低氧激活联合亚硝基脲的作用机理及抗癌活性研究

Nitrosoureas are an important family of alkylating agents in the clinical treatment of cancer. However, the anti-cancer efficacy and clinical application of nitrosoureas have been severely limited by the drug resistance mediated by O6-alkylguanine-DNA alkyltransferase (AGT). Although the combined medication of AGT inhibitor and nitrosourea overcome the drug resistance to some extent, it aggravated the damage to normal cells because of the non-targeting property of the AGT inhibitor when increasing the sensitivity of cancer cells to nitrosourea. In the present proposal, we will design and synthesis a novel series of combi-nitrosourea, which not only inhibits the drug resistance induced by AGT, but also possesses tumor hypoxia targeting property. Moreover, the mechanisms of drug resistance inhibition and hypoxia activation of the combi-nitrosoureas will be investigated in this study. It is proposed that the combi-nitrosoureas can be selectively activated in hypoxia condition and release AGT inhibitor leading to targetedly inhibiting AGT activity in the hypoxia area of tumor, which renders the nitrosourea pharmacophore effectively induce DNA interstrand crosslink. As a result, hypoxia-targeting antitumor effect can be achieve by the combi-nitrosoureas. By quantum chemistry computations, structural-activity relationship study, biochemical analysis and cell experiments, we will reveal the mechanisms of drug resistance inhibition and hypoxia activation, confirm the determining factors for the anticancer activity and targeting property, and establish reliable method for activity evaluation. This study will provide solid foundation for the development of novel targeting anticancer alkylating agents with high efficacy and low toxicity.

亚硝基脲是临床上重要的抗癌烷化剂，但O6-烷基鸟嘌呤-DNA烷基转移酶(AGT)介导的耐药性严重限制了亚硝基脲的治疗效果和临床应用；AGT抑制剂与CENUs联合用药虽在一定程度上克服了耐药性，但由于AGT抑制剂不具有靶向性，在提高肿瘤细胞对亚硝基脲敏感性的同时，也加剧了正常细胞的损伤。本课题拟设计合成一系列既能够抑制AGT介导的耐药性、同时又具有肿瘤低氧靶向性的新型联合亚硝基脲；并对其抗耐药和低氧激活的作用机理进行研究。该类化合物通过特异性地在肿瘤低氧环境下被激活释放AGT抑制剂，靶向性地抑制肿瘤低氧区AGT活性，使亚硝基脲药效团能够有效地导致肿瘤低氧区DNA股间交联，从而实现靶向抗肿瘤作用。本课题将通过量子化学计算、构效关系研究结合生化分析和细胞实验，阐明抗耐药和低氧激活的作用机理，明确决定药物活性和靶向性的关键因素，建立可靠的活性评价方法，为开发高效低毒的新型靶向性抗癌烷化剂奠定基础。

亚硝基脲是临床上重要的抗癌烷化剂，但O6-烷基鸟嘌呤-DNA烷基转移酶(AGT)介导的耐药性严重限制了亚硝基脲的治疗效果和临床应用；AGT抑制剂与CENUs联合用药虽在一定程度上克服了耐药性，但由于AGT抑制剂不具有靶向性，在提高肿瘤细胞对亚硝基脲敏感性的同时，也加剧了正常细胞的损伤。本课题设计并合成了一系列既能够抑制AGT介导的耐药性、同时又具有肿瘤低氧靶向性的新型联合亚硝基脲；并对其抗耐药和低氧激活的作用机理进行研究。证明了该类化合物能够通过特异性地在肿瘤低氧环境下被激活释放AGT抑制剂，进而靶向性地抑制肿瘤低氧区AGT活性，使得亚硝基脲药效团能够有效地导致肿瘤低氧区DNA股间交联，从而实现了靶向抗肿瘤作用。本课题通过量子化学计算和构效关系研究结合生化分析和细胞实验，阐明了该类化合物抗耐药和低氧激活的作用机理，明确了决定药物活性和靶向性的关键因素，建立了可靠的活性评价方法，为开发高效低毒的新型靶向性抗癌烷化剂奠定了基础。