A divergent mode of activation of a nitrosyl iron complex with unusual antiangiogenic activity

J Inorg Biochem. 2020 Sep:210:111133. doi: 10.1016/j.jinorgbio.2020.111133. Epub 2020 Jun 20.

Abstract

Nitric oxide (NO) and nitroxyl (HNO) have gained broad attention due to their roles in several physiological and pathophysiological processes. Remarkably, these sibling species can exhibit opposing effects including the promotion of angiogenic activity by NO compared to HNO, which blocks neovascularization. While many NO donors have been developed over the years, interest in HNO has led to the recent emergence of new donors. However, in both cases there is an expressive lack of iron-based compounds. Herein, we explored the novel chemical reactivity and stability of the trans-[Fe(cyclam)(NO)Cl]Cl2 (cyclam = 1,4,8,11-tetraazacyclotetradecane) complex. Interestingly, the half-life (t1/2) for NO release was 1.8 min upon light irradiation, vs 5.4 h upon thermal activation at 37 °C. Importantly, spectroscopic evidence supported the generation of HNO rather than NO induced by glutathione. Moreover, we observed significant inhibition of NO donor- or hypoxia-induced HIF-1α (hypoxia-inducible factor 1α) accumulation in breast cancer cells, as well as reduced vascular tube formation by endothelial cells pretreated with the trans-[Fe(cyclam)(NO)Cl]Cl2 complex. Together, these studies provide the first example of an iron-nitrosyl complex with anti-angiogenic activity as well as the potential dual activity of this compound as a NO/HNO releasing agent, which warrants further pharmacological investigation.

Keywords: Anti-angiogenesis; Iron complex; Nitric oxide; Nitroxyl; Vasodilation.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenesis Inhibitors / chemical synthesis
  • Angiogenesis Inhibitors / pharmacology*
  • Angiogenesis Inhibitors / radiation effects
  • Animals
  • Cell Line, Tumor
  • Coordination Complexes / chemical synthesis
  • Coordination Complexes / pharmacology*
  • Coordination Complexes / radiation effects
  • Glutathione / chemistry
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Iron / chemistry
  • Iron / radiation effects
  • Mice
  • Nitric Oxide / metabolism
  • Nitric Oxide Donors / chemical synthesis
  • Nitric Oxide Donors / pharmacology*
  • Nitric Oxide Donors / radiation effects
  • Nitrogen Oxides / metabolism
  • Rats
  • Temperature
  • Ultraviolet Rays
  • Vasodilator Agents / chemical synthesis
  • Vasodilator Agents / pharmacology
  • Vasodilator Agents / radiation effects

Substances

  • Angiogenesis Inhibitors
  • Coordination Complexes
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Nitric Oxide Donors
  • Nitrogen Oxides
  • Vasodilator Agents
  • Nitric Oxide
  • Iron
  • Glutathione
  • nitroxyl