Dual EGFR/VEGFR2 inhibitors and apoptosis inducers: Synthesis and antitumor activity of novel pyrazoline derivatives

Alkamaly, Omkulthom M; Altwaijry, Najla; Sabour, Rehab; Harras, Marwa F.

doi:10.1002/ardp.202000351

Cited by 15 publications

(9 citation statements)

References 47 publications

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“…This finding is consistent with previous studies that showed that most pyrazoline derivatives act as EGFR inhibitors in molecular docking and in vitro studies. 23,[26][27][28] Overexpression of tyrosine kinase receptor, EGFR associated with cancer progression, treatment response, and metastasis in various types of cancer. Non-small cell lung cancer (NSCLC) patients with overexpression of EGFR have the worst prognosis with a shorter survival time.…”

Section: Discussionmentioning

confidence: 99%

A Potent EGFR Inhibitor, N-Phenyl Pyrazoline Derivative Suppresses Aggressiveness and Cancer Stem Cell-Like Phenotype of Cervical Cancer Cells

Mustofa¹,

Satriyo²,

Suma³

et al. 2022

DDDT

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Objective Metastasis causes approximately 90% of cancer-related deaths, including in cervical cancer patients. Uncontrolled cell proliferation, migration, and cancer stemness act as critical events in primary tumor growth and cancer metastasis progression in cervical cancer. Here, we investigated the anti-proliferative, anti-migration, and cancer stemness inhibition activity of N-phenyl pyrazoline derivatives against cervical cancer cells. Methods The chalcone and phenylhydrazine were used to synthesize the N-phenyl pyrazoline 2/5 (P2 and P5). The MTT, colony formation, and wound healing assays were performed to evaluate the N-phenyl pyrazoline effect in HeLa cells. The N-phenyl pyrazoline’s protein target was predicted using SwissTargetPrediction and AutoDock Vina software. The Western blotting assay was performed to evaluate the target proteins. The public dataset analysis was used to confirm the clinical relevance of target protein in cervical cancer patients. Results N-phenyl pyrazoline 2 and 5 were successfully synthesized. The N-phenyl pyrazolines 2 and 5 exhibit cytotoxic effect in HeLa cell line with 20.26 µM, 4.708 µM of IC 50, respectively. Further study shows that the N-phenyl pyrazoline 5 suppresses the cell proliferation and migration ability of HeLa cell line in a dose-dependent manner. Target prediction and molecular docking reveal that EGFR and ERBB2 protein as the main target of the N-phenyl pyrazoline 5 compound. The N-phenyl pyrazoline 5 suppresses the EGFR expression level but not the total ERK1/2. Public data and GSEA analysis found that the EGFR high expression level is positively associated with poor survival, cancer metastasis-related signaling pathways, and cancer stem cell markers in cervical cancer patients. In addition, the N-phenyl pyrazoline 5 reduces the HeLa’s tumorsphere size and cancer stem cell marker, CD133. Conclusion N-phenyl pyrazoline 5 suppresses the cell viability, proliferation, migration, and cancer stem cell-like phenotype of cervical cancer cells via EGFR inhibition.

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Section: Discussionmentioning

confidence: 99%

A Potent EGFR Inhibitor, N-Phenyl Pyrazoline Derivative Suppresses Aggressiveness and Cancer Stem Cell-Like Phenotype of Cervical Cancer Cells

Mustofa¹,

Satriyo²,

Suma³

et al. 2022

DDDT

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“…2‐Pyrazolines have been the most studied due to their wide range of biological activity. [ 27 ] The pyrazoline system is part of structures with crucial biological activity such as antimicrobial, [ 28 ] antimalarial, [ 6,19,29 ] analgesic, [ 30 ] anticonvulsant, [ 31 ] anti‐inflammatory, [ 32 ] antituberculosis, [ 33 ] antitumor, [ 34–36 ] antiviral, [ 37 ] among others, [ 38 ] which has increased the interest in this type of heterocyclic compounds. Recently, our group has synthesized and evaluated the anticancer and antiplasmodial activity of 2‐pyrazolines from [(7‐chloroquinolin‐4‐yl)amino]chalcones involving the 4/3‐anilines to obtain derivatives with meta ‐ or para ‐substitution, respectively, where the meta ‐substitution of the ring C in the pyrazoline is essential to obtain compounds with anticancer activity comparable or even higher than the Doxorubicin, as well as, the 2‐pyrazolines showed anti‐ Plasmodium falciparum activity, reaching the EC 50 of 5.54 μg/mL, as previously reported by us.…”

Section: Introductionmentioning

confidence: 99%

“…2-Pyrazolines have been the most studied due to their wide range of biological activity. [27] The pyrazoline system is part of structures with crucial biological activity such as antimicrobial, [28] antimalarial, [6,19,29] analgesic, [30] anticonvulsant, [31] anti-inflammatory, [32] antituberculosis, [33] antitumor, [34][35][36] antiviral, [37] among others, [38] which has increased the interest in this type of heterocyclic compounds.…”

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confidence: 99%

New pyridine‐based chalcones and pyrazolines with anticancer, antibacterial, and antiplasmodial activities

Ramírez‐Prada,

Rocha‐Ortiz,

Orozco

et al. 2024

Archiv der Pharmazie

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New pyridine‐based chalcones 4a–h and pyrazolines 5a–h (N‐acetyl), 6a–h (N‐phenyl), and 7a–h (N‐4‐chlorophenyl) were synthesized and evaluated by the National Cancer Institute (NCI) against 60 different human cancer cell lines. Pyrazolines 6a, 6c–h, and 7a–h satisfied the pre‐determined threshold inhibition criteria, obtaining that compounds 6c and 6f exhibited high antiproliferative activity, reaching submicromolar GI50 values from 0.38 to 0.45 μM, respectively. Moreover, compound 7g (4‐CH3) exhibited the highest cytostatic activity of these series against different cancer cell lines from leukemia, nonsmall cell lung, colon, ovarian, renal, and prostate cancer, with LC50 values ranging from 5.41 to 8.35 μM, showing better cytotoxic activity than doxorubicin. Furthermore, the compounds were tested for antibacterial and antiplasmodial activities. Chalcone 4c was the most active with minimal inhibitory concentration (MIC) = 2 μg/mL against methicillin‐resistant Staphylococcus aureus (MRSA), while the pyrazoline 6h showed a MIC = 8 μg/mL against Neisseria gonorrhoeae. For anti‐Plasmodium falciparum activity, the chalcones display higher activity with EC50 values ranging from 10.26 to 10.94 μg/mL. Docking studies were conducted against relevant proteins from P. falciparum, exhibiting the minimum binding energy with plasmepsin II. In vivo toxicity assay in Galleria mellonella suggests that most compounds are low or nontoxic.

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“…Malignancies continue to be a serious threat to people worldwide. 1 According to reports from the World Health Organization (WHO), cancer was responsible for approximately 10 million deaths in 2020. 2 The increasing rate of resistance to anticancer drugs, their uncontrollable toxicity, and the lack of selectivity, have made the investigation for new anticancer agents an important area of research.…”

Section: Introductionmentioning

confidence: 99%

Application of a Deep Eutectic Solvent for the Synthesis of Novel Imidazole-Containing Quinazoline Derivatives as Potent Cytotoxic Agents

Azmian Moghadam,

Dabirian,

Ebrahimi Tavani

et al. 2024

Pharm Sci

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Background: Drugs containing the 4-anilinoquinazolines scaffold play a critical role in cancer treatment by inhibiting protein kinases, especially tyrosine kinases. In this study, a novel series of 4-anilinoquinazoline derivatives were synthesized and evaluated as cytotoxic agents. Methods: All final compounds were synthesized using two methods, including a conventional approach using potassium iodide and dimethylformamide as well as a green method using a deep eutectic solvent (DES) comprising choline chloride: urea. The cytotoxicity was tested on the A431, HUVEC, and HU02 cell lines. To evaluate the binding pattern of the compounds with EGFR and VEGFR-2, a molecular docking investigation was performed. Finally, the wound healing assay was carried out to assess the potency of compounds in inhibiting cell migration. Results: The final reaction time was approximately 15-20 min with yields of 60-72% using DES, while the conventional method took 3 to 4 h to complete, with yields between 30% and 42%. Compounds 8k and 8l showed better cytotoxicity against both cell lines compared to vandetanib (IC50=0.11 µM and 0.26 µM on A431 and IC50=5.01 µM and 5.24 µM on HUVEC, respectively). Molecular docking studies revealed that compound 8k, which contained 3-methylaniline at the 4-position of the quinazoline core, showed efficient binding affinity to both EGFR and VEGFR-2. An essential hydrogen bond was formed between quinazoline N1 of 8k and the Met796 residue of EGFR with a docking score of -8.76 kcal/mol. The imidazole N3 of 8k interacted with the Cyc919 residue of VEGFR-2, forming a hydrogen bond with a docking score of -9.03 kcal/mol. Moreover, compound 8k exhibited the best inhibitory activity on cell migration and wound healing. Conclusion: DES significantly improved the time and yield of the final reactions. Compound 8k, which showed the best cytotoxicity and inhibitory activity on cell migration, could be a suitable candidate for further structural optimization.

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Dual EGFR/VEGFR2 inhibitors and apoptosis inducers: Synthesis and antitumor activity of novel pyrazoline derivatives

Cited by 15 publications

References 47 publications

A Potent EGFR Inhibitor, N-Phenyl Pyrazoline Derivative Suppresses Aggressiveness and Cancer Stem Cell-Like Phenotype of Cervical Cancer Cells

A Potent EGFR Inhibitor, N-Phenyl Pyrazoline Derivative Suppresses Aggressiveness and Cancer Stem Cell-Like Phenotype of Cervical Cancer Cells

New pyridine‐based chalcones and pyrazolines with anticancer, antibacterial, and antiplasmodial activities

Application of a Deep Eutectic Solvent for the Synthesis of Novel Imidazole-Containing Quinazoline Derivatives as Potent Cytotoxic Agents

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