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A fairly large portion of patients receiving surgical or intensive care will need mechanical ventilation at some point. The potential ventilator-induced lung injury (VILI) is thus of interest. One of the main causal factors in VILI is the cyclic energy shifts, i.e. tidal volumes, in the lung during mechanical ventilation. The problem can be approached in two ways. Firstly, one can utilize apneic oxygenation and thus not cause any tidal injuries at all. Secondly, and more traditionally, one can simply lower the tidal volumes and respiratory rates used. The following describes a series of animal experiments exploring these options. In the first two papers, I explored and improved upon the methodology of apneic oxygenation. There is a generally held belief that it is only possible to perform apneic oxygenation by prior denitrogenation and by using 100% oxygen during the apnea. As 100% oxygen is toxic, this has prevented apneic oxygenation from more widespread use. The first paper proves that it is indeed possible to perform apneic oxygenation with less than 100% oxygen. I also calculated the alveolar nitrogen concentration which would conversely give the alveolar oxygen concentration. The second paper addresses the second large limitation of apneic oxygenation, i.e. hypercapnia. Using a high dose infusion of tris(hydroxymethyl)aminomethane (THAM) buffer, a pH > 7.2 could be maintained during apneic oxygenation for more than 4.5 hours. In the last two papers, THAM’s properties as a proton acceptor are explored during respiratory acidosis caused by very low volume ventilation. In paper III, I found that THAM does not, in the long term, affect pH in respiratory acidosis after stopping the THAM infusion. It does, however, lower PVR, even though the PaCO2 of THAM-treated animals had rebounded to levels higher than that of the controls. In the last experiment, I used volumetric capnography to confirm our hypothesis that carbon dioxide elimination through the lungs was lower during the THAM infusion. Again, the PaCO2 rebounded after the THAM infusion had stopped and I concluded that renal elimination of protonated THAM was not sufficient.

<p>Tris(hydroxymethyl)aminomethane (THAM) was a readily-available and economical amino-triol that was viewed as having a large untapped potential as a starting material. The full chemoselective functionalization and differentiation of the amino group and the three primary alcohol residues present in THAM was extensively investigated. The development of this methodology allowed for the rapid assembly of a differentiated core that lead to existing and new potential drug scaffolds.</p> <p>The discovery of a novel oxidative fragmentation and rearrangement process was made leading to the synthesis of differentiated oxazolidinone rings. This process allowed for the creation of novel chemical library situated around THAM-based oxazolidinones, as well as THAM-based 1,3-dioxanes.</p> <p>THAM was also used as a starting material for sphingosine analogs, including sphingosine 1-phosphate (S1P) and anticancer S1K inhibitors. Selective functionalization of the amine and one alcohol within an oxazolidinone ring allowed access to a new family of Linezolid-type oxazolidinones as well. Additionally, various triazole-based compounds were prepared, which allowed access to a new family of potential antifungal agents based on the lead compound Fluconazole.</p> <p>A total synthesis of the immunosuppressant molecule FTY720 was also reported, employing double Wittig-olefination protocol, from THAM. This synthesis avoided certain pitfalls that were present in previously documented literature methods. Along the pathway to FTY720, many intermediates and analogs were synthesized and tested for biological activity alongside the novel oxazolidinone compounds, resulting in interesting lead compounds for various biological applications. A UV-active FTY720 scaffold was also synthesized for potential future <em>in vivo</em> tracking of the immunosuppressant and its metabolites.</p> / Doctor of Philosophy (PhD)