Design, synthesis and evaluation of new quinazolin-4-one derivatives as apoptotic enhancers and autophagy inhibitors with potent antitumor activity

Elzahabi, Heba S. A.; Nafie, Mohamed S.; Osman, Dina A.; Elghazawy, Nehal H.; Soliman, Dalia H.; El‐Helby, Abdel‐Ghany A.; Arafa, Reem K.

doi:10.1016/j.ejmech.2021.113609

Cited by 45 publications

(31 citation statements)

References 47 publications

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“…We found that caspase 7 protein expression significantly increased after cell treatment with compound 4d (3-, 3.3-and 3.9-fold) and (1.14-, 1.2-and 1.5-fold) with compound 4f in comparison to the control, which suggested involvement of caspase 7 activation during compounds treatment. In line with our findings, several studies have demonstrated the apoptotic behavior of quinazoline derivatives through upregulating the proapoptotic genes and downregulating the antiapoptotic genes [33][34][35]. In particular, quinazoline-based anticancer drugs such as lapatinib and gefitinib were found to inhibit cancer cells growth through increasing the Bax and caspases gene levels and downregulating Bcl-2 levels, which is consistent with our finding in this study [36,37].…”

Section: Effect Of Compounds 4d and 4f On Apoptosis Regulatory Markerssupporting

confidence: 92%

The Antiproliferative and Apoptotic Effects of a Novel Quinazoline Carrying Substituted-Sulfonamides: In Vitro and Molecular Docking Study

et al. 2022

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In order to investigate for a new effective and safe anticancer drug, we synthesized a novel series of quinazoline containing biologically active substituted-sulfonamide moiety at 3- position 4a–n. The structure of the newly prepared compounds was proved by microanalysis, IR, 1H-NMR, 13C-NMR and mass spectral data. All the synthesized compounds were evaluated for their in vitro cytotoxic activity in numerous cancer cell lines including A549, HepG-2, LoVo and MCF-7 and normal HUVEC cell line. The two most active compounds 4d and 4f were then tested for their apoptosis induction using DNA content and Annexin V-FITC/PI staining. Moreover, apoptosis initiation was also confirmed using RT-PCR and Western blot. To further understand the binding preferences of quinazoline sulfonamides, docking simulations were used. Among the fourteen new synthesized compounds, we found that compounds 4d and 4f exerted the strongest cytotoxicity against MCF-7 cells with an IC50 value of 2.5 and 5 μM, respectively. Flow cytometry data revealed the ability of compounds 4d and 4f to mediate apoptosis and arrest cell cycle growth at G1 phase. Furthermore, RT-PCR and Western blot results suggested that both 4d and 4f activates apoptotic cell death pathway in MCF-7 cells. Molecular docking assessments indicated that compounds 4d and 4f fit perfectly into Bcl2’s active site. Based on the biological properties, we conclude that both compounds 4d and 4f could be used as a new type of anticancer agent, which provides a scientific basis for further research into the treatment of cancer.

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Section: Effect Of Compounds 4d and 4f On Apoptosis Regulatory Markerssupporting

confidence: 92%

The Antiproliferative and Apoptotic Effects of a Novel Quinazoline Carrying Substituted-Sulfonamides: In Vitro and Molecular Docking Study

et al. 2022

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“…Tumor proliferation inhibition and the amelioration of hepatic enzymes are the routine methods that are used to explain anticancer activity through in vivo models, examples of which have been previously published [ 45 , 46 ]. As a result of the hepatocellular damage that occurred after tumor inoculation, the ALT and AST hepatic enzymes were significantly elevated to be 79 and 89 (U/L), respectively, compared to 42 and 48 (U/L) in the normal mice.…”

Section: Resultsmentioning

confidence: 99%

In Vitro and In Vivo Studies of Anti-Lung Cancer Activity of Artemesia judaica L. Crude Extract Combined with LC-MS/MS Metabolic Profiling, Docking Simulation and HPLC-DAD Quantification

et al. 2021

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Artemisia judaica L. (Family: Asteraceae) exhibited antioxidant, anti-inflammatory, and antiapoptotic effects. The in vitro cytotoxic activity of A. judaica ethanolic extract was screened against a panel of cancer cell lines. The results revealed its cytotoxic activity against a lung cancer (A549) cell line with a promising IC50 of 14.2 μg/mL compared to doxorubicin as a standard. This was confirmed through the downregulation of antiapoptotic genes, the upregulation of proapoptotic genes, and the cell cycle arrest at the G2/M phase. Further in vivo study showed that a solid tumor mass was significantly reduced, with a tumor inhibition ratio of 54% relative to doxorubicin therapy in a Xenograft model. From a chemical point of view, various classes of natural products have been identified by liquid chromatography combined with tandem mass spectrometry (LC-MS/MS). The docking study of the detected metabolites approved their cytotoxic activity through their virtual binding affinity towards the cyclin-dependent kinase 2 (CDK-2) and epidermal growth factor receptor (EGFR) active sites. Finally, A. judaica is a fruitful source of polyphenols that are well-known for their antioxidant and cytotoxic activities. As such, the previously reported polyphenols with anti-lung cancer activity were quantified by high-performance liquid chromatography coupled with a diode array detector (HPLC-DAD). Rutin, quercetin, kaempferol, and apigenin were detected at concentrations of 6 mg/gm, 0.4 mg/gm, 0.36 mg/gm, and 3.9 mg/gm of plant dry extract, respectively. It is worth noting that kaempferol and rutin are reported for the first time. Herein, A. judaica L. may serve as an adjuvant therapy or a promising source of leading structures in drug discovery for lung cancer treatment.

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“…> 300 • C [Lit. [31,32] 324-326 A 10.0 mmol mixture of pyridazino [4,5-b]indol-4-one (i.e., substance 2), 25 mL of dry pyridine, and (2.25 g, 10 mmol) P 2 S 5 was refluxed for 6 h. It was then cooled and poured into 250 mL ice water. The generated precipitate 3 was then filtered and dried.…”

Section: General Proceduresmentioning

confidence: 99%

“…MBS268899, USA), and an AKT assay kit (Catalog #: MBS9511022, USA) were used. The percentage inhibition of autophosphorylation by substances was estimated using the following equation [32]:…”

Section: Enzymatic Targetingmentioning

confidence: 99%

Synthesis, X-ray Single-Crystal Analysis, and Anticancer Activity Evaluation of New Alkylsulfanyl-Pyridazino[4,5-b]indole Compounds as Multitarget Inhibitors of EGFR and Its Downstream PI3K-AKT Pathway

et al. 2022

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The alkylation of 3,5-dihydro-4H-pyridazino[4,5-b]indole-4-thione with benzyl bromide, ethyl chloroacetate, and allyl bromide in the presence of potassium carbonate (K2CO3) yielded new alkylsulfanylpyridazino[4,5-b]indole derivatives (i.e., compounds 4–6). Hydrazinolysis of ester 6 resulted in hydrazide 7. The structure of compound 6 was verified by X-ray single-crystal analysis. Among the synthesized compounds, compound 6 exhibited the most promising cytotoxicity toward MCF-7 cells with an IC50 value of 12 µM. It showed potential inhibition activity toward EGFR, PI3K, and AKT in MCF-7 cells, with 0.26-, 0.49-, and 0.31-fold reductions in concentration compared to an untreated control. Additionally, it showed apoptosis-inducing activity in MCF-7 cells (47.98-fold); overall apoptosis increased to 38.87% compared to 0.81% in the untreated control, which disrupted the cell cycle at pre-G1 and S phases. Moreover, compound 6 exhibited good binding affinities toward the tested proteins (EGFR, PI3K, and AKT) and had binding energies ranging from −15.87 to −24.87 Kcal/mol. It also formed good interactions with essential amino acids inside the binding sites. Hence, compound 6 is recommended as an anti-breast cancer chemotherapeutic due to its effects on the EGFR-PI3K-AKT pathway.

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Design, synthesis and evaluation of new quinazolin-4-one derivatives as apoptotic enhancers and autophagy inhibitors with potent antitumor activity

Cited by 45 publications

References 47 publications

The Antiproliferative and Apoptotic Effects of a Novel Quinazoline Carrying Substituted-Sulfonamides: In Vitro and Molecular Docking Study

The Antiproliferative and Apoptotic Effects of a Novel Quinazoline Carrying Substituted-Sulfonamides: In Vitro and Molecular Docking Study

In Vitro and In Vivo Studies of Anti-Lung Cancer Activity of Artemesia judaica L. Crude Extract Combined with LC-MS/MS Metabolic Profiling, Docking Simulation and HPLC-DAD Quantification

Synthesis, X-ray Single-Crystal Analysis, and Anticancer Activity Evaluation of New Alkylsulfanyl-Pyridazino[4,5-b]indole Compounds as Multitarget Inhibitors of EGFR and Its Downstream PI3K-AKT Pathway

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