The design and synthesis of potent benzimidazole derivatives <i>via</i> scaffold hybridization and evaluating their antiproliferative and proapoptotic activity against breast and lung cancer cell lines

Elgawish, Mohamed Saleh; Nafie, Mohamed S.; Yaseen, Asmaa; Yamada, Koji; Ghareb, Nagat

doi:10.1039/d1nj05655g

Cited by 13 publications

(15 citation statements)

References 52 publications

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“…V9261, Promega, USA). The following equation was used to calculate the percentage of autophosphorylation inhibition by drugs: Percentage inhibition = 100 − true[ Control Treated − Control false) true] , …”

Section: Methodsmentioning

confidence: 99%

Synthesis of New Bioactive Indolyl-1,2,4-Triazole Hybrids As Dual Inhibitors for EGFR/PARP-1 Targeting Breast and Liver Cancer Cells

et al. 2022

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Cancer is the most severe disease worldwide. Every year, tens of millions of people are diagnosed with cancer, and over half of those people will ultimately die from the disease. Hence, the discovery of new inhibitors for fighting cancer is necessary. As a result, new indolyl-triazole hybrids were synthesized to target breast and liver cancer cells. The synthetic strategy involves glycosylation of the 4-aryltriazolethiones 3a−b with acetylprotected α-halosugars in the presence of K 2 CO 3 in acetone to give a mixture of β-S-glycosides 6a−b, 7a−b, and β-N-glycosides 8a−b, 9a−b. Chemo-selective S-glycosylation was achieved using NaHCO 3 in ethanol. The migration of glycosyl moiety from sulfur to nitrogen (S → N glycosylmigration) was achieved thermally without any catalyst. Alkylation of the triazole-thiones with 2bromoethanol and 1-bromopropan-2-ol in the presence of K 2 CO 3 yielded the corresponding S-alkylated products. The synthesized compounds were tested for their cytotoxicity using an MTT assay and for apoptosis induction targeting PARP-1 and EGFR. Compounds 12b, 13a, and 13b exhibited cytotoxic activities with promising IC 50 values of 2.67, 6.21, 1.07 μM against MCF-7 cells and 3.21, 8.91, 0.32 μM against HepG2 cells compared to Erlotinib (IC 50 = 2.51, 2.91 μM, respectively) as reference drug. Interestingly, compounds 13b induced apoptosis in MCf-7 and HepG2 cells, arresting the cell cycle at the G2/M and S phases, respectively. Additionally, the dual enzyme inhibition seen in compound 13b against EGFR and PARP-1 is encouraging, with IC 50 values of 62.4 nM compared to Erlotinib (80 nM) and 1.24 nM compared to Olaparib (1.49 nM), respectively. The anticancer activity was finally validated using an in vivo SEC-cancer model; compound 13b improved both hematological and biochemical analyses inhibiting tumor proliferation by 66.7% compared to Erlotinib's 65.7%. So, compound 13b may serve as a promising anticancer activity through dual PARP-1/EGFR target inhibition.

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Section: Methodsmentioning

confidence: 99%

Synthesis of New Bioactive Indolyl-1,2,4-Triazole Hybrids As Dual Inhibitors for EGFR/PARP-1 Targeting Breast and Liver Cancer Cells

et al. 2022

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“…All the synthesized compounds were screened for their cytotoxicity using the MTT assay, [36] and the most promising cytotoxic compounds were subjected to VEGFR-2 enzyme assay (BPS Bioscience Corporation catalog#40325) [37] ; finally, apoptotic investigation for the most active compound was carried out using flow cytometry (Annexin V/PI staining and cell-cycle analysis) and RT-PCR assays. [19,38,39] (Detailed methodology was supported in the Supporting Information file).…”

Section: Pharmacological/biological Assaysmentioning

confidence: 99%

2‐Phenylquinazolin‐4(3H)‐one scaffold as newly designed, synthesized VEGFR‐2 allosteric inhibitors with potent cytotoxicity through apoptosis

Elrayess

Elgawish

Nafie

et al. 2023

Archiv der Pharmazie

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New derivatives of 2-phenylquinazolin-4(3H)-one were designed, synthesized, and biologically evaluated as potent allosteric kinase inhibitors with in situ cytotoxicity against MCF-7 and HepG2 cells. Compounds 15 and 18 among the proposed compounds showed promising antiproliferative activity against MCF-7 (IC 50 = 1.35 µM) and HepG2 cells (IC 50 = 3.24 µM), comparable to sorafenib, with IC 50 values of 3.04, 2.93 µM, respectively, according to in situ cytotoxicity testing. Comparing compounds 15 and 18 to sorafenib, the in vitro VEGFR-2 inhibitory activity displayed encouraging selective efficacy with IC 50 values of 13, 67, and 30 nM, respectively. Results of VEGFR-2 inhibition at various ATP concentrations proved that there was no statistically significant difference between the IC 50 values, which improved the non-ATP competitive binding.Compound 15 caused apoptotic breast cancer cell death with 55.11-fold cell-cycle arrest at the S-phase, where it affected the apoptosis-mediated genes through upregulating P53, Bax, caspases 3, 8, and 9 and downregulating the antiapoptotic gene Bcl-2. A molecular docking study was conducted to confirm the binding of the designed compounds to the allosteric site of VEGFR-2 in DFG-out mode, leaving the ATP-binding pocket unoccupied when superimposed to the pose of sorafenib. The designed molecules showed resealable binding affinity toward the DFG loop and the allosteric site. Hence, the 2-phenylquinazolin-4(3H)-one derivative constitutes intriguing starting points for designing apoptotic-inducing drugs.

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“…In a recent work, a novel set of benzimidazo[1,5‐ a ]imidazole, benzimidazo[1,2‐ c ]thiazole, benzimidazotriazine, as well as, benzimidazo[1,2‐ c ]quinazoline platforms were fabricated by means of C−H cycloamination and exploited as efficient anti‐proliferative compounds towards MCF‐7 and A549 cancer cells [76] . The constructed compounds manifested satisfactory in situ cytotoxicity, displaying an IC 50 limit of 9.2–42.3 μM versus MCF‐7 and A549 cancer cell lines, commensurable with 5‐fluorouracil (IC 50 values of 10.32 and 5.8 μM towards above cancer cells).…”

Section: Introductionmentioning

confidence: 99%

Recent Advances in the Anticancer Applications of Benzimidazole Derivatives

Mavvaji,

Akkoc

2023

ChemistrySelect

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Cancer, one of the most deadly diseases worldwide, is still a crucial challenge to human well‐being. Hence, the design and development of modern protocols to cure diverse kinds of cancer seem highly necessary. On the other hand, benzimidazole, as an essential pharmacophore, exhibits various biological and therapeutic potency. This compound is well‐known for its pharmaceutical features, including antifungal, antiviral, antibacterial, and anticancer activities. Therefore, benzimidazole derivatives have played an essential role due to their outstanding anticancer capability, apoptotic effect, and inhibitory potential. In recent decades, numerous anticancer drug types of research have been concentrated on finding new and practical strategies for employing benzimidazole‐based compounds. This review focuses on the latest advancements and methodologies for exploiting various benzimidazole‐bearing compounds for the treatment of varied sorts of cancer, considering the mechanism of their function against cancer cell lines.

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The design and synthesis of potent benzimidazole derivatives via scaffold hybridization and evaluating their antiproliferative and proapoptotic activity against breast and lung cancer cell lines

Abstract: One of the current approaches in drug discovery and development is to synthesize novel small compounds from existing structural motifs via molecular hybridization. In the current study, new series of...

Cited by 13 publications

References 52 publications

Synthesis of New Bioactive Indolyl-1,2,4-Triazole Hybrids As Dual Inhibitors for EGFR/PARP-1 Targeting Breast and Liver Cancer Cells

Synthesis of New Bioactive Indolyl-1,2,4-Triazole Hybrids As Dual Inhibitors for EGFR/PARP-1 Targeting Breast and Liver Cancer Cells

2‐Phenylquinazolin‐4(3H)‐one scaffold as newly designed, synthesized VEGFR‐2 allosteric inhibitors with potent cytotoxicity through apoptosis

Recent Advances in the Anticancer Applications of Benzimidazole Derivatives

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