Thesis (Ph.D.) - Cairo University - Faculty of Pharmacy - Department of Pharmaceutical Chemistry

In light of the molecular reciprocity between the Ras/Raf//MEK/ERK and PI3K/Akt/mTOR pathways, which are considered as major players in tumorigenesis, and together provide cancer cells with the ability to withstand when targeting only one pathway of them. Aiming to tackle the growing antitumor resistance, and to maintain an efficient antiproliferative leverage, a compromised approach between ligand and structure based drug design was utilized to select thirty two compounds, 7,8-disubstituted-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione derivatives, for organic synthesis. The synthesized novel compounds satisfied certain criteria related to insights of modeling studies and crystal structures regards to several oncogenes such as of PI3K and B-Raf.Subsequently, all the synthesized compounds were evaluated for their in vitro anticancer activity according to the US-NCI protocol. Compounds 158 and 163c displayed potent and accepted benchmark according to DTP-NCI and further evaluated in the five doses assay. In addition to their pronounced and prominent antiproliferative activities, their cytotoxic effect against normal WI-38 cell line has been assessed, which revealed non-significant toxicity compared to sorafenib (34). Since the endeavor of the present study is to imbed antitumor efficacy through modulation of biological network, the rebound of multi-kinases targeting were also evaluated. Compounds with the highest mean growth inhibitions percent, were screened in vitro against PI3KÜ and B-RafV600E biological targets which showed potent activities. Compound 155 was found to be the most active in PI3KÜ inhibition with IC50 of 8.46 nM, while compound 157 showed superiority to inhibit the mutant type B-RafV600E with IC50 of 99.6 nM. Interestingly, compounds 158 and 163c anticancer effectiveness was consolidated by inhibition of B-RafWT, EGFR and VEGFR-2 with sub-micromolar IC50, in addition to their PI3KÜ and B-RafV600E inhibitory activities. Their predicted physicochemical and pharmacokinetic properties were also mentioned

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