Study On The Antitumor Effects Of Platinum(?) Complexes And Proteolysis Targeting Chimeras

Two classes of antitumor compounds were designed,synthesized and studied,namely,platinum(?)complexes and PROTAC compounds with the ability of degrading protein.PART ?Platinum-based drugs are the most common chemotherapeutic drugs in clinical practice.Development of novel platinum complexes with lower side effects and the ability of overcoming cisplatin resistance is the goal of the research of platinum-based drugs.Platinum(?)complexes have become the research hotspot of the new generation of platinum-based anticancer drugs because of their different chemical and biological properties from platinum(II)complexes.As an inhibitor of glycolysis,lonidamine(LND)which could enhance the anticancer activity of platinum-based drugs was conjugated to the Pt(?)centre to generate a series of platinum(?)prodrugs.Among them,complex 2-1 which could be reduced to release active Pt(II)species and LND moiety by ascorbic acid possessed more notable anticancer activity toward LNCaP cells than cisplatin.It could induce cells apoptosis by increasing the level of reactive oxygen species(ROS)and reducing the mitochondrial membrane potential.Increased activity of glutathione S-transferases(GSTs)is closely related to the drug resistance of platinum-based drugs.Therefore,a series of platinum(?)prodrugs were synthesized by tethering a GSTs inhibitor named NBDHEX to the axial position of platinum(?)complexes.Among them,complex 3-2 bearing one molecular of NBDHEX and a hydroxyl group at the axial positions owned excellent in vitro and in vivo anticancer activity as well as lower toxicity.By inhibiting the activity of GSTs,it was able to promote platinum uptake and cause more severe DNA damage,leading to the reverse of cisplatin resistance.Further studies revealed that the complex induced cells apoptosis of osteosarcoma U2 OS and non-small cell lung cancer A549 and A549/DDP via endogenous apoptotic pathway,and it also could prevent the migration and invasion of osteosarcoma cells.PART ?Proteolysis targeting chimera(PROTAC)is a heterobifunctional compound that could trigger the degradation of target protein by ubiquitin-proteasome system(UPS).It has become a brand new direction of anticancer drug research due to its different action mechanism from traditional small molecule inhibitors.Casein kinase 2(CK2)plays an important role in cell survival and proliferation,its overexpression is associated with tumorigenesis and progression.Pomalidomide acting as the recruiter of E3 ubiquitin ligase was coupled together with a CK2 inhibitor named CX-4945 via “click reaction” to prepare several PROTACs targeting CK2.Among them,compound 5-2 possessed a new mechanism of action different from that of CX-4945.It could degrade CK2 protein by recruiting UPS resulting in the inhibition of phosphorylation of Akt and the up-regulation of the tumor suppressor p53.Moreover,it could quickly induce the apoptosis of MDA-MB-231 cells overexpressing CK2 protein and arrest the cell cycle at G2/M phase.As the first intracellular signaling molecule,B-Raf protein kinase represents an important target in cancer therapy.Several PROTACs targeting B-Raf were prepared by connecting pomalidomide to a small molecule Rigosertib.Among them,compound 6-2 owned more significant anticancer activity toward MCF-7 cells overexpressing BRaf than the positive control.It could trigger the degradation of B-Raf protein by recruiting UPS and downregulate the anti-apoptotic protein Mcl-1 leading to cell cycle arrest at G2/M phase and cells apoptosis.