Design, synthesis and molecular docking study of new pyrimidine-based hydrazones with selective anti-proliferative activity against MCF-7 and MDA-MB-231 human breast cancer cell lines.

Efforts were directed on the design, synthesis and evaluation of the anticancer activity of some pyrimidine-based hydrazones against two breast cancer cell lines, MCF-7 and MDA-MB-231. Preliminary screening results revealed that some candidates scrutinized for their antiproliferative activities exhibited IC50 values of 0.87 µM-12.91 µM in MCF-7 and 1.75 µM-9.46 µM in MDA-MB-231 cells, indicating almost equal activities on both cell lines and better growth inhibition activities than those of the positive control 5-fluorouracil (5-FU) which displayed IC50 values of 17.02 µM and 11.73 µM respectively. Selectivity of the significantly active compounds was estimated against MCF-10A normal breast cells when compounds 7c, 8b, 9a and 10b exhibited superior activity for cancerous cells than for normal cells when compound 10b presented the best selectivity Index (SI) with respect to both MCF-7 and MDA-MB-231 cancer cells in comparison to the reference drug 5-FU. Mechanisms of their actions were explored by inspecting activation of caspase-9, annexin V staining and cell cycle analysis. It was noticed that compounds 7c, 8b, 8c 9a-c and 10b produced an increase in caspase-9 levels in MCF-7 treated cells with 10b inducing the highest elevation (27.13 ± 0.54 ng/mL) attaining 8.26-fold when compared to control MCF-7 which was higher than that of staurosporine (19.011 ± 0.40 ng/mL). The same compounds boosted caspase-9 levels in MDA-MB-231 treated cells when an increase in caspase-9 concentration reaching 20.40 ± 0.46 ng/mL (4.11-fold increase) was observed for compound 9a. We also investigated the role of these compounds for their increasing apoptosis ability against the 2 cell lines. Compounds 7c, 8b and 10b tested on MCF-7 cells displayed pre-G1 apoptosis and arrested cell cycle in particular at the S and G1 phases. Further clarification of their effects was made by modulating their related activities as inhibitors of ARO and EGFR enzymes when 8c and 9b showed 52.4% and 58.9% inhibition activity relative to letrozole respectively and 9b and 10b showed 36% and 39% inhibition activity of erlotinib. Also, the inhibition activity was verified by docking into the chosen enzymes.

Identification of new 4-(6-oxopyridazin-1-yl)benzenesulfonamides as multi-target anti-inflammatory agents targeting carbonic anhydrase, COX-2 and 5-LOX enzymes: synthesis, biological evaluations and modelling insights.

Multiple inhibitions of CA, COX-2 and 5-LOX enzymes has been recognised as a useful strategy for the development of anti-inflammatory drugs that can avoid the disadvantages of using NSAIDs alone. Here, we report new pyridazine-based sulphonamides (5a-c and 7a-f) as potential multi-target anti-inflammatory candidates. First, the furanone heterocycle in the dual CA/COX-2 inhibitor Polmacoxib was replaced with the pyridazinone one. Then, a hydrophobic tail was appended through benzylation of the 3-hydroxyl group of the pyridazinone scaffold to afford benzyloxy pyridazines 5a-c. Furthermore, the structures were adorned with the polar sulphonate functionality, in pyridazine sulphonates 7a-f, that are expected to be engaged in interactions with the hydrophilic half of the CA binding sites. All of the disclosed pyridazinones were tested for inhibitory activities against 4 hCA isoforms (I, II, IX, and XII), as well as against COX-1/2, and 5-LOX. Furthermore, in vivo anti-inflammatory and analgesic effects of pyridazinones 7a and 7b were examined.

New functionalized 6-thienylpyrimidine-5-carbonitriles as antiproliferative agents against human breast cancer cells.

6-Thienylpyrimidine-5-carbonitrile derivatives were synthesized and screened for their in vitro antiproliferative activities against two human breast cancer cell lines in comparison to 5-fluorouracil as a reference. Compounds 2, 3a-c, and 6b evolved as the most active congeners against both cell lines, while others showed selectivity for only one cell line. Compound 2 exerted its effect through inhibition of the epidermal growth factor receptor (EGFR), while 6b showed less aromatase inhibitory activity than letrozole. The rest of the tested compounds did not show significant inhibition, and it can be assumed that they exert their antiproliferative activity through different target mechanisms. In addition, caspase-9 protein activation assays, cell cycle analysis using flow cytometry, and annexin V-fluorescein isothiocyanate-propidium iodide (FITC/PI) dual staining assays were performed for the most active compounds. All the tested compounds were found to be potent pyrimidine derivatives able to initiate apoptosis in MCF-7 and MDA-MB-231 cells.

2-Anilinopyrimidine derivatives: Design, synthesis, in vitro anti-proliferative activity, EGFR and ARO inhibitory activity, cell cycle analysis and molecular docking study.

Novel anti-proliferative agents possessing pyrimidine scaffolds were designed, synthesized and evaluated for their IC50 values using MTT assay. Most compounds displayed good to excellent activity against the two tested breast cancer lines (MCF-7 and MDA-MB-231) as compared to 5-FU. The observed IC50 values for active compounds ranged from 0.27 to 10.57 µM in MCF-7 compared to the reference drug 5-FU (IC50 = 10.80 µM) and from 0.73 to 29.07 µM in MDA-MB-231 (IC50 for 5-FU = 11.40 µM). SAR analysis indicated that compounds 2c, 3b with hydrazone functionalities and compound 12 possessing pyrazolone ring exhibited superior activities. The most promising compounds were evaluated for their inhibitory activity against epidermal growth factor receptor (EGFR) and aromatase (ARO) enzymes and were further tested for caspase-9 activation, apoptosis and Annexin V/PI staining. Results of enzyme-based experiments indicated that the tested compounds 2c and 12 exert their activities through EGFR inhibition while compound 3b exhibited remarkable ARO inhibition activity. Furthermore, they remarkably induce caspase-9 activation and showed pre G1 apoptosis and cell cycle arrest at G2/M phase. In addition, docked compounds displayed good binding affinities to the target enzymes. Binding interaction details for the most promising inhibitors with the active site of the target enzymes EGFR and ARO utilizing MOE-dock method are also reported.