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 ... -  《-》

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 ... -  《-》

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 ... -  《-》

New molecular hybrids integrated with quinoxaline and pyrazole structural motifs: VGFR2 inhibitors and apoptosis inducers.

The vascular endothelial growth factor receptor is essential for the angiogenesis of cancer. Tumor propagation was effectively suppressed by inhibiting VEGFR-2 activity. As a result, the target quinoxaline-pyrazole hybrids were created in a way that closely resembled the structural characteristics of VEGFR-2 inhibitors. The synthesized compounds were assessed in vitro using the MTT assay with doxorubicin serving as a reference standard for their cytotoxic properties against the HCT-116 and MCF-7 cell lines. Additionally, when tested on human normal fibroblasts (WI38), the promising cytotoxic compounds 8, 11, 13, and 15 were shown to be selective to cancer cells. Using ELISA, they showed mechanistically inhibitory activities against VEGFR-2; compound 13 was the most effective inhibitor, with an IC50 of 0.045 ± 6.24 uM, surpassing sorafenib (IC50 of 0.049 ± 5.24 μM). Notably, it was discovered that our target compound, 13, was 1.1 times more potent than sorafenib and 3.19 times more potent than sunitinib as a VGFRA2 inhibitor. Furthermore, Western blot analysis revealed that its VEGFR2 protein levels were noticeably higher than the control. Compound 13's selectivity towards VEGFR2 was further confirmed by testing it against other kinases, such as PDGFRA (IC50 0.329 ± 0.014 μM) and EGFR (IC50 0.6 ± 0.019 μM). Furthermore, 13 demonstrated a 50 % decrease in VEGF-A secretion in comparison to the control group, demonstrating its anti-angiogenic quality. A scratch closure percentage of 57.78 %, which was much lower than the 97.04 percent of untreated control cells, showed 13's anti-migratory capability. According to the cell cycle study, compound 13 induces apoptosis at the sub-G1 phase and terminates the cell cycle at the G1 phase. Consequently,flow cytometric analysis revealed that it caused apoptosis; compound 13 increases the BAX/Bcl-2 ratio from control to 13.66, and it also activates caspase 3 to 422.48 ± 43.82 and induces p53 to 366.79 ± 40.21. Docking simulations revealed potential binding modes and crucial structural elements of active drugs, and they were almost in agreement with enzymatic examination. For every hybrid, in silico physicochemical attributes, drug likeness metrics, and ligand efficiency were plausible. It's interesting to note that 13 and 15 are plausible medication candidates.

Ismail MMF ，Shawer TZ ，Ibrahim RS ，Elnagar MR ，Ammar YA ... -  《-》

Discovery of new pyrimidine-5-carbonitrile derivatives as anticancer agents targeting EGFR(WT) and EGFR(T790M).

Nasser AA ，Eissa IH ，Oun MR ，El-Zahabi MA ，Taghour MS ，Belal A ，Saleh AM ，Mehany ABM ，Luesch H ，Mostafa AE ，Afifi WM ，Rocca JR ，Mahdy HA ... -  《-》