Synthesis And Biological Evaluation Of Chemotherapeutic Agents That Target Cellular Redox Systems

Reactive oxygen species(ROS)are a family of oxygen-containing reactive molecules that are constantly produced,transformed,and consumed by living organisms during their aerobic metabolism.Under normal physiological conditions,ROS are maintained at a basal level by many antioxidative regulating mechanisms.Importantly,ROS are implicated in a diverse array of cellular biological activities,such as signal transduction,cell proliferation/differentiation,regulation of enzymatic activity,mediation of inflammatory response,and removal/killing of xenobiotics/pathogens.However,once the cells are encountered with abnormal metabolism,mitochondrial dysfunction,and/or exogenous stimulation,large amount of ROS would be generated which overwhelms the capacity of cellular antioxidative regulating systems and ultimately leads to the oxidative stress.In turn,oxidative stress is bound to cause deleterious effects on various cellular components including nucleic acids,proteins,and lipid membrane.On the one hand,oxidative stress-related damages are considered to be constantly involved in the pathogenesis and advancement of numerous diseases.For example,the etiology of neurodegenerative disorders is intimately correlated with oxidative stress-induced injuries.In this sense,effectively scavenging of ROS and timely rescuing of cells from the status of oxidative stress are one of the feasible and promising therapeutical strategies toward curing,or at least retarding,neurodegenerative diseases.On the other hand,tumor cells are sensitive to oxidative stress owing to their special physiological and metabolic properties,which makes oxidative stress-induced apoptosis a viable strategy for the treatment of cancer.In the present works,a variety of structurally diverse small molecules were synthesized in order to investigate their modes of redox-regulation and mechanisms of action,which lays the groundwork and provides the preliminary insights for the discovery and development of agents targeting the regulation of redox systems.The contents of our works are summarized as below:1.We briefly reviewed several aspects of Keap1-Nrf2-ARE signalling pathway including its components,biological function,and modes of regulation in cells.Further,the relationship between several diseases and the dysfunction of the pathway was discussed respectively,and thus the regulating agents for the pathway are categorized and summarized.In addition,the members and biological functions of the thioredoxin(Trx)system were also introduced,and the interrelation between Trx system and cancer was comprehensively discussed.Moreover,the typical and newly developed inhibitors against Trx system were classified and discussed.2.Dithiolethione skeleton-containing compounds are abundant in cruciferous vegetables,certain of which were demonstrated to be chemo-preventive against cancer.However,the clinical trials of them were terminated due to the severe toxic side effects.These research information fuel us an impetus to do further studies on whether dithiolethione derivatives are effective on neuroprotection.In this work,59structurally diverse dithiolethione derivatives were synthesized and screened for neuroprotection,and compounds 10 and 11 were identified to confer remarkable protection on a Parkinson's disease model based on PC12 cells,and were also better than several reported classical dithiolethione derivatives in protective effects.Further studies demonstrated that both compounds exerted neuroprotection via upregulating a battery of antioxidative genes as well as corresponding genes'products.3.Plenty of?,?-unsaturated ketones(also renowned as Michael acceptors)were found to be potent Nrf2 activators owing to their electrophilic double bonds which were demonstrated to be able to react with sulfydryls on Keap1,thereby leading to the activation of Nrf2.Similar to?,?-unsaturated ketones,vinyl sulfone scaffolds also possess electrophilic double bonds,so the derivatives of them are presumed to be capable of activation of Nrf2.In this work,a total of 47 vinyl sulfone derivatives were synthesized through two rounds of screening and SAR analysis,along with the elucidation of the structural determinants responsible for neuroprotection.And compounds 9b and 9c proved to exert robust protective effects against H₂O₂-mediated lesions to PC12 cells even at 1?M.Mechanistic studies demonstrated that translocation of Nrf2 from cytoplasm to nucleus stimulated by 9b and 9c was responsible for the up-regulation of a panel of ARE-directed antioxidant genes and corresponding gene products,which confers the neuroprotection to PC12 cells.4.Arsenic trioxide(ATO)is a traditional Chinese medicine used for the treatment of acute promyelocytic leukemia(APL).However,the development of ATO is restricted due to its severe toxicity and poor bioavailability.Based on our previous work revealing that organic arsenic molecules selectively target thioredoxin reductase,we herein designed and synthesized 32 organic arsenic molecules with the aim of discovering lead compounds exhibiting low toxicity and high therapeutical effect toward APL.After initial screening,compound 10 was identified to possess the best toxicity against HL-60 cells with IC₅₀⁰.1?M.Further,the screening results and mechanistic studies both clarified the preliminary mechanism concerning the structural determinants of organic arsenic molecules responsible for their selective interaction with TrxR,which is instrumental for further optimization and substantialization of these molecules.In addition,mechanistic studies revealed that compound 10 could inhibit TrxR selectively,which gave rise to the accumulation of excessive ROS and collapse of the intracellular redox homeostasis.As a result,compound 10 induced apoptosis of HL-60 cells via eliciting oxidative stress.5.A summary of the whole works presented above was conducted,and a brief discussion and perspective of the challenges faced with regulators targeting redox systems were made.