Characterisation of Novel Nitric Oxide and Carbon Monoxide Donors
Nitrogen monoxide (NO) and carbon monoxide (CO) are small messenger molecules which play multiple roles in mammalian physiology. Currently, available NO and CO donor drugs are limited in therapeutic potential due to a lack of organ or tissue specificity and stability. These limitations have stimulated great interest in the development of compounds that can generate NO and CO in a controlled and sustained manner with minimal toxicity. Two new therapeutic agents are under development at the University of Otago, New Zealand, tDodSNO, a photoactivated NO donor and CO-13, an organic based CO donor. This thesis examines some of their pharmacological characteristics trialing as cardiovascular and anticancer therapeutics. Our data demonstrate that photosensitive tDodSNO had a half life of > 4 h under photoactivation (25 W/m2) and was highly stable in vitro in the absence of photoactivation (0 W/m2). The NO release kinetics of tDodSNO was then compared to other commonly studied SNT’s, GSNO and SNAP. We found a steady state concentration of 8 ± 2 μM NO was achieved under photoactivation (300 W/m2) of 100 μM tDodSNO which could be regulated by modulating intensity of photostimulus. The CO release kinetics of CO-13 was also investigated and we found that CO-13 was a slow releasing CO donor compared to commonly studied metal based CO donor (CORM-2). To test the efficacy as vasorelaxing agent, vasorelaxation on vascular smooth muscle tissue was investigated. There was an 8 fold decrease in EC50 value of tDodSNO upon photoactivation. In contrast, both GSNO and SNAP induced NO dependent vasorelaxation, at lower concentrations than tDodSNO, but this activity may be due to their rapid metabolic decomposition, and could not be modulated by photoactivation. Similar to tDodSNO, CO-13 was found to be a potent vasorelaxing agent compared to CORM-2. We also evaluated the cytotoxicity of tDodSNO and CO-13 on A549 lung cancer cell line. Our data with tDodSNO revealed that the photoactivation (25 W/m2) induced highly significant increases in cytotoxicity compared to nonphotoactivation. A time and concentration dependent decrease in cell viability was observed with CO-13, which was substantially different compared to its CO depleted form BP-13. In conclusion, our study suggests that photosensitive tDodSNO and CO-13 have the potential to be promising novel cardiovascular and anticancer therapeutic agents.
Advisor: Giles, Greg; Sammut, Ivan
Degree Name: Doctor of Philosophy
Degree Discipline: Pharmacology and Toxicology
Publisher: University of Otago
Keywords: Nitric oxide; Carbon Monoxide; Cancer; Vasorelaxation
Research Type: Thesis