against the topoisomerase IIα and Src-kinase (−8.7 and −8.9 kcal/mol, respectively). Thus, molecular docking led to establish some insights into the predicted binding modes. Results suggest that prostaglandin 2 can be considered as a potential lead for development inhibitors against some enzymes present in cancer processes.

show abstract

Section: Binding Mode Analysis After Molecular Docking Studiessupporting

confidence: 93%

Prostaglandins Isolated from the Octocoral Plexaura homomalla: In Silico and In Vitro Studies Against Different Enzymes of Cancer

et al. 2020

View full text Add to dashboard Cite

show abstract

“…In this regard, our research group has previously reported coumarin, furochromone, and benzofuran derivatives for BC therapy, revealing their actions via reversible interactions supported by molecular modeling, which is applicable for this kind of interaction. [ 15–17 ] Moreover, these core moieties have been reported well by other research groups to reveal their actions via reversible interactions. [ 32–34 ] It was solely reported that the coumarin‐like derivatives administration blocked MCF‐7 cells in the irreversible (senescent and differentiated) G0 state of cell cycle arrest.…”

Section: Resultsmentioning

confidence: 99%

“…[ 14 ] A large number of coumarins and benzofurans have been recognized as key pharmacophores for several clinically utilized drugs, natural compounds incorporating both scaffolds (e.g., compounds I and II ) were previously reported to have significant anti‐BC and multikinase inhibition activities. [ 15–22 ] Moreover, pyrimidines, nicotinonitriles (pyridine carbonitriles), and pyrazoles (e.g., compounds III and IV ) were identified as remarkable anticancer agents with kinase inhibitory properties as well. [ 23–29 ] Based on the aforementioned information, a hybridization strategy of the two privileged scaffolds with different nitrogenous heterocycles was adapted to design multikinase inhibitors that could target BC (Figure 1).…”

Section: Introductionmentioning

confidence: 99%

Antitumor and multikinase inhibition activities of some synthesized coumarin and benzofuran derivatives

Ahmed

Abdelhafez

Zaafar

et al. 2022

Archiv der Pharmazie

Self Cite

View full text Add to dashboard Cite

Two new series of coumarin and benzofuran derivatives were designed, synthesized, and assessed for their in vitro and in vivo antitumor activities against breast cancer. Compounds 8, 9, 14, 15, and 17 exhibited the best antiproliferative activities (IC 50 : 0.07−2.94 μM) against the MCF-7 cell line, compared with lapatinib (IC 50 : 4.69 μM). Compound 14, with the most potent cytotoxic activity against MCF-7 cells, was capable of enhancing preG1 apoptosis and triggering cell cycle arrest at the G2/M phase. The kinase inhibitory activity of compound 14 against a panel of 22 kinases was examined to reveal multikinase inhibition within −39% to −97%. Furthermore, compound 14 exhibited potent in vivo Ehrlich (mammary adenocarcinoma) tumor regression, positive caspase-3, and negative EGFR immunoreaction, and was capable of elevating the catalase level. The physicochemical properties and pharmacokinetic parameters of compound 14 were investigated in silico for its druglikeness.

show abstract

“…Taking the aforementioned data into account and in continuation to our work on kinase inhibitors as anticancer agents (Abdel Latif et al, 2016;Abdelhafez et al, 2014Abdelhafez et al, , 2015Abdelhafez et al, , 2019Ahmed et al, 2020;Batran et al, 2017Batran et al, , 2021El-Daly et al, 2016;Gamal-Eldeen et al, 2013;Mohamed et al, 2019), herein we adopted the hybrid pharmacophore approach to design and synthesize two series of quinoline-dihydrothiazoles 3a-c, 4a,b, 5a,b and 6a,b and quinoline-thiazolidinones 7a-c and 8a,b (Figure 1) with the aim of developing potent anti-breast cancer agents with EGFR, phosho-EGFR, and phospho-Akt-inhibiting activities. The promising compounds were further evaluated for their effect on Bcl-2, survivin, and BAX.…”

Section: Introductionmentioning

confidence: 93%

Design, synthesis, and molecular modeling of quinoline‐based derivatives as anti‐breast cancer agents targeting EGFR/AKT signaling pathway

et al. 2022

Self Cite

View full text Add to dashboard Cite

Two series of quinoline-thiazole and quinoline-thiazolidinone hybrids were designed, synthesized, and evaluated for their in vitro antitumor activity on MCF-7 breast cancer cell line. In comparison with lapatinib (IC 50 = 4.69 µM), compounds 4b and 6b exhibited the best antiproliferative activity with IC 50 values of 33.19 and 5.35 µM, respectively. Although compound 6b showed higher cytotoxicity, compound 4b exhibited better inhibitory activity toward the epidermal growth factor receptor (EGFR) pathway than compound 6b as represented by the significant reduction in the EGFR kinase activity and the levels of phosho-EGFR and phosho-AKT when compared to lapatinib as a reference standard. Moreover, compound 4b was capable of down-regulating the anti-apoptotic genes Bcl-2 and survivin and up-regulating the level of the pro-apoptotic gene BAX. Molecular modeling study was carried out to predict the binding interactions of both compounds into the target kinase. Finally, the physicochemical properties were investigated in silico as well.

show abstract

Design and molecular modeling of novel P38α MAPK inhibitors targeting breast cancer, synthesized from oxygen heterocyclic natural compounds

Cited by 23 publications

References 51 publications

Prostaglandins Isolated from the Octocoral Plexaura homomalla: In Silico and In Vitro Studies Against Different Enzymes of Cancer

Prostaglandins Isolated from the Octocoral Plexaura homomalla: In Silico and In Vitro Studies Against Different Enzymes of Cancer

Antitumor and multikinase inhibition activities of some synthesized coumarin and benzofuran derivatives

Design, synthesis, and molecular modeling of quinoline‐based derivatives as anti‐breast cancer agents targeting EGFR/AKT signaling pathway

Contact Info

Product

Resources

About