Functionalized Derivatives of 1,4-Dimethylnaphthalene as Precursors for Biomedical Applications: Synthesis, Structures, Spectroscopy and Photochemical Activation in the Presence of Dioxygen

Anti-Cancer and Anti-Malaria Drug Development: Decomposition of endoperoxide containing molecules is an attractive approach for the delayed release of singlet oxygen under mild reaction conditions. Here we describe a new method for the adaptation of the corresponding decay times by controlling the supramolecular functional structure of the surrounding matrix in the immediate vicinity of embedded singlet oxygen precursors. Enabling such a prolonged decomposition period is crucial for biomedical applications of endoperoxide containing molecules, since sufficient time for an appropriate cell uptake and a transport to the desired target region must be available under physiological conditions. Two novel polyaromatic systems for the intermediate storage and transport of endoperoxides and the controlled release of singlet oxygen in the context of anticancer and antibiotic activity have been prepared and characterized. In contrast to previously known systems of similar photoreactivity, the endoperoxide carrying molecules have been designed with optimized molecular properties in terms of potential chemotherapeutical applications. These include modifications of polarity to improve their incorporation into various biocompatible carrier materials, the introduction of hydrogen bonding motifs to additionally influence the endoperoxide decay kinetics, and the synthesis of bifunctional derivatives to enable synergistic effects of multiple singlet oxygen binding sites with an enhanced local concentration of reactive species. With these compounds, a promising degree of endoperoxide stability adjustment within the carrier matrix has been achieved (polymer films or nanoparticles), which now opens the stage for an appropriate targeting of the corresponding pro-drugs into live cells. First results on cytocidal and cytostatic properties of these compounds embedded in ethylcellulose nanoparticles are presented.