新型多面体烷类氮氧化物的构建及抗肝癌活性的研究

Hepatocellular carcinoma is the most serious threat to human health. However, there are several problems associated with first-line drugs, including less efficacy, more drug resistance and toxic side effects. It is imminent to develop new drugs for hepatocellular carcinoma with high efficiency and low toxicity. Polyhedra have emerged as important functional groups in antitumor compounds to improve their activities because of their special space structure and tumor targeting. We have also reported that nitroxyl nitroxide radicals exhibited significant antitumor activity against hepatocellular carcinoma, especially NIT derivatives possessed the activities of NO donors and antioxides. Based on the above research, we will use the principle of dual-target drug design to build up a series of novel polyhedral nitrogen oxide derivatives, which contained a polyhedra moiety and a nitroxyl nitroxide radicals. In order to investigate the most active compounds with improved efficacy, high selectivity and less side effects, MTT assay and pharmacological experiments in vivo are measured. Flow cytometry, transmission electron microscope, mitochondrial membrane potential, DNA Ladder assay are performed to explore the antitumor mechanism and structure-activity relationship of the compounds. This study will provide a theoretical basis and experimental data for development of new drugs against hepatocellular carcinoma with high efficiency and low toxicity.

肝癌是严重威胁人类健康的重大疾病，即使临床一线药物也存在疗效低、易产生耐药性和毒副作用大等问题，研发高效低毒的新型抗肝癌药物迫在眉睫。多面体烷具有特殊的空间结构和肿瘤靶向性，将其引入抗肿瘤化合物中可明显提高其对肿瘤细胞的活性和选择性。课题组前期研究还发现，氮氧自由基表现出明显的抗肝癌活性，特别是NIT类氮氧自由基兼具NO释放和抗氧化损伤的双重抗肝癌作用。在此基础上，本项目根据双靶标药物设计原理，将靶向性的多面体烷结构巧妙引入到具有显著抗肝癌活性的Tempo类和NIT类氮氧自由基中，构建一系列新型的多面体烷类氮氧化物。通过MTT法和体内药效学实验，筛选出抗肝癌活性高、选择性好、毒副作用低的最佳活性化合物。并采用流式细胞术、透射电镜、线粒体膜电位、DNA Ladder分析等方法，探讨活性化合物的抗肝癌作用机制和构效关系，为研发高效低毒的新型抗肝癌药物提供理论基础和实验数据。

肝癌是严重威胁人类健康的重大疾病，即使临床一线药物也存在疗效低、易产生耐药性和毒副作用大等问题。本项目设计、合成了3类5个新颖的金刚烷类氮氧化物，并利用IR、MS、元素分析和X-单晶衍射等方法对目标化合物进行了结构确证。体内外的抗肝癌活性实验发现，金刚烷类氮氧化物可明显抑制肝癌细胞的增殖，且对正常细胞无明显的毒性。特别是化合物2可通过抑制迁移、侵袭和阻滞细胞G2/M期来发挥抗肝癌作用，同时也可通过活化线粒体凋亡通路，诱导肝癌Bel-7404细胞发生快速凋亡。另外，考察了该类化合物的抗心脑缺血/再灌注损伤的作用，发现了一个新型、高效的心脑I/R损伤保护剂。本项目共发表SCI收录论文4篇，中文核心期刊论文4篇，培养硕士研究生1名，获得国家发明专利2项。