基于低氧微环境的小分子激活前药与HIF-1抑制剂研究进展

低氧是实体瘤普遍存在的特征，是肿瘤细胞增殖、转移、侵袭、产生放疗抗性的重要原因。因此，肿瘤缺氧被认为是肿瘤诊断与治疗的一个重要靶点。低氧激活前药可在缺氧微环境下通过电子还原靶向低氧区域的肿瘤细胞，产生并释放细胞毒性代谢产物，从而杀死肿瘤细胞。目前已报道的低氧激活前药主要包括硝基化合物、醌类、氮氧化物、金属配合物、偶氮化合物五大类。而低氧诱导因子-1(hypoxia-inducible factor-1，HIF-1)也在肿瘤细胞的低氧存活与发展中扮演重要角色，抑制HIF-1可抑制其下游基因主导的肿瘤血管生成、转移、耐药等生存发展进程。当前，已有低氧激活前药与HIF-1抑制剂正处于临床试验阶段，并表现出良好的抗肿瘤活性，并有可能在未来的肿瘤诊断与治疗中发挥重要作用。

Research Progress in the Study of Small Molecule Hypoxia-activated Prodrugs and HIF-1 Inhibitors Based on Hypoxia Microenvironment

Hypoxia is a prevalent feature of solid tumors and it is an important cause of tumor cell proliferation, metastasis, invasion, and development of resistance to radiotherapy. Therefore, tumor hypoxia is considered to be an important target for cancer diagnosis and treatment. Hypoxia-activated prodrugs can kill tumor cells by targeting tumor cells in hypoxic regions via electron reduction in a hypoxic microenvironment to produce and release cytotoxic metabolites. Currently, five major classes of hypoxia-activated prodrugs have been reported, including nitro compounds, quinones, nitrogen oxides, metal complexes, and azo compounds. The hypoxia-inducible factor-1(HIF-1) also plays an important role in the hypoxic survival and development of tumor cells, and inhibition of HIF-1 can inhibit its downstream gene-driven tumor angiogenesis, metastasis, drug resistance and other survival development processes. Currently, hypoxia-activated prodrugs with HIF-1 inhibitors are in clinical trials and have shown good anti-tumor activity and may play an important role in tumor diagnosis and treatment in the future.