Design, Synthesis, Docking Studies, and Investigation of Dual EGFR/VEGFR-2 Inhibitory Potentials of New Pyrazole and Pyrazolopyridine Derivatives.

The anticancer potential of certain newly synthesized pyrazole and pyrazolopyridine derivatives has been estimated. NCI 60 cancer cells cytotoxic screening pointed out compounds 3e and 3f as the highest cytotoxic agents with % mean growth inhibition of 67.69% and 87.34%, respectively. The five dose outcomes outlined 3f as the most potent cytotoxic agent with promising MG-MID GI50 = 3.3 µM when compared to erlotinib (MG-MID GI50 = 7.68 µM). In the in vitro assays, compounds 3d, 3e, 3f, and 4a demonstrated dual inhibitory potential on EGFRWT and VEGFR-2 with IC50 range of 0.066-0.184 µM and 0.102-0.418 µM, respectively. The best dual EGFR/VEGRF-2 inhibitory effect was shown by the compound 3f. Moreover, the latter compound stopped the cell cycle at the G1/S phase. Also, it greatly boosted total apoptosis, including early and late apoptosis, by 54.5- and 84.7-fold, respectively, which supposes HCT-116 cell death via inducing apoptosis. This was confirmed by the elevation of the BAX and caspase-3 levels, and the decreased BCL-2 level. Moreover, the safety of the most active compound 3f was assessed and the results showed promising selectivity of compound 3f toward HCT-116 over FHC (selectivity index [SI]: 20.84) when compared to erlotinib (SI: 3.42). Finally, compound 3f demonstrated efficient binding to both EGFR and VEGFR-2 enzymes, which could explain the sufficient inhibition level of each enzyme.

Alhamaky SM ，Khalil NA ，Bass AKA ，Osama N ，Hassan MSA ... -  《-》

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 《-》

Phthalazine Derivatives as VEGFR-2 Inhibitors: Docking, ADMET, Synthesis, Design, Anticancer Evaluations, and Apoptosis Inducers.

New phthalazine-derived inhibitors for VEGFR-2 were synthesized for anticancer evaluations. Also, docking studies were performed to explore the suggested binding orientations of the novel derivatives inside the binding site of VEGFR-2. The achieved biological data were extremely interrelated to that of docking study. In specific, derivative 3f was the greatest effective compound against HepG2 and MCF-7 cancer cell lines with IC50 = 0.17 ± 0.01 and 0.08 ± 0.01 µM individually. The six highly active derivatives 3b, 3e, 3f, 3g, 6a, and 6b were estimated for their VEGFR-2 inhibitory effects. Derivative 3f was the greatest effective compound which inhibited VEGFR-2 at IC50 = 0.0557 ± 0.002 µM. The activities of 3f were assessed against MCF-7 cancer cells for apoptosis induction, cell cycle distribution, and growth inhibition. Compound 3f induced early apoptosis (21.44%) by more than 36 folds over the control (0.59%). The obtained results showed that compound 3f induced necrotic effect (6.03%) by more than threefolds over the control (1.75%). On the other hand, compound 3f improved the level of the pro-apoptotic protein; Bax by approximately fivefolds. Moreover, compound 3f noticeably decreased the levels of the anti-apoptotic proteins Bcl-2 by nearly fourfolds in comparison to the control. In addition, derivative 3f remarkably enhanced the Bax/Bcl2 ratio by nearly 18 folds, as compared to the control. Finally, our derivatives 3f, 3g, and 6b revealed good in silico considered ADMET profile in comparing to sorafenib.

Bayoumi HH ，Ibrahim MK ，Dahab MA ，Khedr F ，El-Adl K ... -  《-》

Design, synthesis and biological evaluation of a new series of thiazolyl-pyrazolines as dual EGFR and HER2 inhibitors.

Epidermal growth factor receptor (EGFR, also known as HER1) and HER2, prominent members of receptor tyrosine kinase (RTK) superfamily, have been reported as diagnostic or prognostic markers in tumor progression. Based on the importance of molecular hybridization of pyrazoline and thiazole scaffolds in the discovery of potent anticancer agents, new thiazolyl-pyrazoline derivatives (3a-v) were synthesized and screened for their cytotoxic effects on A549 human lung adenocarcinoma, MCF-7 human breast adenocarcinoma and A375 human melanoma cell lines. 1-(4-(4-Fluorophenyl)thiazol-2-yl)-3-(4-morpholinophenyl)-5-(4-chlorophenyl)-2-pyrazoline (3c),1-(4-(4-cyanophenyl)thiazol-2-yl)-3-(4-morpholinophenyl)-5-(4-chlorophenyl)-2-pyrazoline (3f) and 1-(4-(4-cyanophenyl)thiazol-2-yl)-3-(4-piperidinophenyl)-5-(4-chlorophenyl)-2-pyrazoline (3q) were found as the most potent anticancer agents against A549 and MCF-7 cell lines compared to erlotinib. Compound 3q also showed moderate cytotoxic activity against A375 cell line. Moreover, these compounds exert a cancer cell-selective action against Jurkat cell line posing no toxicity on peripheral blood mononuclear cells (PBMCs). In order to enlighten the mechanism of action underlying anticancer activity, compounds 3c, 3f and 3q were investigated for their apoptotic effects on A549 and MCF-7 cell lines and inhibitory potencies against eight different RTKs including EGFR and HER2 compared to erlotinib. The results indicated that compounds 3f and 3q induced apoptosis in both cell lines and showed significant EGFR inhibitory activity with IC50 values of 4.34 ± 0.66 μM and 4.71 ± 0.84 μM, respectively when compared with erlotinib (IC50 = 0.05 ± 0.01 μM). Besides, compound 3f also inhibited HER2 notably with an IC50 value of 2.28 ± 0.53 μM making it a dual EGFR and HER2 inhibitor. Molecular docking studies, which were conducted to support the in vitro assays, pointed out that compound 3f showed high affinity into the ATP binding sites of EGFR and HER2.

Sever B ，Altıntop MD ，Radwan MO ，Özdemir A ，Otsuka M ，Fujita M ，Ciftci HI ... -  《-》

Dual EGFR/VEGFR2 inhibitors and apoptosis inducers: Synthesis and antitumor activity of novel pyrazoline derivatives.

Novel derivatives of the pyrazoline scaffold were synthesized and investigated for their cytotoxicity against prostate (PC-3), hepatocellular (HepG2), and breast (MDA-MB-231) carcinoma cells. The most active compounds, 4a, 4b, 5b, and 7c, revealed significant and broad-spectrum anticancer activities with IC50 values of 1.30-7.18 μM in comparison with doxorubicin (IC50  = 5.12-7.33 μM). Additionally, they exhibited lower cytotoxicity against normal WI-38 cells, indicating their high safety profiles. Aiming to enlighten the inhibitory potential on receptor tyrosine kinases (RTKs), compounds 4a, 4b, 5b, and 7c were assessed for their activities against four different RTKs (EGFR, FGFR2, HER2, and VEGFR2) and their apoptotic potencies on PC-3 cells. The results revealed that compounds 5b and 7c are potent dual EGFR and VEGFR2 inhibitors (IC50  = 0.21 and 0.23 μM, respectively, against EGFR; 0.22 and 0.21 μM, respectively, against VEGFR2), whereas they displayed moderate inhibitory activities against HER2 and FGFR2. Besides, compounds 4a, 4b, 5b, and 7c prompted apoptosis via the upregulation of Bax, p53, and caspase-3, together with the downregulation of the levels of Bcl-2. Also, it was found that compounds 5b and 7c are more potent as apoptosis inducers than the other tested derivatives. Furthermore, molecular docking analyses of compounds 4a, 4b, 5b, and 7c in the EGFR and VEGFR ATP binding sites were performed, to confirm the in vitro assays.

Alkamaly OM ，Altwaijry N ，Sabour R ，Harras MF ... -  《-》