الفهرس 
Synthesis and pharmacokinetic evaluation of some new isatin derivatives as cytotoxic agents
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Abstract
A series of novel isatin derivatives IVa-k was synthesized via molecular hybridization approach and evaluated sequentially to explore its cytotoxic activity. Firstly, NCI screening of the target compounds highlighted the renal cytotoxicity activity of the N-cyclohexyl thiazolidinone derivative IVf against five renal cancer cell lines namely A498, ACHN, CAKI-1, RXF393 and UO-31. These results were further explored by in vitro determination of its IC50 values against these 5 cell lines where the best results were against CAKI-1 and UO-31 cell lines with IC50 values 5.03 and 4.39 æM which were comparable to those of sunitinib along with good safety threshold against normal renal cell line. Further emphasis on compound IVf renal cytotoxicity was achieved via enzyme assays against VEGFR2, PDGFRÜ/Ý, CDK1a/b and CDK2a enzymes. Besides, CAKI-1 and UO-31 cell cycle analysis. All these are supported by in silico studies to explore its physicochemical, pharmacokinetic and drug-likeness properties. Molecular docking study of compound IVf rationalized its potent PDGFR inhibitory activity through its interaction with the key amino acids in the ATP binding site. Finally, compound IVf was subjected to an in vivo pharmacokinetic study on two different routes of administration oral and intravenous by developing bioanalytical HPLC{u2212}UV method for the determination of compound IVf in rat plasma showing excellent oral bioavailability.The research represents compound IVf as a promising candidate against renal cell carcinoma