Development of novel benzofuran-isatin conjugates as potential antiproliferative agents with apoptosis inducing mechanism in Colon cancer

Eldehna, Wagdy M.; Salem, Rofaida; Elsayed, Zainab M.; Al‐Warhi, Tarfah; Knany, Hamada R.; Ayyad, Rezk R.; Traiki, Thamer Bin; Abdulla, Maha-Hamadien; Ahmad, Rehan; Abdel‐Aziz, Hatem A.; El-Haggar, Radwan

doi:10.1080/14756366.2021.1944127

Cited by 25 publications

(25 citation statements)

References 67 publications

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“…The search for new anticancer drugs requires potent inhibitory effects on cancer cell migration, invasion, and tumorigenesis. Thus, in this present study, after confirming the reported cytotoxic effect of the synthetic Compound 5a, a benzofuran-isatin conjugate, on colorectal adenocarcinoma HT29 and metastatic CRC SW620 cells (Eldehna et al, 2021c), we showed that Compound 5a exerted anticancer activities by inhibiting CRC cell proliferation, migration, invasion, and colony formation. Compound 5a also reversed epithelial-mesenchymal transition (EMT) phenotype markers by elevating E-cadherin expression and suppressing N-cadherin expression.…”

Section: Discussionsupporting

confidence: 89%

“…A complex process occurred in activating the extrinsic death receptor-dependent and intrinsic signaling pathways, and flow cytometry was applied for apoptosis determination and MtMP evaluation. Herein, after confirming the reported pro-apoptotic effect of Compound 5a, an increase in apoptotic cells was observed when both CRC cells were exposed to a higher concentration (20 μM) of Compound 5a (Eldehna et al, 2021c). At lower concentrations (5-10 μM), Compound 5a doubled (i.e., 10 vs. 5 μM) the percentage of apoptotic CRC cells, which aligned with Compound 5a-induced p53 upregulation, tumor suppressor protein well described to mediate apoptosis (Marei et al, 2021).…”

Section: Discussionsupporting

confidence: 85%

“…We also previously reported that the observed Compound 5ainduced apoptosis resulted in the suppression of the mitochondrial pro-apoptotic protein Bcl-2 expression and the enhancement of PARP cleavage, suppressing DNA repair (Eldehna et al, 2021c).…”

Section: Compound 5a Prompted Apoptosis Downregulated Bcl-xl Upregula...mentioning

confidence: 66%

“…Moreover, several recent studies have adopted the hybridization approach to conjugate the isatin moiety with diverse heterocycles to develop promising anticancer molecules ( El-Naggar et al, 2018 ; Eldehna et al, 2021a ; Eldehna et al, 2021b ). Recently we have reported a series of benzofuran-isatin conjugates as a novel anticancer agent with apoptosis-inducing molecular mechanisms using colon cancer cell lines ( Eldehna et al, 2021c ). In particular, Compound 5a (3-methyl-N'-(2-oxoindolin-3-ylidene)benzofuran-2-carbohydrazide) displayed potent and selective anti-proliferative action towards SW620 and HT29 CRC cell lines and provoked apoptosis in a dose-dependent manner in SW620 cells ( Eldehna et al, 2021c ).…”

Section: Introductionmentioning

confidence: 99%

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The Anticancer Effects of the Pro-Apoptotic Benzofuran-Isatin Conjugate (5a) Are Associated With p53 Upregulation and Enhancement of Conventional Chemotherapeutic Drug Efficiency in Colorectal Cancer Cell Lines

et al. 2022

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The present study aimed to investigate in-depth a cytotoxic novel benzofuran-isatin conjugate (5a, 3-methyl-N'-(2-oxoindolin-3-ylidene)benzofuran-2-carbohydrazide) with promising potential anticancer activities in colorectal adenocarcinoma HT29 and metastatic colorectal cancer (CRC) SW620 cell lines. Thus, the primary cell events involved in tumorigenicity, tumor development, metastasis, and chemotherapy response were explored. Both CRC cell lines were exposed to different concentrations of Compound 5a and then subjected to real-time cell viability, migration, and invasion assays, colony formation and cytotoxicity assays, and flow cytometry for cell cycle analysis and apoptosis determination. Western blot and RT-qPCR were performed to assess the protein and transcript expression levels of epithelial-mesenchymal transition (EMT), cell cycle, and apoptosis markers. We showed that the Compound 5a treatment exhibited anticancer effects through inhibition of HT29 and SW620 cell viability, migration, and invasion, in a dose-dependent manner, which were associated with the upregulation of the tumor suppressor p53. Compound 5a also inhibited the colony formation ability of HT29 and SW620 cells and reversed EMT markers E-cadherin and N-cadherin expression. CRC cell exposure to Compound 5a resulted in a cell cycle arrest at the G1/G0 phase in HT29 cells and at the G2/M phase in SW620 cells, along with the downregulation of cyclin A1 expression, described to be involved in the S phase entry. Furthermore, Compound 5a-induced apoptosis was associated with the downregulation of the anti-apoptotic Bcl-xl marker, upregulation of pro-apoptotic Bax and cytochrome c markers, and increased mitochondrial outer membrane permeability, suggesting the involvement of mitochondria-dependent apoptosis pathway. In addition, the combination studies of Compound 5a with the main conventional chemotherapeutic drugs 5-fluorouracil, irinotecan, and oxaliplatin showed a more potent cytotoxic effect in both CRC cells than a single treatment. In conclusion, our findings described the interesting in vitro anticancer properties of Compound 5a, shown to have possible antitumor, antimetastatic, and pro-apoptotic activities, with the enhancement of the cytotoxic efficiency of conventional chemotherapeutic drugs. In vivo studies are requested to confirm the promising anticancer potential of Compound 5a for CRC therapy.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionsupporting

confidence: 85%

Section: Compound 5a Prompted Apoptosis Downregulated Bcl-xl Upregula...mentioning

confidence: 66%

Section: Introductionmentioning

confidence: 99%

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The Anticancer Effects of the Pro-Apoptotic Benzofuran-Isatin Conjugate (5a) Are Associated With p53 Upregulation and Enhancement of Conventional Chemotherapeutic Drug Efficiency in Colorectal Cancer Cell Lines

et al. 2022

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“…The anticancer test was conducted using the methods of the Drug Evaluation Branch, National Cancer Institute, Bethesda, MD, using 59 human tumour cell lines derived from nine human tissues. The GI 50 , TGI, and LC 50 dose-response parameters were calculated for each medication 37–39 .…”

Section: Methodsmentioning

confidence: 99%

Novel 3-(6-methylpyridin-2-yl)coumarin-based chalcones as selective inhibitors of cancer-related carbonic anhydrases IX and XII endowed with anti-proliferative activity

Tawfik

Shaldam

Nocentini

et al. 2022

Journal of Enzyme Inhibition and Medicinal Chemistry

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Carbonic anhydrases (CAs) are one of the promising targets for the development of anticancer agents. CA isoforms are implicated in various physiological processes and are expressed in both normal and cancerous cells. Thus, non-isoform selective inhibitors are associated with several side effects. Consequently, designing selective inhibitors towards cancer-related h CA IX/XII rather than the ubiquitous cytosolic isozymes h CA I and II is the main research objective in the field. Herein, a new series of 3-(6-methylpyridin-2-yl)coumarin derivatives 3 and 5a–o was designed and synthesised. The CA inhibition activities for the synthesised coumarins were analysed on isoforms h CA I, II, IX, and XII. Interestingly, both cancer-linked isoforms h CA IX/XII were inhibited by the prepared coumarins with inhibition constants ranging from sub- to low-micromolar range, whereas h CA I and II isoforms haven’t been inhibited up to 100 µM. Furthermore, the target coumarins were assessed for their antitumor activity on NCI-59 human cancer types.

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New [1,2,4]triazolo[4,3‐c]quinazoline derivatives as vascular endothelial growth factor receptor‐2 inhibitors and apoptosis inducers: Design, synthesis, docking, and antiproliferative evaluation

Azab

Alesawy

Eldehna

et al. 2022

Archiv der Pharmazie

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In continuation of our previous efforts in the field of design and synthesis of vascular endothelial growth factor receptor (VEGFR)-2 inhibitors, a new series of [1,2,4] triazolo [4,3-c]quinazoline derivatives were designed and synthesized as modified analogs of some reported VEGFR-2 inhibitors. The synthesized compounds were designed to have the essential pharmacophoric features of VEGFR-2 inhibitors.Antiproliferative activities of the synthesized compounds were investigated against two tumor cell lines (HepG2 and HCT-116) using sorafenib as a positive control.Compound 10k emerged as the most promising antiproliferative agent with IC 50 values of 4.88 and 5.21 µM against HepG2 and HCT-116 cells, respectively. Also, it showed the highest inhibitory activity against VEGFR-2 with an IC 50 value of 53.81 nM compared to sorafenib (IC 50 = 44.34 nM). Cell cycle analysis revealed that compound 10k can arrest HepG2 cells at both the S and G2/M phases. In addition, this compound produced a tenfold increase in apoptotic cells compared to the control. Furthermore, the effect of compound 10k on the expression level of BAX, Bcl-2, and caspase-3 was assessed. This compound caused a 3.35-fold increase in BAX expression levels and a 1.25-fold reduction in Bcl-2 expression levels. The BAX/Bcl-2 ratio was calculated to be 4.57, indicating a promising apoptotic effect. It also showed a significant increase in the level of caspase-3 (4.12-fold) compared to the control cells. In silico docking, absorption, distribution, metabolism, excretion, and toxicity, and toxicity studies were performed for the synthesized compounds to investigate their binding patterns against the proposed biological target (VEGFR-2) and to assess the drug-likeness characters.

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Development of novel benzofuran-isatin conjugates as potential antiproliferative agents with apoptosis inducing mechanism in Colon cancer

Cited by 25 publications

References 67 publications

The Anticancer Effects of the Pro-Apoptotic Benzofuran-Isatin Conjugate (5a) Are Associated With p53 Upregulation and Enhancement of Conventional Chemotherapeutic Drug Efficiency in Colorectal Cancer Cell Lines

The Anticancer Effects of the Pro-Apoptotic Benzofuran-Isatin Conjugate (5a) Are Associated With p53 Upregulation and Enhancement of Conventional Chemotherapeutic Drug Efficiency in Colorectal Cancer Cell Lines

Novel 3-(6-methylpyridin-2-yl)coumarin-based chalcones as selective inhibitors of cancer-related carbonic anhydrases IX and XII endowed with anti-proliferative activity

New [1,2,4]triazolo[4,3‐c]quinazoline derivatives as vascular endothelial growth factor receptor‐2 inhibitors and apoptosis inducers: Design, synthesis, docking, and antiproliferative evaluation

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