Design, Synthesis And Biological Evaluation Of Indolin-2-one And Berbamine Derivatives

Most of the signal transduction pathways are mediated by protein kinases regulating every aspect of cell function including cell growth,differentiation,migration, and apoptosis.Protein kinases were overexpressed or their function displayed aberrant activation or both result in many diseases such as cancers.There are two main subdivisions within the protein kinases superfamily:the protein tyrosine kinases(PTKs) and the protein serine/threonine kinases.One of the most exciting developments in cancer research in recent years has been the clinical validation of molecularly targeted drugs that inhibit the action of pathogenic tyrosine kinases.There are two classes of PTKs present in cells:the receptor protein tyrosine kinases and the nonreceptor protein tyrosine kinases.3-phosphoinositide-dependent protein kinase-1(PDK-1)and protein kinase B(PKB)are serine/threonine kinases,they play key roles in cell signal transduction pathways.In multiple human tumours,protein kinases(e.g.:EGFR,PDK-1 or PKB)are overexpressed and/or protein kinases signalling are upregulated,promoting tumour invasiveness,angiogenesis,and progression.Protein kinases are considered as significant anti-cancer drug targets.The partâ… of this thesis reviewed on several protein kinases and the current advance of the small molecular protein kinases inhibitors.In this thesis,we chosed the protein tyrosine kinase inhibitor SU5416 as lead compound,three classes of novel indolin-2-ones were designed.Trisubsititued indolin-2-one derivatives were synthesized by using a traceless solid-phase approach with mercaptomethyl resin.109 Indolin-2-ones that designed based on SU5416 were synthesized in solution phase.Most of the synthesized compounds have been used for the biological evaluation in vitro.From the biological evaluation results,a series of indolin-2-ones were found to have moderate cytotoxic activity against the selected tumor cell lines.Compounds 2.94,2.96 and 2.171 were found to have more potent cytotoxicity against the K562 cell line compared to Sunitinib.Compound 2.94 exhibited the most potent inhibition activities against K562 and HepG2 cell lines with IC₅₀values of 0.089μM and 1.7μM.Compound 2.171 exhibited the most potent inhibition activities against PC-3 cell line with an IC₅₀value of 9.0μM.Natural small molecules were considered as significant lead compounds in drug discoveries.Berbamine is a well-known bisbenzylisoquinoline alkaloid isolated from traditional Chinese herbal medicines such as berberis amurensis.Previous studies showed that berbamine was effective for inhibiting both Imatinib sensitive-and resistant-Ph⁺ chronic myeloid leukemia(CML)cells.30 Berbamine derivatives were designed,synthesized and the anti-leukemia activity of them against imatinib-resistant K562 leukemia cell line was evaluated.From the biological evaluation results,most compounds displayed potent cytotoxic activity in vitro.14 derivatives were found have potent cytotoxic activity against K562-R cell line with IC₅₀values at 48 hours were in the submicromolar range.Compounds 3.6,3.8,3.19 and 3.29 showed the most potent inhibition activities against K562-R,whose IC₅₀values at 48 hours were 0.36μM,0.40μM,0.40μM and 0.46μM.The cell cycle analysis on K562-R cell line indicated that derivative 3.16 can reduce quiescent(G0/G1)phase cells,suggesting that berbamine derivatives may have potential to kill leukemia stem cells.In particular,compounds 3.14,3.15,3.16 and 3.17 also displayed potent inhibition of the cytoplasm-to-nucleus translocation of NF-κB p65 which is critical for survival of leukemia stem cells.