Studies On Synthesis,Structural Characterization And Antitumor Activities Of Gold And Rhodium Complexes With Isoquinoline As Ligand

Transition metal complexes offer an excellent opportunity to develop anticancer drugs due to their versatile coordination geometry,variable oxidation states,unique structural features,and useful chemical and physical characteristics.In this regard,the unique features of metal ions were exploited in the field of medicinal inorganic chemistry for the designing and synthesis of metal-based drugs.Because of these remarkable properties of metal ions,the scientists were able to develop metal-based drugs for the treatment of cancer,such as cisplatin,carboplatin,and oxaliplatin,etc.Since platinum drugs have severe side effects and generate resistance,which limited its application in clinics,the researchers seek the alternative of platinum drugs.Therefore,non-platinum transition metals were used for the synthesis of anticancer drugs.In medicinal resources,the natural products have a significant contribution by providing a large number of compounds which are biologically active and possesses high pharmacological values used in the development of anticancer drugs.Very recently,more attention has been paid to the synthesis of novel drugs by the structural modification of natural products,and to increase the anticancer activity and selectivity.Accordingly,in this thesis,four transition metal Au?????,and Rh?????complexes with isoquinoline?dihydroisoquinoline?as a ligand were synthesized and characterized,and their possible anticancer mechanisms were also investigated.The main contents of the thesis are as follows:Chapter 1:In this chapter,the progress in the platinum,gold,and rhodium-based drugs were reviewed and summarized.Firstly,the development and action mechanism of platinum-based drugs were described in the treatment of cancer.Besides this,the development and limitation of platinum-based drugs,including cisplatin,carboplatin,and oxaliplatin due to its adverse side effect,were reviewed.Secondly,the development and application of gold complexes in medicine for the treatment of different diseases,including cancer,bacteriostatic,and parasitic diseases,were summarized.The recent development in the gold complexes with various natural and synthetic organic compounds as a ligand,their in vitro and in vivo antitumor activity,and possible anticancer mechanism were discussed in detail.Thirdly,the rhodium complexes with various ligands were discussed briefly,whereas rhodium complexes and a new strategy for cancer drugs development were discussed in detail.Finally,the isoquinoline metal-based anticancer complexes have been summarized.Chapter 2:Two dihydroisoquinoline ligands,which are the derivatives of isoquinoline,namely,[6,7-dimethoxy-1-?2-aminophenyl?-3,4-dihydroisoquinoline?L¹?and,6-methoxy-1-?-2-aminophenyl?-3,4dihydroisoquinoline?L²?were synthesized and characterized.Using these ligands to react with corresponding metal salts,four metal complexes:[Au?L¹?Cl₂]?1,Au1?,[Au?L²?Cl₂]?2,Au2?,[Rh?L¹??DMSO?Cl₃]?3,Rh1?,[Rh?L²??DMSO?Cl₃]?4,Rh2?were synthesized.All the structures of these metal complexes were fully characterized by single crystal X-ray diffraction analysis,¹H-NMR,¹³C-NMR,ESI-MS,and elemental analysis.Au1 and Au2 have distorted square planner geometry.The central Au?III?ions are coordinated by bidentate ligand as N^N-L¹ and N^N-L² of the isoquinoline heterocyclic nitrogen and two chlorine atoms.In the reaction of complexes formation,the-NH₂ of the ligand has taken place deprotonation and lost one H.In Rh1 and Rh2,one aminophenyl dihydroisoquinoline,one dimethyl sulfoxide,and three chlorine atoms coordinated to Rh?III?to give a six-coordinated distorted octahedral geometry.The coordination of N1 and N2atoms of bidentate aminophenyl dihydroisoquinoline ligand with Rh atom is responsible for the formation of a six-membered ring?N1-N2/C1/C6/C7?in a half-chair conformation.The Rh-N2 and Rh-S1 are assembled closely perpendicular to each other,and three chlorine atoms of the bidentate aminophenyl dihydroisoquinoline ligand are located on the basal positions of the square.Rings C1-C6 and C8-C13 of aminophenyl dihydroisoquinoline are both planar.From the UV-Vis and HPLC results,the solution stability of all these complexes was confirmed,which are stable in PBS and DMSO solution of 7.4 pH at room temperature for 24 h.Chapter 3:In this chapter,the in vitro and in vivo anticancer activity and action mechanism were investigated.Against T-24 cells,Au1 and Au2 exhibited higher cytotoxicity than their corresponding ligands,gold salt,and cisplatin.These gold complexes are less toxic towards human normal HL-7702 liver cell lines.Both the gold complexes Au1 and Au2 arrested cell cycle at S-phase,which is the DNA synthesis phase,and all the genetic information of an organism are copied and transferred to the next generation.The arresting of cell cycle was possible by a mechanism of upregulation of some cell cycle-related proteins such as p53,p27,and p21,and downregulation of some cyclin including cyclin A and cyclin E.The depolarization of the mitochondrial membrane potential,generation of ROS,and stimulated Ca²⁺release which activated the caspase cascade and ultimately caused apoptosis by increasing the levels of Bax and Bak,and decreasing the levels of Bcl-2 and Bcl-xl.Cell apoptosis was achieved via mitochondria-mediated pathways.The in vivo studies of Au1 and Au2 on the tumor xenograft mouse model bearing T24 demonstrated that they were safer than cisplatin and could effectively inhibit tumor growth comparable to cisplatin.Both the rhodium complexes,namely Rh1 and Rh2,displayed vigorous anticancer activity against various cancer cells and low cytotoxicity against non-cancer cells.Their IC₅₀ values were found less than cisplatin against T-24 cell line,which is the most sensitive cells against these complexes.These complexes triggered apoptosis via mitochondrial dysfunction that increased the levels of ROS and Ca²⁺and released cytochrome C,which ultimately activated caspases and the apoptotic pathways.Moreover,Rh1 has arrested the cell cycle at S-phase,whereas Rh2 arrested at G2-phase.In vivo studies showed that Rh1 effectively inhibited tumor growth in a xenograft mouse model bearing T-24 with less adverse effect than cisplatin.Overall,Rh1 and Rh2 induced apoptosis via mitochondrial pathways and could be developed as effective anticancer agents.Structure-Activity Relationships:From the studies of biological activity and anticancer mechanism,the following SARs trend could be established with the ligands and complexes.Au1 and Rh1 have two methoxy groups whereas Au2 and Rh2 have only one methoxy group in the ligands.Cytotoxicity studies showed that Au1 and Rh1 are more effective than Au2and Rh2 against T-24 cells because of the two electron donor groups.Similarly,the studies of the anticancer mechanism of these complexes Au1,Rh1,and Au2,Rh2 provide an understanding of their different biological performance.For example,Au1 and Rh1 triggered apoptosis more effectively,produced more significant damage to the mitochondrial membrane,and achieved a greater extent of activation of the caspase pathway as compared with Au2 and Rh2.Also,the Au1 and Rh1 arrested the cell cycle more effectively than Au2and Rh2.Additionally,the xenograft model of mice bearing T-24 cells also presented the same SARs trend concerning Au1,Rh1,and Au2,Rh2.All these complexes contained electron-donating methoxy groups.However,Au1 and Rh1 have two methoxy groups at the carbon-6 and carbon-7 position of the isoquinoline,whereas Au2 and Rh2 have only one methoxy group.It is considered that the more basic isoquinoline ligand led to the more effective activities of complexes.Therefore,it is suggested that complexes having more basic ligands will have more significant cytotoxicity.Au1 and Rh1 exhibited a more favorable in vivo safety profile than cisplatin,and the tumor inhibition ratios were comparable.Au1 and Rh1 are the potential leading compound for further development as an anticancer agent.