University thesis:
Dissertation, Universität Freiburg, 2021
Footnote:
Description:
Abstract: A series of water-soluble anthrancene (Ant) endoperoxides (EPOs) have been synthesized and their oxygen release kinetics were investigated. From Singlet Oxygen Sensor Green (SOSG) assay and trapping of singlet oxygen with fufuryl alcohol, we could derive that there was more than 39% singlet oxygen release during the thermolyses of our new Ant EPOs in water at 37 °C, which is significantly higher than the known compound EPO 18 that was used to promote cell survival under anoxic conditions. Therefore, applying new EPOs to rescue anoxic tissues was not evaluated. Instead, the activity of new Ant EPOs against a wide range of bacteria (M. smegmatis, M. tuberculosis, E. coli, S. aureus, S. epidermis) was investigated. Some pyridinium modified Ant EPOs displayed good antibacterial activity, mainly based on the membrane binding and disruption by pyridinium moiety and toxic singlet oxygen release in situ from EPO moiety. By adjusting the charge distance and substitution patterns, the oxygen release kinetics as well as antibacterial activity can be tuned. These results showed that the combination of bis-pyridinium quaternary ammonium compounds (QACs) with EPO moiety is a good strategy for the development of new antibiotics.<br>A couple of trehalose-photosensizer conjugates were synthesized and their photo-toxicity against mycobacteria was investigated. Most of these trehalose-photosensizer conjugates displayed better activity than non-conjugated photosensizers (including protoporphyrin, BODIPY and methylene blue) against M. smegmatis and M. abscessus. The activity of some trehalose-photosensizer conjugates is comparable to some clinical drugs, such as rifampicin, ciprofloxacin, amikacin and SQ109. Applying trehalose led to accumulation of photosensizers in the mycomembrane, and upon irradiation, pathogens can be selectively destroyed. This strategy is promising to treat mycobacteria-caused infections and trehalose-photosensitizer conjugates represent an exciting new class of antimycobacterial agents