| dc.description.abstract | Hydrogen sulfide (H2S) is a human physiological mediator, enzymatically produced primarily in the mitochondria. Its administration in vitro or in vivo ameliorates mitochondrial dysfunction. Mitochondria-targeted H2S donor compounds were previously synthesised by coupling two H2S donor moieties (ADTOMe and HTB) to a known mitochondrial-targeting moiety, making AP39 and AP123, respectively. Although AP39 was effective against mitochondrial dysfunction in vitro and in vivo, its efficacy and tolerability may be improved by appropriate changes in its structure. Thus, in this work, new donors were generated by using ADOMe, as a new donor moiety making RT01, by changing the linking approach obtaining RT03, RT05 and RT06 or using a different cationic targeting compound, creating RTC1. Another approach to deliver H2S donor moieties inside the mitochondria, independently from the mitochondrial potential, was explored, using a known a tetrapeptide, therefore, RTP10 and RTP12 were synthesised. The H2S-releasing molecules were also linked to a compound known for its antioxidant and beneficial properties towards mitochondrial bioenergetics, obtaining RT154, RTI63, RTI64 and RTI65. Although the novel compounds synthesised reduced mitochondrial dysfunction more efficiently than their non-bonded equivalent control compounds, in an in vitro hyperglycaemia-induced model, only RTI63, RTI64, RTI65 and RTC1 exerted an improvement in AP39/AP123 tolerability and had comparable efficacy thus, they might be further evaluated as drug candidates. Another compound was synthesised using a different approach for delivering H2S in cells. The compound was evaluated in a few cell dysfunction models, in which it showed promising results. Furthermore, studies on the stability, the reactivity and the possible H2S generation mechanism of three H2S donor moieties (ADTOMe, HTB and ADOMe) commonly used in H2S-releasing drug hybrids were conducted, identifying the conditions under which they may react. Indeed, despite their biological effects being widely studied, the chemical mechanisms by which they may generate H2S have never been appropriately investigated and their metabolites have never been properly characterised. Here, studies on the identification of the possible metabolites of the three donors were conducted and their activity was evaluated in the same in vitro model, in which they did not exert significant beneficial effects. Also, they did not cause toxicity at the active concentration range of their corresponding donor. The main decomposition products of ADTOMe were identified as ADOMe, plus the carboxylic acid and ketone derivatives. HTB generated primarily, the corresponding nitrile, in addition to the corresponding carboxylic acid and amide. ADOMe may form the corresponding carboxylic acid and ketone and it may also react with thiols, forming a sulfur-sulfur bond. ADTOMe, HTB and ADOMe are stable at room temperature in water/DMSO solutions. They are stable at harsh acidic pH and at pH = 8 but are susceptible to hydrolysis at strong basic pH. ADTOMe and HTB but not ADOMe, are reactive in presence of hydrogen peroxide. | en_GB |
