Design And Properties Of Platinum-based Anticancer Prodrugs Targeting At Energy Metabolism And Inflammatory Cytokines

Cancer is one of the leading causes of death in the current world.Although the success of platinum-based anticancer drugs has motivated the exploration of novel metallodrugs for several decades,problems such as drug-resistance and systemic toxicity hampered their clinical applications and efficacy.Platinum(?)complexes are prodrugs of cisplatin with multiple potential advantages over platinum(?)drugs These prodrugs could be activated to their Pt? metabolites by reduction at the tumor sites in vivo with leaving of two axial ligands,which could minimize the side-effects and improve the pharmacological properties of platinum(?)drugsCancer cells are mutant ones with the characteristics of easy metastasis,transformation and infinite proliferation.Abnormal proliferation and differentiation of cells are closely related to the occurrence of tumors,but also to the abnormal apoptosis,that is,the apoptosis is inhibited in cancer cells,leading to the infinite proliferation.Therefore,apoptosis of cancer cells can be induced by regulating their physiological state,which could play an important role in the treatment of cancer Energy metabolism is crucial for-the apoptosis,invasion and metastasis of cancer cells Inflammation in tumor microenvironment can also promote the survival and proliferation of cancer cells,as well as angiogenesis and metastasis.Thus,regulating energy metabolism or inflammation can change the tumor microenvironment,inhibit the proliferation of cancer cells and promote their apoptosis.Accordingly,a series of platinum(?)complexes were designed to study their antitumor activity and potentials to regulate cell energy metabolism and apoptosis.Mitochondrial metabolism provides energy for cell growth,division and survival.Cancer is a disease characterized by abnormal cellular energy metabolism,which preferentially switch to aerobic glycolysis rather than oxidative phosphorylation as a means of glucose metabolism.This typical feature provides an opportunity to regulate apoptosis of cancer cells.We first designed two platinum(?)complexes,PMT and PDT,to explore the effect of mitochondrion-targeting group(s)on the bioactivity and cytotoxicity of platinum(?)complexes.The structures were characterized and the effects of TPP+ on the biological and cytotoxic activities of the complexes were investigated.The introduction of triphenylphosphonium targeting group(s)markedly influences the reactivity and cytotoxicity of the Pt? complexes.The targeted complex displays more potent disruptive effect on mitochondria but less inhibitory effect on cancer cells than cisplatin.The lipophilicity of the platinum(?)complexes is enhanced by the targeting group(s).As a result,the mitochondrial morphology and ATP producing ability are impaired,which constitutes an alternative pathway to inhibit cancer cells.This study shows that both the reactivity of platinum(?)center and the property of axial targeting ligand exert influences on the cytotoxicity of targeted platinum(?)complexes.For targeting groups with pharmacological activities,the cytotoxicity of the double substituted complexes is better than that of the single substituted complexes.Next,in order to avoid the "off-target effect" caused by anticancer drugs in the treatment of tumors and to understand the role of energy metabolism in regulating the apoptosis,a novel platinum(?)complex,DPB,was designed to explore the effects of axial ligands on the reactivity and bioactivity of the complex as well as on the energy metabolism of tumor cells.DPB not only enhances the tumor-targeting potential of the complex,but also alters the mitochondrial membrane potential and disrupts the mitochondrial morphology.Furthermore,the mitochondrial function of tumor cells was impaired by DPB,leading to the inhibition of both glycolysis and glucose oxidation,and finally to the death of cancer cells via mitochondria-mediated apoptotic pathway.These findings demonstrate that DPB suppresses cancer cells mainly through altering metabolic pathways,and highlight the importance of dual-targeting to the design of high efficient anticancer drugs.Chronic inflammation is the basis of various debilitating diseases including neurodegenerative,autoimmune,metabolic diseases and cancer.It plays a crucial role in the development of tumors at various stages,including initiation,growth,invasion and metastasis.The regulation of inflammatory factors or related biological enzymes could also inhibit the proliferation of tumor cells.Two NSAIDs-platinum(?)complexes NP and DNP derived from cisplatin and naproxen were synthesized to inhibit the proliferation of cancer cells.NP and DNP exhibited superior cytotoxicity and anti-inflammatory properties over cisplatin and naproxen.Inhibition of cyclooxygenase-2(COX-2)deterred the migration of cancer cells.These findings demonstrate that the cytotoxic activity of double substituted complexes was superior to that of single substituted complexes when platinum(?)complexes were modified with bioactive functional groups.In summary,aiming at the defects and challenges of current platinum antitumor drugs,a series of platinum(?)precursors with different bioactivity or targeting functions were designed based on the prodrug strategy.The results of these studies provide new insight into the mechanism of platinum(?)complexes,and will benefit the design of more potent platinum complexes.