Study On The Biological Activity And Mechanism Of Aryl Metal Complexes

Metal-arene complexes have attracted great attentions in the past decades,due to their structural diversity,as well as their applications as the potent anticancer drugs.Cisplatin(DDP)as the standard chemotherapy medicine was applied to treat cancers,which has shown serious side-effects and high drug resistance.Metal-arene complexes have been proved to be an effective and potent substitution to the DDP for the cancer treatment.The current bottleneck for the development of metal-arene drugs was how to improve the selectivity to the targeted cancer cells.In this case,we have designed and synthesized a series novel metal-arene complexes to study their significance in the biological applications(such as the inhibition of the FTO and anticancer)and crystal engineering(the spontaneous conformation conversion).In this dissertation,with the adoption of the functionalized natural product as the auxiliary ligand,the selectivity and the drug-resistance of the metal-arene drugs have been significantly improved.Glycyrrhetinic acid,a natural product with biological activity,was chosen as the organic guidance molecule and coordinated to metal-arene center.The synthesized complexes shown both anti-tumor and anti-bacterial activities.And different bridging ligands(4'-methyl-[2.2'-bipyridin]-4-yl)methanamine and 2-(1-imidazolyl)ethanamine were introduced to regulate the structure of complexes and compare their biological activity.The results indicated that the complex containing N,N-chelating ligand is more active than that with monodentate imidazole ligand.CD spectra and gel electrophoresis suggested that the complexes could induce the change of the secondary structure of DNA and resulted in the polymerization of DNA.Furthermore,the complexes assistanted the generation of ROS and lead to the death of tumor cells due to stress damage,which were highly related to the introduction of glycyrrhetinic acid.Rhein,was also adopted in this dissertation,due to the FTO inhibition(obesity gene)and anti-tumor activities.With the post-modification of rhein,the target metal-arene complexes with rhein functional molecular,has exhibited excellent selective inhibition of FTO and anti-tumor activities.Up to date,only six kind of organic molecules were found to be effective FTO inhibitors.In this case,the developed rhein-modified metal-arene complexes were the first coordination complex showing the property of FTO inhibition.With the investigation results,we have found these complexes could selective inhibition of FTO over AlkBH5.Moreover,the complexes shown the excellent anti-tumor activity against NB4 leukemia cell(high expression for FTO),illustrating that FTO protein may be a new anticancer target of the metal-arene drugs.The anti-tumor mechanism was also investigated that the complexes mainly located in lysosomes,and induced cells to produce reactive oxygen species through lysosome damage,and resulted in the autophagy.Furthermore,the complexes could induce the configuration conversion of the DNA,from B-DNA to Z-DNA,due to the tail junction of rhein,which provided the prospective in the nucleic acid research.To probe the structural diversity of the metal-arene based coordination complex,flexible bidentate ligand and metal-arene precursors were selected to construct the dinuclear metallomacrocycle complexes with different counter anions.The coexistence of the cyclohexane-like boat/chair or twist-boat/chair forms for the fresh synthesized product has been demonstrated by single crystal X-ray diffaction,HPLC-MS and 1D 1H NMR and 2D[1H,1H]NMR.It is worthy to note that the conformation of the resulted metallomacrocycle complexes was highly dependent on the the counter anions during the crystallization from the mother solution.For example,Cl-,the complex have been defined as the boat and chair forms with Cl-as the counter anions,the twist-boat and chair forms,however,was found as the counter anion switched to NO3-.Spontaneous conformational interconversion between boat/twist-boat and chair forms has been observed in the solution with the confirmation of the 1H NMR specta.The rate constant(k)and free energy of activation(?G(?))were also calculated,where the rate of the conversion for the complexes(1·PF6>1·NO3>1·BF4>1·Cl),was opposite to their hydrogen binding abilities,suggesting that cleavage of this hydrogen interaction is rate-determining step.Anion titrations further indicated that the counter anion plays a decisive role in controlling the metallomacrocyclic conformation by binding to the backbone.DFT calculations provided insight into the mechanism for the interconversion of conformations,involving cleavage and reformation of a Ru-N coordination bond after ligand rotation.Meanwhile,the metallomacrocycle complexes also showed moderate anti-tumor activities,which were closely related to their conformations.Controlled release is an important factor to evaluate the drug delivery system in pharmacology.Therefore,azo ligands with different substituents,were selected,with the consideration of the property of cis-trans interconversion under light and heat.A series of arene-iridium complexes with the azo ligand were synthesized,which owned the reversible release and recombination with the irradiation of different wavelength light,accompanying the trans to cis-form transformation of the azo ligand.DFT calculations provided the possible pathway for the reversible release and recombination,involving a trans-to cis-form transformation of azo ligand and cleavage of a Ir-N coordination bond due to the high steric hindrance and followed the release of the azo ligands.The intriguing phenomenon could offer a fundamental understanding for the development of controlled release of anticancer drugs.