Enhanced anti‐angiogenic activity of novel melatonin‐like agents

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.