ABSTRACT
To find novel effective Aurora kinases inhibitors, a series of structurally interesting nitroxide labeled pyrimidines were synthesized and evaluated their anti-proliferative and Aurora kinases inhibitory activities. Among them, butyl 2-(3-((5-fluoro-2-((4-((1-oxyl-2,2,6,6-tetramethylpiperidin-4-yl)carbamoyl) phenyl) amino)pyrimidin-4-yl)amino)-1H-pyrazol-5-yl)acetate (22) possessed the most potent anti-proliferative effects against four carcinoma cell lines with IC50 values in range of 0.89-11.41⯵M, and kinases inhibition against Aurora A and B with the IC50 values were 9.3 and 2.8â¯nM, respectively. Furthermore, compound 22 blocked the phosphorylation of Aurora A (T288), Aurora B (Thr232) and HisH3, decreased the expression of proteins TPX2, Eg5 and Bora, as well as disrupted the mitotic spindle formation in HeLa cells. Molecular docking studies indicated that compound 22 well interact with both Aurora A and B. The results showed that compound 22 is a potential anticancer agent as promising pan-Aurora kinase inhibitor.
Subject(s)
Aurora Kinases/antagonists & inhibitors , Nitrogen Oxides/chemistry , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Pyrimidines/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Screening Assays, Antitumor , Humans , Inhibitory Concentration 50 , PhosphorylationABSTRACT
A series of deoxypodophyllotoxin-5-fluorouracil hybrid compounds were synthesized, and their cytotoxic activity was evaluated using four human cancer cell lines (HeLa, A549, HCT-8, and HepG2) and the human normal cell line WI-38. The synthesized compounds exhibited greater cytotoxic activity in tumor cells and reduced toxicity in the normal cell line compared with the anticancer drug VP-16 and 5-FU. Additionally, the most potent of these compounds-4'-O-demethyl-4-deoxypodophyllotoxin-4'-yl 4-((6-(2-(5-fluorouracil-yl) acetamido) hexyl) amino)-4-oxobutanoate (compound 22)-induced cell-cycle arrest in the G2/M phase by regulating levels of cdc2, cyclinB1, and p-cdc2 in A549 cells. Furthermore, compound 22 may inhibited the migration of A549 cells via down-regulation of MMP-9 and up-regulation of TIMP-1.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Cell Cycle Checkpoints/drug effects , Cell Movement/drug effects , Podophyllotoxin/analogs & derivatives , Antineoplastic Agents/chemistry , Cell Line , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Matrix Metalloproteinase 9/metabolism , Molecular Structure , Podophyllotoxin/chemical synthesis , Podophyllotoxin/chemistry , Podophyllotoxin/pharmacology , Structure-Activity Relationship , Tissue Inhibitor of Metalloproteinase-1/metabolismABSTRACT
A series of novel conjugates of podophyllotoxin and norcantharidin was designed using association strategy, and synthesized by coupling 4'-demethylepipodophyllotoxin with N-amino acid norcantharimides, and their cytotoxicitiy was evaluated against four human tumor cell lines (A-549, HepG2, HeLa and HCT-8) and normal human diploid fibroblast line WI-38. These compounds exhibited potent cytotoxic effects on tumor cell lines, whereas it was less toxic to WI-38 cells than anticancer drug VP-16 or its parent compound norcantharidin. Furthermore, conjugates 7a, 7c, 7f, 7j, 7k and 7l displayed excellent PP2A inhibition activity with IC50 values of 0.49-9.52 µM. The most potent compound 7l also exhibited topoisomeraseâ ¡inhibition activity. In addition, compound 7l induced cell-cycle arrest in the G2/M phase in HepG2 by regulating levels of cyclinB1 and cdc2.