Hypoxia-inducible factor-1 (HIF-1) plays an important role in cellular responses to hypoxia, including the transcriptional activation of several genes involved in tumor angiogenesis. Melatonin, also known as N-acetyl-5-methopxytryptamine, is produced naturally by the pineal gland and has anti-angiogenic effects in cancer through its ability to modulate HIF-1α activity. However, the use of melatonin as a therapeutic is limited by its low oral bioavailability and short half-life. Here, we synthesized melatonin-like molecules with enhanced HIF-1α targeting activity and less toxicity and investigated their effects on tumor growth and angiogenesis, as well as the underlying molecular mechanisms. Among melatonin derivatives, N-butyryl-5-methoxytryptamine (NB-5-MT) showed the most potent HIF-1α targeting activity. This molecule was able to (a) reduce the expression of HIF-1α at the protein level, (b) reduce the transcription of HIF-1α target genes, (c) reduce reactive oxygen species (ROS) generation, (d) decrease angiogenesis in vitro and in vivo, and (e) suppress tumor size and metastasis. In addition, NB-5-MT showed improved anti-angiogenic activity compared with melatonin due to its enhanced cellular uptake. NB-5-MT is thus a promising lead for the future development of anticancer compounds with HIF-1α targeting activity. Given that HIF-1α is overexpressed in the majority of human cancers, the melatonin derivative NB-5-MT could represent a novel potent therapeutic agent for cancer.

中文翻译：

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新型褪黑激素样药物的抗血管生成活性增强

缺氧诱导因子-1 (HIF-1) 在细胞对缺氧的反应中起重要作用，包括参与肿瘤血管生成的几个基因的转录激活。褪黑激素，也称为 N-乙酰-5-甲氧基色胺，由松果体自然产生，通过其调节 HIF-1α 活性的能力在癌症中具有抗血管生成作用。然而，褪黑激素作为治疗剂的使用受到其口服生物利用度低和半衰期短的限制。在这里，我们合成了具有增强的 HIF-1α 靶向活性和较低毒性的褪黑激素样分子，并研究了它们对肿瘤生长和血管生成的影响，以及潜在的分子机制。在褪黑激素衍生物中，N-丁酰-5-甲氧基色胺 (NB-5-MT) 显示出最有效的 HIF-1α 靶向活性。该分子能够 (a) 在蛋白质水平上减少 HIF-1α 的表达，(b) 减少 HIF-1α 靶基因的转录，(c) 减少活性氧 (ROS) 的产生，(d) 减少血管生成体外和体内，以及 (e) 抑制肿瘤大小和转移。此外，与褪黑激素相比，NB-5-MT 显示出更好的抗血管生成活性，因为它增强了细胞摄取。因此，NB-5-MT 是未来开发具有 HIF-1α 靶向活性的抗癌化合物的有希望的先导。鉴于 HIF-1α 在大多数人类癌症中过度表达，褪黑激素衍生物 NB-5-MT 可能代表一种新型的有效癌症治疗剂。