Optimization of pyrazole/1,2,4-triazole as dual EGFR/COX-2 inhibitors: Design, synthesis, anticancer potential, apoptosis induction and cell cycle analysis.
A novel series of pyrazol-4-yl-1,2,4-triazole-3-thiol derivatives 14a-l was designed, prepared and characterized by many spectroscopic techniques. All the novel compounds were screened for their anti-proliferative activity towards breast cancer cell line (MCF-7), colon cancer cell line (HT-29) and lung cancer cell line (A-549) utilizing celecoxib, erlotinib and osimertinib as standards. Compounds 14b, 14g and 14k were the most active towards HT-29, MCF-7 and A-549 cell lines, sequentially with IC50 = 1.20-2.93 μM compared with celecoxib (IC50 = 16.47-41.45 μM), erlotinib (IC50 = 1.95-33.57 μM) and osimertinib (IC50 = 0.75-3.45 μM). These most active derivatives 14b, 14g and 14k were further investigated for their inhibitory potential against COX and EGFR enzymes. These compounds 14b, 14g and 14k suppressed COX-2 (IC50 = 0.560-4.692 μM), EGFRWT (IC50 = 0.121-0.423 μM) and EGFRT790M (IC50 = 0.076-0.764 μM) enzymes. Compounds 14b, 14g and 14k displayed apoptosis induction by up-regulating Bax and down-regulating Bcl-2 protein levels. Cell cycle analysis recorded that exposure of MFC-7 cells to compound 14g resulted in a significant increase in the percentage of cells at the G2/M to 39.15 % compared to the standard erlotinib (9.87 %). Docking study of the most potent candidates 14b, 14g and 14k within COX-2, EGFRWT and EGFRT790M active regions was conducted to suggest the binding mode of these compounds inside these target enzymes.
Kahk NM
，Mohamed FEA
，Abdelhakeem MM
，Bakr RB
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Discovery of novel pyrazole based Urea/Thiourea derivatives as multiple targeting VEGFR-2, EGFR(WT), EGFR(T790M) tyrosine kinases and COX-2 Inhibitors, with anti-cancer and anti-inflammatory activities.
A novel series of pyrazole derivatives with urea/thiourea scaffolds 16a-l as hybrid sorafenib/erlotinib/celecoxib analogs was designed, synthesized and tested for its VEGFR-2, EGFRWT, EGFRT790M tyrosine kinases and COX-2, pro-inflammatory cytokines TNF-α and IL-6 inhibitory activities. All the tested compounds showed excellent COX-2 selectivity index in range of 18.04-47.87 compared to celecoxib (S.I. = 26.17) and TNF-α and IL-6 inhibitory activities (IC50 = 5.0-7.50, 6.23-8.93 respectively, compared to celecoxib IC50 = 8.40 and 8.50, respectively). Screening was carried out against 60 human cancer cell lines by National Cancer Institute (NCI), compounds 16a, 16c, 16d and 16 g were the most potent inhibitors with GI% ranges of 100 %, 99.63-87.02 %, 98.98-43.10 % and 98.68-23.62 % respectively, and with GI50 values of 1.76-15.50 µM, 1.60-5.38 µM, 1.68-7.39 µM and 1.81-11.0 µM respectively, in addition, of showing good safety profile against normal cell line (F180). Moreover, compounds 16a, 16c, 16d and 16 g had cell cycle arrest at G2/M phase with induced necrotic percentage compared to sorafenib of 2.06 %, 2.47 %, 1.57 %, 0.88 % and 1.83 % respectively. Amusingly, compounds 16a, 16c, 16d and 16 g inhibited VEGFR-2 with IC50 of 25 nM, 52 nM, 324 nM and 110 nM respectively, compared to sorafenib (IC50 = 85 nM), and had excellent EGFRWT and EGFRT790M kinase inhibitory activities (IC50 = 94 nM, 128 nM, 160 nM, 297 nM), (10 nM, 25 nM, 36 nM and 48 nM) respectively, compared to both erlotinib and osimertinib (IC50 = 114 nM, 56 nM) and (70 nM, 37 nM) respectively and showed (EGFRwt/EGFRT790M S.I.) of (range: 4.44-9.40) compared to erlotinib (2.03) and osmertinib (1.89).
Fadaly WAA
，Nemr MTM
，Kahk NM
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Novel quinazolin-2-yl 1,2,3-triazole hybrids as promising multi-target anticancer agents: Design, synthesis, and molecular docking study.
In our study, a series of quinazoline-1,2,3-triazole hybrids (14a-r) have been designed and synthesized as multi-target EGFR, VEGFR-2, and Topo II inhibitors. All synthesized hybrids were assessed for their anticancer capacity. MTT assay revealed that compounds 14a, 14d, and 14k were the most potent hybrids against four cancer cell lines, HeLa, HePG-2, MCF-7, and HCT-116 at low micromolar range while exhibiting good selectivity against normal cell line WI-38. Sequentially, the three compounds were evaluated for EGFR, VEGFR-2, and Topo II inhibition. Compound 14d was moderate EGFR inhibitor (IC50 0.103 µM) compared to Erlotinib (IC50 0.049 µM), good VEGFR-2 inhibitor (IC50 0.069 µM) compared to Sorafenib (IC50 0.031 µM), and stronger Topo II inhibitor (IC50 19.74 µM) compared to Etoposide (IC50 34.19 µM) by about 1.7 folds. Compounds 14k and 14a represented strong inhibitory activity against Topo II with (IC50 31.02 µM and 56.3 µM) respectively, compared to Etoposide. Additionally, cell cycle analysis and apoptotic induction were performed. Compound 14d arrested the cell cycle on HeLa at G2/M phase by 17.53 % and enhanced apoptosis by 44.08 %. A molecular Docking study was implemented on the three hybrids and showed proper binding interaction with EGFR, VEGFR-2, and Topo II active sites.
El Hamaky NFM
，Hamdi A
，Bayoumi WA
，Elgazar AA
，Nasr MNA
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Exploring 1,2,3-triazole-Schiff's base hybrids as innovative EGFR inhibitors for the treatment of breast cancer: In vitro and in silico study.
EGFR inhibitors are a class of targeted therapies utilized in the management of certain tumor kinds such as NSCLC and breast cancer. Series of 1,2,3-triazole-Schiff's base hybrids were designed, synthesized, and estimated for their antitumor effect toward breast cancer cells, MCF-7 and MDA-MB-231. The safety and selectivity of the new compounds were tested using normal cell (WI-38). Analogs 4a, 4b, and 5f demonstrated significant antitumor effects toward both MCF-7 and MDA-MB-231 with IC50 range of 5.61-18.01 µM in comparison to Doxorubicin (6.72 µM). Moreover, they proved considerable selectivity toward the tested cancer cells (SI values of 4.36-5.33). The superior compounds were investigated for EGFR inhibition where compounds 4b and 5f showed the highest EGFR inhibition effect with IC50 equal 0.16 and 0.15 µM, respectively utilizing Gefitinib as reference (IC50 = 0.081 µM). Further mechanistic studies for hybrid 5f in MDA-MB-231 cells, exhibited cell cycle arrest at G2/M phase by 29.85 % that was accompanied by the elevation of apoptosis percent by 48-fold more than the control. The apoptosis studies indicated that hybrid 5f was able to upregulate Bax (9.43 folds) while downregulate Bcl-2 (0.27) with substantial remarkable elevation of Bax/Bcl-2 ratio (35:1). Furthermore, it upregulated both caspases 8 and 9 by 2.93 and 6.54-fold, respectively. Molecular modeling studies showed the good binding affinity of compounds 4b and 5f with EGFR kinase active site explaining their potent biological effects. Drug likeness and ADMET features of compounds 4b and 5f demonstrated that they represent promising drug like candidates against breast cancer.
Nawareg NA
，Yassen ASA
，Husseiny EM
，El-Sayed MAA
，Elshihawy HA
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