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

In a search for new cytotoxic agents with improved activity and selectivity, certain new N-pyridylsulfonamide derivatives have been synthesized. All the newly synthesized compounds were subjected to in vitro cytotoxic screening against human hepatocellular liver carcinoma cell line (HEPG2). The most potent compounds, as concluded from this screening, were selected to be evaluated for their in-vitro cytotoxic activity in combination with Þ-radiation. The new compounds were docked inside the active site of vascular endothelial growth factor receptor 2 (VEGFR2) kinase enzyme in an attempt to predict their mechanism of action and assayed for their inhibitory activity against VEGFR2. It has been concluded that 7 new synthesized compounds 11a, (5, 6)b and (10-13)b showed higher in-vitro cytotoxic activity against HEPG2 cell line than Sorafenib (IC50 range 0.12- 0.66 æM and IC50 for sorafenib = 1.06 æM), while the 3 newly synthesized compounds 5b, 11b and 12b are nearly equipotent to Sorafenib in decreasing the activity level of VEGFR2 kinase enzyme (IC50 33, 37 and 37 nM respectively and IC50 for sorafenib = 30 nM). Additionally the most 9 potent compounds showed a synergistic effect with radiation in the radiosensitizing evaluation, so the drug dose can be decreased and consequently the toxicity will be also decreased

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