Design, synthesis and in silico insights of new 7,8-disubstituted-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione derivatives with potent anticancer and multi-kinase inhibitory activities

Abstract

Aiming to obtain an efficient anti-proliferative activity, structure- and ligand-based drug design approaches were expanded and utilized to design and refine a small compound library. Subsequently, thirty-two 7,8-disubstituted-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione derivatives were selected for synthesis based on the characteristic pharmacophoric features required for PI3K and B-Raf oncogenes inhibition. All the synthesized compounds were evaluated for their in vitro anticancer activity. Compounds 17 and 22c displayed an acceptable potent activity according to the DTP-NCI and were further evaluated in the NCI five doses assay. To validate our design, compounds with the highest mean growth inhibition percent were screened against the target PI3Kα and B-Raf_V600E to confirm their multi-kinase activity. The tested compounds showed promising multi-kinase activity. Compounds 17 and 22c anticancer effectiveness and multi-kinase activity against PI3Kα and B-Raf_V600E were consolidated by the inhibition of B-Raf_WT, EGFR and VEGFR-2 with IC₅₀ in the sub-micromolar range. Further investigations on the most potent compounds 17 and 22c were carried out by studying their safety on normal cell line, in silico profiling and predicted ADME characteristics.

Keywords: Anticancer; B-Raf; Multi-kinase targeting; PI3K; Xanthine.