Background: Cancer is still a major world health threat, causing a high rate of mortality. VEGFR-2 inhibitor anticancer agents are of great significance. However, they showed some serious side effects. Purpose: To discover new effective and safer anticancer agents, a new series of piperazinylquinoxaline-based derivatives was designed and synthesized on the basis of the pharmacophoric features of VEGFR-2 inhibitor drugs. Methods: The new candidates were evaluated against A549 lung cancer cells, HepG-2 hepatoma cells, Caco-2 colon cancer cells, MDA breast cancer cells, and VEGFR-2 kinase. Moreover, cell cycle kinetics and apoptosis rates were studied in HepG-2 cells treated with compound 11, which was the most promising candidate. Results: The new derivatives revealed better antitumor results (IC₅₀ from 6.48 to 38.58 μM) against the aforementioned cancer cell lines than sorafenib. Also, the new candidates showed VEGFR-2 inhibition with IC₅₀ values ranging from 0.19 to 0.60 μM compared to 0.08 μM for sorafenib. Compound 11, meanwhile, showed IC₅₀ values equal to 10.61, 9.52, 12.45, 11.52, and 0.19 μM against the cancer cell lines and VEGFR-2, respectively. Moreover, compound 11 raised the apoptosis rate in HepG-2 cells from 5% to 44% and caused 4, 2.3, and 3-fold increases in BAX/Bcl-2 ratio, caspase-3 level, and P53 expression, respectively, compared to control untreated cells. Finally, the new derivatives displayed the correct binding mode into VEGFR-2 kinase pocket, giving interactions with the essential residues. Conclusion: This work suggests that compound 11 is a very significant anticancer candidate, and piperazinylquinoxaline is an important scaffold in the development of new potential effective and safer VEGFR-2 inhibitor agents.

Cancer is still a dangerous disease with a high mortality rate all over the world. In our attempt to develop potential anticancer candidates, new quinazoline and phthalazine based compounds were designed and synthesized. The new derivatives were built in line with the pharmacophoric features of thalidomide. The new derivatives as well as thalidomide were examined against three cancer cell lines, namely: hepatocellular carcinoma (HepG-2), breast cancer (MCF-7) and prostate cancer (PC3). Then the effects on the expression levels of caspase-8, VEGF, NF-κB P65, and TNF-α in HepG-2 cells were evaluated. The biological data revealed the high importance of phthalazine based compounds (24a–c), which were far better than thalidomide with regard to the antiproliferative activity. 24b showed IC₅₀ of 2.51, 5.80 and 4.11 μg mL⁻¹ compared to 11.26, 14.58, and 16.87 μg mL⁻¹ for thalidomide against the three cell lines respectively. 24b raised caspase-8 level by about 7 folds, compared to 8 folds reported for thalidomide. Also, VEGF level in HepG-2 cells treated with 24b was 185.3 pg mL⁻¹, compared to 432.5 pg mL⁻¹ in control cells. Furthermore, the immunomodulatory properties were proven to 24b, which reduced TNF-α level by approximately half. At the same time, NF-κB P65 level in HepG-2 cells treated with 24b was 76.5 pg mL⁻¹ compared to 278.1 and 110.5 pg mL⁻¹ measured for control cells and thalidomide treated HepG-2 cells respectively. Moreover, an in vitro viability study against Vero non-cancerous cell line was investigated and the results reflected a high safety profile of all tested compounds. This work suggests 24b as a promising lead compound for development of new immunomodulatory anticancer agents.

A new set of 4,6,7,8-tetrahydroquinolin-5(1H)-ones were designed as cytotoxic agents against breast cancer cell line (MCF-7) and synthesised under ultrasonic irradiation using chitosan decorated copper nanoparticles (CS/CuNPs) catalyst. The new compounds 4b, 4j, 4k, and 4e exhibited the most potent cytotoxic activity of IC₅₀ values (0.002 − 0.004 µM) comparing to Staurosporine of IC₅₀; 0.005 μM. The latter derivatives exhibited a promising safety profile against the normal human WI38 cells of IC₅₀ range 0.0149 − 0.048 µM. Furthermore, the most promising cytotoxic compounds 4b, 4j were evaluated as multi-targeting agents against the RTK protein kinases; EGFR, HER-2, PDGFR-β, and VEGFR-2. Compound 4j showed promising inhibitory activity against HER-2 and PDGFR-β of IC₅₀ values 0.17 × 10⁻³, 0.07 × 10⁻³ µM in comparison with the reference drug sorafenib of IC₅₀; 0.28 × 10⁻³, 0.13 × 10⁻³ µM, respectively. In addition, 4j induced apoptotic effect and cell cycle arrest at G2/M phase preventing the mitotic cycle in MCF-7 cells. Graphical Abstract

This review reports the developed methods for the synthesis of polyfunctional 1,2,4-triazine systems bearing and/or containing phosphorus atoms as donor-acceptors interactions. Most of the synthetic methods depend on the interaction between an amino group of the side chain of 1,2,4-triazine with phosphorus reagents. The biological activities, i.e. their biocidal affects as antioxidants, antimicrobials, anti-inflammatory as well as molluscicidal agents against some snails are discussed.

New fluorine compounds bearing 4-amino-1,2,4-triazino[4,3-b] - 1,2,4-triazin-8-one (4) and the related derivativesN-acyl,N-alkyl, and Schiff base have been obtained from condensation of 6(2 '-aminophenyl-3-thioxo-1,2,4-triazin-5-one (1) with 4-fluorobenzaldehyde followed by treated with 4-tollyl sulfonic acid hydrazide and finally undergo ring closure reaction with chloro-acetonitrile to give the starting4. The presence of free amino-group of4confirmed from acylation5, aroylation6and alkylation7-9. A simple addition of n-butyl-thiophenol to Schiff base 4 gave a type of thioethers10and11, respectively. The structure of the targets has been established from then elemental analysis and spectral measurements. The compounds4-12evaluated as CDK2 inhibitors of tumor cell, were the activity in the order of 12 > 11 > 10 > 3>9 > 8>5 > 2.

Novel fluorine or phosphorus compounds bearing an aminopyrimidine-substituted pyrazolo[3,4-d]pyrimidine moiety (5–12) were synthesized by the heterocyclization of 1-heteroaryl guanidine 4 with diethyl malonate, followed by reactions with electrophilic phosphorus compounds and/or aromatic 3,5-dinitrobenzoyl chloride under various conditions. Elemental analysis and spectral data confirmed the product structures. In addition, the molluscicidal activity of the new compounds against some snails was evaluated.