Design, synthesis and molecular modeling studies of 2-styrylquinazoline derivatives as EGFR inhibitors and apoptosis inducers

Amin, Noha H.; El‐Saadi, Mohammed T.; Zaki, Shimaa S.; Abdel‐Rahman, Hamdy M.

doi:10.1016/j.bioorg.2020.104358

Cited by 15 publications

(8 citation statements)

References 39 publications

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“…To assess the effect of compound 4 on the cell cycle of MCF-7 cells, we treated the MCF-7 cells with compound 4 and analyzed the cell cycle arrest at different stages as previously reported [ 82 ]. Briefly, after MCF-7 cells (3 × 10 5 cells/well) were incubated for 12 h at 37 °C, the cells were treated with compound 4 (5.73 µM) and incubated for another 24 h at the same temperature.…”

Section: Methodsmentioning

confidence: 99%

Novel 1,3-Thiazole Analogues with Potent Activity against Breast Cancer: A Design, Synthesis, In Vitro, and In Silico Study

et al. 2022

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Breast cancer is the most common cancer in women, responsible for over half a million deaths in 2020. Almost 75% of FDA-approved drugs are mainly nitrogen- and sulfur-containing heterocyclic compounds, implying the importance of such compounds in drug discovery. Among heterocycles, thiazole-based heterocyclic compounds have demonstrated a broad range of pharmacological activities. In the present study, a novel set of 1,3-thiazole derivatives was designed and synthesized based on the coupling of acetophenone derivatives, and phenacyl bromide was substituted as a key reaction step. The activity of synthesized compounds was screened against the proliferation of two breast cancer cell lines (MCF-7 and MDA-MB-231). Almost all compounds exhibited a considerable antiproliferative activity toward the breast cancer cells as compared to staurosporine, with no significant cytotoxicity toward the epithelial cells. Among the synthesized compounds, compound 4 exhibited the most potent antiproliferative activity, with an IC50 of 5.73 and 12.15 µM toward MCF-7 and MDA-MB-231 cells, respectively, compared to staurosporine (IC50 = 6.77 and 7.03 µM, respectively). Exploring the mechanistic insights responsible for the antiproliferative activity of compound 4 revealed that compound 4 possesses a significant inhibitory activity toward the vascular endothelial growth factor receptor-2 (VEGFR-2) with (IC50 = 0.093 µM) compared to Sorafenib (IC50 = 0.059 µM). Further, compound 4 showed the ability to induce programmed cell death by triggering apoptosis and necrosis in MCF-7 cells and to induce cell cycle arrest on MCF-7 cells at the G1 stage while decreasing the cellular population in the G2/M phase. Finally, detailed in silico molecular docking studies affirmed that this class of compounds possesses a considerable binding affinity toward VEGFR2 proteins. Overall, these results indicate that compound 4 could be a promising lead compound for developing potent anti-breast cancer compounds.

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Section: Methodsmentioning

confidence: 99%

Novel 1,3-Thiazole Analogues with Potent Activity against Breast Cancer: A Design, Synthesis, In Vitro, and In Silico Study

et al. 2022

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“…Amin NH et al, synthesized and screened 2styrylquinazoline derivatives as EGFR inhibitors and apoptosis inducers for the screening MTT cytotoxicity, in-vitro cell-free EGFR and antiproliferative activity against EGFR/ A549 cell line were used; among the synthesized compounds, Compound 8c is found to be a prominent candidate with (IC50 = 8.62 μM, 0.190 μM and = 79.25%), if compared tolapatanib (IC50 = 11.98 μM, 0.190 μM, and 79.25%) 35 .…”

Section: Niemantowski Reactionmentioning

confidence: 99%

Untitled

2022

IJPSR

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The aim of this review is to provide an extensive overview of the diverse pharmacological activities of quinazoline moiety. Quinazolines are well-known and important nitrogen-containing heterocyclic compounds made chemical formula C 8 H 6 N 2 . For the last few years, the heterocyclic fused nucleus quinazoline has drawn immense attention due to its diversified application in medicinal chemistry research. In the growing world of intense research, Quinazoline was considered as a privileged scaffold; the modification made with different substituents around the centroid paved the researchers away to deal with at ease. Being a fused ring, the heterocycle itself is capable of great pharmacological quality. Quinazoline is one of the heterocycles with diversifying scaffolds for various important biological activities for which considerable research has been done in order to examine its biomedical applications. In a number of biologically active compounds and drug molecules, the quinazoline nucleus is used as a basic framework. This paper is a sincere attempt to highlight the tremendous potential of this ring system because of its wide spectrum of pharmacological actions. This study can also speed up the design and synthesis process in order to create more therapeutically viable clinical candidates. INTRODUCTION:Quinazoline heterocycle consists of two fused six-member aromatic rings, benzene & pyrimidine. Quinazoline derivatives, which belong to the N-containing heterocyclic compounds, have caused universal concerns due to their wide and distinct biopharmaceutical activities. The research on the biological activity of quinazoline compounds started when the compound 2-methyl-1,3-aryl-4-quinazoline derivative was synthesized 1 .

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“…[23] Co-targeting of ER and EGFR enzymes was one of our objectives as various reports evidenced better effectiveness and achievable reversal of resistance when ER and growth factor receptor pathways were targeted simultaneously. [27] Here, compounds with the best antiproliferation activity against MCF-7 cells were tested for in vitro inhibition of ARO using letrozole as the reference standard in accordance to the reported method [62] and/or the EGFR enzyme with erlotinib as the reference, [63] while some of the most active antiproliferative candidates against MDB-MB-231 cells were screened for in vitro inhibition of the EGFR enzyme. The results outlined in 5b).…”

Section: In Vitro Enzyme Inhibition Assaysmentioning

confidence: 99%

“…[64] Caspase-9 is known to directly cleave and activate effector caspases such as caspase-3. [64,65] Consequently, caspase-9 activation [63] was estimated to identify a sui-…”

Section: Caspase-9 Activation Assaymentioning

confidence: 99%

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New functionalized 6‐thienylpyrimidine‐5‐carbonitriles as antiproliferative agents against human breast cancer cells

Aboulwafa

Daabees

Badawi

2021

Archiv der Pharmazie

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6-Thienylpyrimidine-5-carbonitrile derivatives were synthesized and screened for their in vitro antiproliferative activities against two human breast cancer cell lines in comparison to 5-fluorouracil as a reference. Compounds 2, 3a-c, and 6b evolved as the most active congeners against both cell lines, while others showed selectivity for only one cell line. Compound 2 exerted its effect through inhibition of the epidermal growth factor receptor (EGFR), while 6b showed less aromatase inhibitory activity than letrozole. The rest of the tested compounds did not show significant inhibition, and it can be assumed that they exert their antiproliferative activity through different target mechanisms. In addition, caspase-9 protein activation assays, cell cycle analysis using flow cytometry, and annexin V-fluorescein isothiocyanate-propidium iodide (FITC/PI) dual staining assays were performed for the most active compounds. All the tested compounds were found to be potent pyrimidine derivatives able to initiate apoptosis in MCF-7 and MDA-MB-231 cells.

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Design, synthesis and molecular modeling studies of 2-styrylquinazoline derivatives as EGFR inhibitors and apoptosis inducers

Cited by 15 publications

References 39 publications

Novel 1,3-Thiazole Analogues with Potent Activity against Breast Cancer: A Design, Synthesis, In Vitro, and In Silico Study

Novel 1,3-Thiazole Analogues with Potent Activity against Breast Cancer: A Design, Synthesis, In Vitro, and In Silico Study

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New functionalized 6‐thienylpyrimidine‐5‐carbonitriles as antiproliferative agents against human breast cancer cells

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