School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China.
Curr Med Chem. 2011;18(21):3168-89. doi: 10.2174/092986711796391606.
The discovery of hypoxia-inducible factor-1 has led to a rapidly increasing understanding of the molecular mechanism of tumor hypoxia in the past two decades. Today it is generally accepted that HIF-1 plays a pivotal role in the cellular response to tumor hypoxia which represents a major obstacle to the success of radiotherapy and chemotherapy. Meanwhile, many details involved in the expression, accumulation and transactivation of HIF-1 have been well elucidated. Targeting HIF-1 has become a novel and efficient strategy for cancer therapy and a number of agents have been developed aiming to suppress HIF-1. This review will concisely introduce the general knowledge on the molecular biology of HIF-1 and possible targets along the HIF-1 pathway. Moreover, a number of compounds reported with anti-HIF-1 activity are included and mainly classified as direct and indirect inhibitors based on their different modes of action. While direct HIF-1 inhibitors prevent HIF-1 from transactivation, DNA binding and subsequently initiating transcriptional activity, indirect HIF-1 inhibitors generally block the transcription or translation of HIF-1α or promote the degradation of HIF-1α protein. According to different structural features, direct HIF-1 inhibitors are divided into several groups: polyamides, quinols and naphthoquinone spiroketal analogues, shikonin derivatives, epidithiodiketopiperazines, and two representative drugs: echinomycin and bortezomib. In the same way, indirect inhibitors comprise the following classes: polyphenols, benzoazaheterocycles, rapamycins, camptothecins, geldanamycins, (aryloxyacetylamino)benzoic acid analogues, 2-methoxyestradiol and analogues, hydroxamic acid compounds and others. The rest with mechanism still not so clear would also be listed and introduced, with an emphasis on the marinederived natural products. The in vitro and/or in vivo activities of these compounds and their mechanisms of HIF-1 inhibition would be discussed and the SARs of unique structural types of HIF-1 inhibitors will be briefly concluded.
缺氧诱导因子-1 的发现使得人们在过去二十年中对肿瘤缺氧的分子机制有了迅速的了解。如今，普遍认为 HIF-1 在细胞对肿瘤缺氧的反应中起着关键作用，这是放疗和化疗成功的主要障碍。同时，HIF-1 的表达、积累和反式激活所涉及的许多细节也得到了很好的阐明。针对 HIF-1 已成为癌症治疗的一种新的有效策略，并且已经开发了许多旨在抑制 HIF-1 的药物。本综述将简要介绍 HIF-1 的分子生物学的一般知识和 HIF-1 途径中的可能靶点。此外，还包括了一些具有抗 HIF-1 活性的化合物，并根据其不同的作用方式主要分为直接和间接抑制剂。虽然直接 HIF-1 抑制剂可阻止 HIF-1 的反式激活、DNA 结合，从而启动转录活性，但间接 HIF-1 抑制剂通常阻断 HIF-1α 的转录或翻译，或促进 HIF-1α 蛋白的降解。根据不同的结构特征，直接 HIF-1 抑制剂分为以下几类：多聚酰胺、醌和萘醌螺缩酮类似物、紫草素衍生物、表二硫代二酮哌嗪、两种代表性药物：埃博霉素和硼替佐米。同样，间接抑制剂包括以下几类：多酚、苯并杂环、雷帕霉素、喜树碱、金霉素、（芳氧基乙酰氨基）苯甲酸类似物、2-甲氧基雌二醇及其类似物、羟肟酸化合物等。其他作用机制尚不清楚的化合物也将被列出和介绍，重点是海洋来源的天然产物。这些化合物的体外和/或体内活性及其 HIF-1 抑制作用的机制将被讨论，并简要总结独特结构类型的 HIF-1 抑制剂的 SAR。
