Journal
JOURNAL OF INORGANIC BIOCHEMISTRY
Volume 210, Issue -, Pages -Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.jinorgbio.2020.111133
Keywords
Nitric oxide; Nitroxyl; Iron complex; Vasodilation; Anti-angiogenesis
Funding
- CNPq [303355/2018-2, 308383/2018-4, Universal 403866/2016-2, Universal 428741/2016-9]
- FUNCAP [PRONEX PR2 0101-00030.01.00/15 SPU, 3265612/2015]
- Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior - Brasil (CAPES) [001]
- CAPES/COFECUB [88887.130198/2017-01]
- NIH Intramural Research Programs
- Cancer and Inflammation Program
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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]Cl-2 (cyclam = 1,4,8,11-tetraazacyclotetradecane) complex. Interestingly, the half-life (t(1/2)) for NO release was 1.8 min upon light irradiation, vs 5.4 h upon thermal activation at 37 degrees 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-1 alpha (hypoxia-inducible factor 1 alpha) accumulation in breast cancer cells, as well as reduced vascular tube formation by endothelial cells pretreated with the trans-[Fe(cyclam)(NO)Cl]Cl-2 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.
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