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 IC 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 IC 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.