Heparin–polynitroxides: Synthesis and preliminary evaluation as cardiovascular EPR/MR imaging probes and extracellular space-targeted antioxidants

• Published in: European journal of medicinal chemistry 2012-12, Vol.58, p.265-271
• Main Authors: Kleschyov, Andrei L., Sen', Vasily, Golubev, Valery, Münnemann, Kerstin, Hinderberger, Dariush, Lackner, Karl J., Weber, Stefan, Terekhov, Maxim, Schreiber, Laura M., Münzel, Thomas
• Format: Article
• Language: English
• Subjects: Anticoagulants - blood; Anticoagulants - chemistry; Anticoagulants - metabolism; Anticoagulants - pharmacology; Antioxidants - chemistry; Antioxidants - metabolism; Electron paramagnetic resonance; Electron Spin Resonance Spectroscopy; Endothelium, Vascular - chemistry; Endothelium, Vascular - metabolism; Extracellular Matrix - chemistry; Extracellular Matrix - metabolism; Factor Xa - metabolism; Factor Xa Inhibitors; Heparin; Heparin - chemistry; Heparin - metabolism; Hexosamines - chemistry; Humans; Magnetic Resonance Imaging; Molecular Probes - chemistry; Molecular Probes - metabolism; MR imaging; Nitrogen Oxides - chemistry; Nitrogen Oxides - metabolism; Nitroxide; Oxidative stress; Partial Thromboplastin Time; Superoxides - chemistry; Superoxides - metabolism; Uronic Acids - chemistry; Vascular disease
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2012.09.028

We report here the synthesis of heparin–polynitroxide derivatives (HPNs) in which nitroxide moieties are linked either to uronic acid or glycosamine residues of the heparin macromolecule. HPNs have low anticoagulant activity, possess superoxide scavenging properties, bind to the vascular endothelium/extra-cellular matrix and can be detected by EPR and MRI techniques. As the vascular wall-targeted redox-active paramagnetic compounds, HPNs may have both diagnostic (molecular MRI) and therapeutic (ecSOD mimics) applications. [Display omitted] ► Three novel heparin–polynitroxide derivatives were synthesized. ► They exhibit low anticoagulant activity and posses superoxide scavenging properties. ► They bind to vascular endothelium and have long in vivo life time. ► They can be detected in the vascular wall by EPR and MRI techniques. ► They may become a platform for the creation of new diagnostic and therapeutic agents.