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-1 alpha 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-1 alpha 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-1 alpha targeting activity. This molecule was able to (a) reduce the expression of HIF-1 alpha at the protein level, (b) reduce the transcription of HIF-1 alpha 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-1 alpha targeting activity. Given that HIF-1 alpha is overexpressed in the majority of human cancers, the melatonin derivative NB-5-MT could represent a novel potent therapeutic agent for cancer.

Automated summary

A novel melatonin derivative, N-butyryl-5-methoxytryptamine (NB-5-MT), showed potent targeting activity against HIF-1 alpha, leading to decreased angiogenesis, reactive oxygen species generation, and tumor growth, with enhanced anti-angiogenic effects compared to melatonin. NB-5-MT represents a promising lead for the development of anticancer compounds targeting HIF-1 alpha, offering potential as a novel therapeutic agent for cancer with overexpressed HIF-1 alpha.