Novel oxindole/benzofuran hybrids as potential dual CDK2/GSK-3β inhibitors targeting breast cancer: design, synthesis, biological evaluation, and <i>in silico</i> studies

Eldehna, Wagdy M.; Al-Rashood, Sara T.; Al‐Warhi, Tarfah; Eskandrani, Razan O.; Alharbi, Amal; Kerdawy, Ahmed M. El

doi:10.1080/14756366.2020.1862101

Cited by 60 publications

(37 citation statements)

References 119 publications

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“…Furthermore, our most active candidate 6 c was assayed for apoptosis induction using the FITC Annexin-V/PI kit (Becton Dickenson, Franklin Lakes, NJ) following the manufacture’s protocol. The previous compound was analyzed by FACS as we previously described ( Al-Rashood et al, 2020 ; Eliaa et al, 2020 ; Eldehna et al, 2021 ).…”

Section: Methodsmentioning

confidence: 99%

Design and Synthesis of New Quinoxaline Derivatives as Potential Histone Deacetylase Inhibitors Targeting Hepatocellular Carcinoma: In Silico, In Vitro, and SAR Studies

Taghour

Belal

et al. 2021

Front. Chem.

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Guided by the structural optimization principle and the promising anticancer effect of the quinoxaline nucleus, a new series of novel HDAC inhibitors were designed and synthesized. The synthesized compounds were designed to bear the reported pharmacophoric features of the HDAC inhibitors in addition to an extra moiety to occupy the non-used vacant deep pocket of the HDAC receptor. The newly prepared compounds were evaluated for their in vitro anti-proliferative activities against HepG-2 and HuH-7 liver cancer cell lines. The tested compounds showed promising anti-proliferative activities against both cell lines. The most active ten candidates (6c, 6d, 6f, 6g, 6k, 6l, 7b, 8, 10h, and 12) were further evaluated for their effect on the gene expression levels of Bax as an apoptotic marker and Bcl-2 as an anti-apoptotic one. Moreover, they were evaluated for their ability to inhibit histone deacetylase (HDAC1, HDAC4, and HDAC6) activities. Compound 6c achieved the best cytotoxic activities on both HepG-2 and HuH-7 cell lines with IC50 values of 1.53 and 3.06 µM, respectively, and also it showed the most inhibitory activities on HDAC1, HDAC4, and HDAC6 with IC50 values of 1.76, 1.39, and 3.46 µM, respectively, compared to suberoylanilide hydroxamic acid (SAHA) as a reference drug (IC50 = 0.86, 0.97, and 0.93 µM, respectively). Furthermore, it achieved a more characteristic arrest in the growth of cell population of HepG-2 at both G0/G1 and S phases with 1.23-, and 1.18-fold, respectively, compared to that of the control, as determined by cell cycle analysis. Also, compound 6c showed a marked elevation in the AnxV-FITC apoptotic HepG-2 cells percentage in both early and late phases increasing the total apoptosis percentage by 9.98-, and 10.81-fold, respectively, compared to the control. Furthermore, docking studies were carried out to identify the proposed binding mode of the synthesized compounds towards the prospective target (HDAC4). In silico ADMET and toxicity studies revealed that most of the synthesized compounds have accepted profiles of drug-likeness with low toxicity. Finally, an interesting SAR analysis was concluded to help the future design of more potent HDACIs in the future by medicinal chemists.

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Section: Methodsmentioning

confidence: 99%

Design and Synthesis of New Quinoxaline Derivatives as Potential Histone Deacetylase Inhibitors Targeting Hepatocellular Carcinoma: In Silico, In Vitro, and SAR Studies

Taghour

Belal

et al. 2021

Front. Chem.

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“…All the utilised procedures for the biological evaluations have been performed as described previously; cytotoxicity 15 , 30 , 31 , cell cycle 32 , 33 , apoptosis Annexin V-FITC/PI 34 and VEGFR-2 inhibitory 35 assays, and was described in details in the Supplementary Materials .…”

Section: Methodsmentioning

confidence: 99%

Natural inspired piperine-based ureas and amides as novel antitumor agents towards breast cancer

Elimam

Elgazar

El-Senduny

et al. 2021

Journal of Enzyme Inhibition and Medicinal Chemistry

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In this work, the natural piperine moiety was utilised to develop two sets of piperine-based amides ( 5a–i ) and ureas ( 8a–y ) as potential anticancer agents. The anticancer action was assessed against triple negative breast cancer (TNBC) MDA-MB-231, ovarian A2780CP and hepatocellular HepG2 cancer cell lines. In particular, 8q stood out as the most potent anti-proliferative analogue against TNBC MDA-MB-231 cells with IC 50 equals 18.7 µM, which is better than that of piperine (IC 50 = 47.8 µM) and 5-FU (IC 50 = 38.5 µM). Furthermore, 8q was investigated for its possible mechanism of action in MDA-MB-231 cells via Annexin V-FITC apoptosis assay and cell cycle analysis. Moreover, an in-silico analysis has proposed VEGFR-2 as a probable enzymatic target for piperine-based derivatives, and then has explored the binding interactions within VEGFR-2 active site (PDB:4ASD). Finally, an in vitro VEGFR-2 inhibition assay was performed to validate the in silico findings, where 8q showed good VEGFR-2 inhibitory activity with IC 50 = 231 nM.

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“…All adopted procedures for the conducted in vitro biological assays were performed as described earlier; CA (stopped-flow [ 4 , 30 , 36 ]), cytotoxicity (MTT [ 37 , 38 ]), and assessment of apoptotic markers [ 39 , 40 ] assays, as well as induction of hypoxia with cobalt chloride [ 41 , 42 ], and were mentioned in the Supporting Materials .…”

Section: Methodsmentioning

confidence: 99%

Development of Novel Quinoline-Based Sulfonamides as Selective Cancer-Associated Carbonic Anhydrase Isoform IX Inhibitors

Shaldam

Nocentini

Elsayed

et al. 2021

IJMS

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A new series of quinoline-based benzenesulfonamides (QBS) were developed as potential carbonic anhydrase inhibitors (CAIs). The target QBS CAIs is based on the 4-anilinoquinoline scaffold where the primary sulphonamide functionality was grafted at C4 of the anilino moiety as a zinc anchoring group (QBS 13a–c); thereafter, the sulphonamide group was switched to ortho- and meta-positions to afford regioisomers 9a–d and 11a–g. Moreover, a linker elongation approach was adopted where the amino linker was replaced by a hydrazide one to afford QBS 16. All the described QBS have been synthesized and investigated for their CA inhibitory action against hCA I, II, IX and XII. In general, para-sulphonamide derivatives 13a–c displayed the best inhibitory activity against both cancer-related isoforms hCA IX (KIs = 25.8, 5.5 and 18.6 nM, respectively) and hCA XII (KIs = 9.8, 13.2 and 8.7 nM, respectively), beside the excellent hCA IX inhibitory activity exerted by meta-sulphonamide derivative 11c (KI = 8.4 nM). The most promising QBS were further evaluated for their anticancer and pro-apoptotic activities on two cancer cell lines (MDA-MB-231 and MCF-7). In addition, molecular docking simulation studies were applied to justify the acquired CA inhibitory action of the target QBS.

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Novel oxindole/benzofuran hybrids as potential dual CDK2/GSK-3β inhibitors targeting breast cancer: design, synthesis, biological evaluation, and in silico studies

Cited by 60 publications

References 119 publications

Design and Synthesis of New Quinoxaline Derivatives as Potential Histone Deacetylase Inhibitors Targeting Hepatocellular Carcinoma: In Silico, In Vitro, and SAR Studies

Design and Synthesis of New Quinoxaline Derivatives as Potential Histone Deacetylase Inhibitors Targeting Hepatocellular Carcinoma: In Silico, In Vitro, and SAR Studies

Natural inspired piperine-based ureas and amides as novel antitumor agents towards breast cancer

Development of Novel Quinoline-Based Sulfonamides as Selective Cancer-Associated Carbonic Anhydrase Isoform IX Inhibitors

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