Tumor hypoxia is a common feature in most solid tumors and is associated with overexpression of the hypoxia response pathway. Overexpression of the hypoxia‐inducible factor (HIF‐1) protein leads to angiogenesis, metastasis, apoptosis resistance, and many other pro‐tumorigenic responses in cancer development. HIF‐1 is a promising target in cancer drug development to increase the patient's response to chemotherapy and radiotherapy as well as the survival rate of cancer patients. Since up to 1% of genes are hypoxia‐sensitive, a target‐specific HIF‐1 inhibitor may be a better clinical candidate in cancer drug discovery. Though no HIF‐1 inhibitor is clinically available to date, a lot of effort has been applied during the last decade in search of potent HIF‐1 inhibitors. In this review, we will summarize the structure–activity relationship of ten different chemotypes reported to be HIF‐1 inhibitors in the last decade (2007–2016), their mechanisms of action for HIF‐1 inhibition, progress in the way of target‐specific inhibitors, and problems associated with current inhibitors. It is anticipated that the results of these research on the medicinal chemistry of HIF‐1 inhibitors will provide decent information in the design and development of future inhibitors.

中文翻译：

---

过去十年（2007年至2016年）的低氧诱导因子-1（HIF-1）抑制剂：“结构-活性关系”的观点

肿瘤缺氧是大多数实体瘤的常见特征，并且与缺氧反应途径的过度表达有关。缺氧诱导因子（HIF-1）蛋白的过度表达会导致血管生成，转移，凋亡抗性以及癌症发展过程中的许多其他促癌前反应。HIF-1是癌症药物开发中有希望的目标，可以提高患者对化学疗法和放射疗法的反应以及癌症患者的存活率。由于多达1％的基因对缺氧敏感，因此靶向特异性的HIF-1抑制剂可能是癌症药物发现中更好的临床候选药物。尽管迄今为止尚无临床上可用的HIF-1抑制剂，但在过去的十年中，人们为寻找有效的HIF-1抑制剂付出了很多努力。在这篇评论中，我们将总结过去十年（2007-2016年）报告为HIF-1抑制剂的十种不同化学型的结构-活性关系，其抑制HIF-1的作用机理，靶标特异性抑制剂的研究进展以及与电流抑制剂相关的问题。可以预期的是，这些有关HIF-1抑制剂药物化学研究的结果将为未来抑制剂的设计和开发提供良好的信息。