Synthesis of some novel indole derivatives of expected anti-cancer activity / Eman Adel Shams Eldin Elkhouly ; Supervised Mona Monir Kamel Mikhail , Mohamed Kamal Abdelhameid , Hala Bakr Elnassan

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

Marine sponges and tunicates have been a wealthy source of cytotoxic compounds such as indole alkaloids. Most of the indole alkaloids showed in vitro cytotoxic activities against wide range of cancer cell lines. Series of bioisosteres of marine indole alkaloids (meridianins and nortopsentins) were synthesized and the compounds were tested for their in vitro anti-proliferative activity against HCT-116 cell line. The cytotoxic screening of the synthesized compounds reveals that pyrazolo[1,5- a]pyrimidines (compounds Xc and XIIa) display the most potent cytotoxic activity with IC50 = 0.31 æM and 0.34 æM, respectively. Compounds Xc and XIIa were further investigated for their kinase inhibitory potencies towards six kinases (CDK5/p25, CK1ð/{u025B}, GSK-3Ü/Ý, Dyrk1A, Erk2 and CLK1). They exhibit effective inhibition of GSK-3Ü/Ý (IC50 = 0.196 æM and 0.246 æM, respectively) and Erk2 (IC50 = 0.295 æM and 0.376 æM, respectively). Moreover, compound XIXc (IC50 = 2.6 æM) was subjected for further investigation on its effect on HCT-116 cell cycle progression. The flow cytometry analysis display an accumulation of cells in G1 phase that indicated anti-proliferative effect

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