Synthesis Of Naphthyl Quinoxaline Thymidine Conjugate And Its Application In Induced Immunological Inhibition Against Tumor

Cancer therapy is one of the biggest medical challenges in the world.There were more than 18 million newly registered cancer cases worldwide in 2018,of which 9.6 million people died.Chemotherapy is widely used in cancer,and chemotherapy drugs can be broadly classified into two categories according to their mechanisms: cytotoxic drugs and targeted drugs.Most chemotherapy drugs have strong side effects.For example,anthracyclines are broad-spectrum anticancer drugs,but have severe cardiotoxicity.Studies have shown that anthracyclines can also induce immunogenic cell death(ICD).Dendritic cells can be maturated by immunogenic dead tumor cells and present tumor-specific antigens to T cells to produce an anti-tumor immune response in vivo.However,the immunogenic potency is quite limited,possibly due to that these chemotherapeutic agents are not specifically developed as ICD inducers.Therefore,targeted research on novel ICD inducers is crucial for enhancing the antitumor effect.In this study,we synthesized a naphthyl quinoxaline thymidine conjugate as a new antitumor compound.The relative fluorescence quantum yield of the compounds were measured by a comparative method,and it showed that the compound is a weak fluorescent thymidine analog.The cytotoxic effect of naphthyl conjugate on four tumor cells was determined by CCK-8 assay.The results showed that naphthyl conjugate had significant anticancer activity in the nanomolar range after UVA activation.Tumor cells were treated with naphthyl conjugate,10 min after UVA activation,a large amount of active oxygen species were produced which can induce tumor cell death.The potent activity of naphthyl conjugate was able to induce the marked detection of ICD markers including ATP and HMGB1 extracellular and calreticulin intracellularly at 2?h post UVA activation.Finally,H22 cells treated with naphthyl conjugate and UVA were used as vaccine.Anti-tumor immunity was verified by injecting high tumorigenic H22 tumor cells.The results showed that the cancer cell vaccine can comprehensively and effectively inhibit the growth of tumors.The induced immunogenic inhibition was much more effective than that of mitoxantrone anthracycline drug.All these results demonstrated the high potential of naphthyl quinoxaline conjugate for the cancer cell vaccine against tumor.