Synthesis, cytotoxic evaluation, and molecular docking studies of novel quinazoline derivatives with benzenesulfonamide and anilide tails: Dual inhibitors of EGFR/HER2

Alkahtani, Hamad M.; Abdalla, Ashraf N.; Obaidullah, Ahmad J.; Alanazi, Mohammed M.; Almehizia, Abdulrahman A.; Alanazi, Mashael G.; Ahmed, Ahmed Y.; Alwassil, Osama I.; Darwish, Hany W.; Abdel‐Aziz, Alaa A.‐M.; El‐Azab, Adel S.

doi:10.1016/j.bioorg.2019.103461

Cited by 46 publications

(41 citation statements)

References 55 publications

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“…First, the MTT assay was performed for each of the three compounds, and the IC 50 values are shown in Table 3 . The IC 50 of HAA 2020 was similar to a previous report in MCF7 cells: 480 nM [ 22 ]. Following this, a combination study was performed in MCF7 cells (72 h) between HAA 2020 and tamoxifen (this ratio was selected based on the two compounds’ IC 50 values: 1:1.5, respectively) which showed synergistic activity (CI: 0.964, calculated using Compusyn).…”

Section: Resultssupporting

confidence: 87%

“…Based on the previous PA results of this study, the multi-kinase inhibitor HAA 2020 (previously described novel quinazoline that showed potent EGFR, VEGFR-2, Her2, and Hsp90 inhibition activities [ 22 , 23 ]) was selected for combination studies with tamoxifen using the MTT assay. Additionally, to address the importance of the cell cycle G 1 /S phases, the pan CDK and cyclin D1 inhibitor dinaciclib was selected for the comparative MTT combination studies with tamoxifen and HAA 2020.…”

Section: Resultsmentioning

confidence: 99%

“…Compound 1 also showed cytotoxicity against MCF7, HL60, K562, and HT29 cancer cell lines, and displayed selectivity towards these cancer cells compared to MRC5 normal cells, all of which was comparable to sorafinib. The IC 50 of compound 1 against MCF7 was better compared to sorafinib against the same cells (0.65 and 2.50 µM, respectively) [ 22 ]. In another study, the Hsp90 inhibition activity of compound 1 (named HAA 2020 ) was tested using the surface plasmon resonance (SRB).…”

Section: Discussionmentioning

confidence: 99%

“…Dinaciclib and tamoxifen were purchased from Selleckchem, Houston, TX, USA. HAA 2020 was thankfully provided by our collaborating group [ 22 ] ( Figure 10 ). All reagents and kits used in this study were purchased from Sigma-Aldrich (St. Louis, MO, USA) unless another manufacturer is shown.…”

Section: Methodsmentioning

confidence: 99%

“…The objective of this study was to determine the most important targetable kinase pathways and networks that are differentially upregulated in collected Saudi hormonal luminal-A clinical samples using PamChip pathway analysis. In addition, based on this result, the multi-kinase inhibitor (compound 1 “HAA 2020 ”: [ 22 ]) and the pan CDK inhibitor (dinaciclib) were used to target the resulting pathways in MCF7 cells as a model for luminal-A breast cancer. The effect of HAA 2020 and dinaciclib was compared with tamoxifen in single and combined treatments.…”

Section: Introductionmentioning

confidence: 99%

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Significance of Targeting VEGFR-2 and Cyclin D1 in Luminal-A Breast Cancer

et al. 2020

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The hormonal luminal-A is the most pre-dominant sub type of breast cancer (BC), and it is associated with a high level of cyclin D1 in Saudi patients. Tamoxifen is the golden therapy for hormonal BC, but resistance of cancer cells to tamoxifen contributes to the recurrence of BC due to many reasons, including high levels of AIB1 and cyclin D1. Overcoming drug resistance could be achieved by exploring alternative targetable therapeutic pathways and new drugs or combinations. The objective of this study was to determine the differentially enriched pathways in 12 samples of Saudi women diagnosed with luminal-A using the PamChip peptide microarray-based kinase activity profiling, and to compare the activity of HAA2020 and dinaciclib with tamoxifen in singles and combinations in the MCF7 luminal-A cell line. Our results of network and pathway analysis of the 12 samples highlighted the importance of VEGFR and CDKs in promoting luminal-A breast cancer. The activation of VEGF signaling via VEGFR-2 leads to activation of PI3K/AKT kinases and an increase of cell survival, and leads to activation of Hsp90, which induces the phosphorylation of FAK1, resulting in cytoskeleton remodeling. PLC-gamma 1 is also activated, leading to FAK-2 and PKC activation. Notably, the G1/S cell cycle phases and phosphorylation processes contribute to the top seven tumorigenesis processes in the 12 samples. Further, the MTT combination of HAA2020 and dinaciclib showed the best combination index (CI), was more clonogenic against MCF7 cells compared to the other combinations, and it also showed the best selectivity index (SI) in normal MRC5 cells. Interestingly, HAA2020 and dinaciclib showed a synergistic apoptotic and G1 cell cycle effect in MCF7 cells, which was supported by their synergistic CDK2, cyclin D1, and PCNA inhibition activities. Additionally, the combination showed VEGFR-2 and Hsp90 inhibition activities in MCF7 cells. The results show the significance of targeting VEGFR-2 and cyclin D1 in Saudi luminal-A breast cancer patients, and the effect of combining HAA2020 and dinaciclib on those targets in the MCF7 model. It also warrants further preclinical and in vivo investigations for the combination of HAA2020 and dinaciclib as a possible future second-line treatment for luminal-A breast cancers.

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Section: Resultssupporting

confidence: 87%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Significance of Targeting VEGFR-2 and Cyclin D1 in Luminal-A Breast Cancer

et al. 2020

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Synthesis, cytotoxicity and apoptosis‐inducing activity of novel 1H‐benzo[d]imidazole derivatives of dehydroabietic acid

Yang

Wang

et al. 2020

J Chinese Chemical Soc

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With the expectation of finding new and effective antitumor drugs, a series of novel N-(1H-benzo[d]imidazole-2-yl)-benzamide/benzenesulfonamide derivatives of dehydroabietic acid were synthesized and evaluated for cytotoxic activity against three human cancer cell lines (MCF-7, HeLa, and HepG2 cells) and one human normal hepatocyte cell line (LO2). As a result, a number of derivatives showed moderate to good antitumor activities. Among them, compound 8h exhibited the most potent activities against three cancer cell lines with IC 50 values of 0.87 ± 0.18, 9.39 ± 0.72, and 8.31 ± 0.64 μM, respectively, and was less active to normal hepatocyte LO2 cells. Further mechanism studies revealed that compound 8h could arrest the cell cycle of MCF-7 cells at S phase and induce the apoptosis of MCF-7 cells in ROS-mediated mitochondrial pathway.

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Green synthesis of 2‐thioxo‐4‐quinazolinones from 2‐aminobenzamide and isothiocyanates

Vo,

Nguyen,

Tran

et al. 2024

Vietnam Journal of Chemistry

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Novel green synthesis protocols of 2‐thioxo‐4‐quinazolinones starting from 2‐aminobenzamide and isothiocyanates have been reported. Method A: the reaction was carried out at 60 °C, in water, reaction time of 16 h. Method B: The reaction was carried out under solvent‐free conditions at 100 °C for 16 h. Based on these methods, six 2‐thixo‐4‐quinazolinone derivatives were synthesized with good yield. These methods have advantages, including no use of organic solvents, additives that avoid the generation of toxic waste, simple processes, cost‐effectiveness, good yields, ease of product isolation, and purification.

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Synthesis, cytotoxic evaluation, and molecular docking studies of novel quinazoline derivatives with benzenesulfonamide and anilide tails: Dual inhibitors of EGFR/HER2

Cited by 46 publications

References 55 publications

Significance of Targeting VEGFR-2 and Cyclin D1 in Luminal-A Breast Cancer

Significance of Targeting VEGFR-2 and Cyclin D1 in Luminal-A Breast Cancer

Synthesis, cytotoxicity and apoptosis‐inducing activity of novel 1H‐benzo[d]imidazole derivatives of dehydroabietic acid

Green synthesis of 2‐thioxo‐4‐quinazolinones from 2‐aminobenzamide and isothiocyanates

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