新型三氮唑骈萘酰亚胺类抗肿瘤药物研究

Naphthalimides, a class of wide-spectrum antitumor agents which interclate into the base-pair of DNA, and poison the topoisomerase. Many naphthalimides have been, or are involved in the different phases of clinical trials. No multi-drug resistance was reported on naphathalimides up to date, though dose-limiting toxicity was observed. At the preliminary research, we chose amonafide (in several phase III clinical trials) as a lead compound, and found an unprecedented synthetic method for fused triazoles. Novel triazolonaphthalimide derivatives with excellent anticancer activities were discovered after in vitro screening, for example, compound lss-11 have a 6-89 nM IC50 range against five cancer cell lines, that is about 100-fold stronger than amonafide. In addition, lss-11 is more potent than taxol and topotican against liver cancer (HepG2). A docking result shows that this compound is a strong poison to topo II. This sereis of triazonathphalimides is easy for structure modification, and merits further investigation. This project aims to find a patented,anti-MDR candidate with high selectivity for tumor tissue after chemical modification and optimization, designing bio-reduciable prodrugs for hypoxia tumor tissue, and various in vitro/in vivo assays.

萘酰亚胺类化合物是一类能嵌插于DNA碱基对之间的广谱抗肿瘤药物，也是topo II的致毒剂，有多个化合物曾经或正在进行临床试验，迄今没有发现耐药性，但有不同程度的剂量依赖性毒性。在前期工作中，我们以正在进行多项III期临床试验的氨萘菲特为先导化合物，发现了在其5,6-位骈接三氮唑环的新方法，筛选出了一系列具有极佳体外抗肿瘤活性的三氮唑骈萘酰亚胺类化合物，其中化合物LSS-11抑制五种肿瘤细胞增殖的IC50在6-89 nM间，比氨萘菲特强约100倍，而且对肝癌细胞株（HepG2）的活性强于紫杉醇和拓扑替康。分子对接结果预测该类化合物对topo II有强抑制作用，有很大结构改造潜力，具有深入研究的价值。本课题计划通过进一步结构优化、设计对低氧肿瘤组织具有靶向性、可生物还原的前药，经过多轮体外与体内活性筛选，期望发现对肿瘤组织具有较高选择性、抗多重耐药性、具有独立知识产权的抗肿瘤候选药物。

萘酰亚胺类化合物是一类能嵌插于DNA碱基对之间的广谱抗肿瘤药物，也是topo II的致毒剂，有多个化合物曾经或正在进行临床试验，迄今没有发现耐药性，但有不同程度的剂量依赖性毒性。在前期工作中，我们以正在进行多项III期临床试验的氨萘菲特为先导化合物，发现了在其5,6-位骈接三氮唑环的新方法，筛选出了一系列具有极佳体外抗肿瘤活性的三氮唑骈萘酰亚胺类化合物，有很大结构改造潜力，具有深入研究的价值。.在此基础上，本课题通过进一步结构优化、设计并合成了新的衍生物，经过多轮体外与体内活性筛选，发现了体外、体内均有显著抗肿瘤、对抗多重耐药性、具有独立知识产权的抗肿瘤候选药物，其中最优化合物抑制近20种肿瘤细胞增殖的IC50平均值在几十nM水平，比阳性对照药物氨萘菲特强约100倍，而且对肝癌细胞株（HepG2）的活性强于紫杉醇和拓扑替康，分子对接结果及酶活性测试均表明该类化合物对topo II有强抑制作用，课题还对该类化合物与DNA的作用机制进行了详细研究。

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