In silico Design, Synthesis and in vitro Anticancer Activity of Novel 4- Methylbenzamide Derivatives Containing 2,6- Substituted Purines
DOI:
https://doi.org/10.9734/bpi/ctcb/v4/3048AKeywords:
Purine derivatives, anticancer activity, protein kinase inhibitors, cellular apoptosis, molecular dockingAbstract
The disruption of the protein kinases functioning leads to various pathologies, including the occurrence of certain types of cancer. Inhibition of the specific protein kinases’ activity remains an important target for the development of antitumor drugs. A novel class of potential protein kinase inhibitors 7–16 was synthesized in high yields using various substituted purines and 3-(trifluoromethyl)phenyl.
In this study, we used purine derivatives as substituents attached to the methyl group of 4-methylbenzamide via N-9 atom while leaving 3-(trifluoromethyl)phenyl moiety. Purine is a part of ATP and thus can theoretically form necessary hydrogen bonds in the ATP-pocket of protein kinase. At the same time, 3-(trifluoromethyl)aniline is known to have excellent affinity to the kinase’s allosteric pocket and can be seen in the majority of known inhibitors. On the other hand, targeted structures could be classified as modified nucleosides in which sugar part is replaced by 4-methylbenzamide.
The most promising compounds 7 and 10, containing chlorine atoms in the C-2 and C-6 positions of the purine heterocycle, exhibited inhibitory activity against seven cancer cell lines, comparable to the data for sorafenib. The IC50 values for compounds 7 and 10 were 2.27 \(\mu\)M and 2.53 \(\mu\)M for K562 cells, 1.42 \(\mu\)M and 1.52 for HL-60 cells, 4.56 \(\mu\)M and 24.77 \(\mu\)M for OKP-GS cells, respectively. In addition, compounds 7 and 10 dose-dependently induced the apoptosis and cell cycle arrest at G2/M phase preventing cell division of OKP-GS cells. Compounds 7, 9 and 10 showed 36%-45% inhibitory activity against of PDGFR\(\alpha\) and PDGFR\(\beta\) at the concentration of 1 \(\mu\)M.
The results of docking and molecular dynamics showed that the presence of a 4-methylimidazole fragment in the structure of titled compounds promotes their binding to protein kinases predominantly as type 2 inhibitors. However, in the case of Aurora kinases, 1 type of binding prevailed, regardless of the presence of a 4-methylimidazole fragment.
