Synthesis And Study Of Antitumor Properties Of Cyclometalated Iridium(Ⅲ) Complexes Modified With Bioactive Molecules

Cisplatin,as a representative of platinum compounds,is widely used in the clinical treatment of a variety of solid tumors with significant curative effects.However,cisplatin is easily attacked by protein in plasma,leading to a dramatical decrement of its therapeutic efficacy as well as causing severe side effects including nephrotoxicity,ototoxicity,drug resistance and so on,which limit the development of platinum compounds.In recent years,cyclometalated iridium(Ⅲ)complexes,as a non-platinum compound,have attracted widespread attention.Cyclometalated iridium(Ⅲ)complexes have rich photochemical and photophysical properties and it can be used for organelle imaging.At the same time,they have various geometric configurations and good solubility.By conjugating cyclometalated iridium(Ⅲ)complexes with molecules with anti-cancer activity,the bioavailability of the compounds can be improved or it can overcome some side effects.Also the anti-cancer effect of the obtained complex is enhanced.Cyclometalated iridium(Ⅲ)complexes have a high affinity for mitochondria.Studies have shown that mitochondria play a key regulatory role in apoptosis,and the mechanism has been gradually elucidated.In recent years,the development of mitochondria-targeted cyclometalated iridium(Ⅲ)complexes has become a research hotspot,and the conjugation of cyclometalated iridium(Ⅲ)complexes with molecules with anti-cancer activity has become a new research direction.Artesunate and aspirin are two important molecules with anti-cancer activity.Their anti-cancer activity is limited by low bioavailability or side effects.We conjugate them with cyclometalated iridium(Ⅲ)complexes to make a prodrug to overcome the above problems,and at the same time,the complex can play a synergistic anti-cancer effect.At present,most cancer patients are died of recurrence and metastasis of cancer cells.Studies have shown that most of them are attributed to the existence of cancer stem cells.In recent years,cancer stem cells targeted drugs have been a hot spot for anti-cancer drugs research.Based on the above researches,a series of mitochondria-targeted or cancer stem cells targeted cyclometalated iridium(Ⅲ)complexes have been designed and synthesized in this thesis,and their anti-cancer mechanisms also have been studied.This thesis consists of five parts.The first part: We summarize the research progress of mitochondria-targeted anti-cancer drugs and the research status of cyclometalated iridium(Ⅲ)complexes for bioimaging and anti-cancer drugs.At the same time,the research status of anti-cancer activity of artesunate or aspirin and the research progress of cancer stem cells targeted drugs are introduced.The second part: Three compounds Ir-ART-1–3 have been designed and synthesized by conjugating cyclometalated iridium(Ⅲ)complexes with artesunate.Ir-ART-1–3 exhibit higher cytotoxicity towards human liver cancer cells(Hep G2),and less toxicity towards human normal liver cells(LO2).The cellular uptake experiment shows that Ir-ART-1–3 can effectively uptake into Hep G2 cells and selectively targeted mitochondria.Further mechanistic studies reveal that Ir-ART-1–3 cause G2/M phase cell cycle arrest and induce apoptosis through mitochondrial damage,including the depolarization of mitochondrial membrane potential(MMP),cellular ATP depletion,reactive oxygen species(ROS)elevation and caspase-3/7 activation.Furthermore,Ir-ART-1 displays obvious tumor growth inhibition in vivo.The third part: Two compounds Ir-As-1 and Ir-As-2 have been designed and synthesized by conjugating cyclometalated iridium(Ⅲ)complexes with aspirin.Two complexes are well taken up by human cervical cells(Hela)and their anti-cancer activity is better than cisplatin.The cellular uptake experiment shows that Ir-As-1 and Ir-As-2 are enriched in mitochondria.Further mechanistic studies show that compounds Ir-As-1 and Ir-As-2 can induce apoptosis through mitochondrial damage,such as the changes of mitochondrial membrane permeability,the increased intracellular ROS levels,also the effect of Ir-As-1 is stronger than Ir-As-2.The fourth part: Two glioma stem cells(GSCs)targeted cyclometalated iridium(Ⅲ)complexes Ir1 and Ir2 have been synthesized.They can inhibit GSCs proliferation significantly and localize to the mitochondria of GSCs specifically.Further mechanism studies show that they induce GSCs apoptosis by mitochondrial membrane depolarization,ROS generation and caspases activation.The fifth part: The summary of the work in this paper.