Functionalized derivatives of 1,4-dimethylnaphthalene as precursors for biomedical applications: synthesis, structures, spectroscopy and photochemical activation in the presence of dioxygen

Abstract

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. Thus, a significant prolongation of the lifetime of the endoperoxide species is possible by raising the energy barrier of the thermal 1 O 2 -releasing step via a restriction of the free volume of the applied carrier material. Enabling such a prolonged decomposition period is crucial for potential biomedical applications of endoperoxide containing molecules, since sufficient time for appropriate cell uptake and transport to the desired target region must be available under physiological conditions before the tissue damaging-power of the reactive oxygen species formed is completely exhausted. 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. These compounds are based on functionalized derivatives of the 1,4-dimethylnaphthalene family which are readily forming metastable endoperoxide species in the presence of dioxygen, a photosensitizer molecule such as methylene blue and visible light. In contrast to previously known systems of similar photoreactivity, the endoperoxide carrying molecules have been designed with optimized molecular properties in terms of potential chemotherapeutic 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 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. Furthermore, an efficient low-cost method for the photochemical production of reactive endoperoxides based on high-power 660 nm LED excitation at room temperature and ambient conditions in ethanol solution is reported.

A Bifunctional Photosensitizer for Enhanced Fractional Photodynamic Therapy: Singlet Oxygen Generation in the Presence and Absence of Light

“…[7][8][9] In fact, it has been already reported that singlet oxygen produced by the thermal decomposition of 2-pyridone endoperoxides lead to cell death by ap rocess resembling apoptosis in cancer cell cultures. [10] In addition, phthalocyanine [11] and porphyrin endoperoxide [12] derivatives were reported where the endoperoxides are obtained by selfphotosensitization. Thus,i ti se vident that ar ationally designed bifunctional photosensitizer/2-pyridone conjugate may be an optimal agent for an ovel approach to fractional photodynamic therapy.2 ,6-Dibromo (and iodo) distyryl BODIPY derivatives (BODIPY = boron-dipyrromethene) were shown [13][14][15][16] to be promising long-wavelength sensitizers of molecular oxygen.…”

Polyvinyl butyral DMN-conjugates for the controlled release of singlet oxygen in medical and antimicrobial applications

“…As an extension of our previous work (Posavec et al 2012), we wish to report here our results on the covalent attachment of such functional 1,4-dimethyl-naphthalen-2-yl subunits to a polyvinylbutyrate (PVB) polymer backbone. PVB has been selected as a carrier medium for drug delivery because of its excellent biocompatibility, non-toxicity and the possibility of preparing spherical PVB nanoparticles that have been shown to be efficiently taken up without further surface modifications by human cancer cells (Posavec et al 2011).…”

“…We have recently presented a novel strategy for controlling the delayed release of singlet oxygen ( 1 O 2 ) in the context of different biomedical applications including cancer chemotherapy or the deactivation of bacteria, viruses and parasites (Posavec et al 2012). The singlet oxygen releasing system applied is based on the intermediate storage and transport of metastable endoperoxides photochemically generated from functionalized dimethylnaphthalene derivatives Corresponding author, Professor, E-mail: guenther.knoer@jku.at such as 1-(1, 4-dimethyl-naphthalen-2-yl)-ethanol (DMN-OH) and related compounds (Fig.…”

“…This novel approach enables to reach a very high local concentration of endoperoxide-forming groups in the target region. At the same time, the endoperoxide decay process and thus also the 1 O 2 -release period will be drastically prolonged by an incorporation of the DMN-derivatives into the polymer matrix and an additional adaptation modifying the functional structures present in the material system, which is a crucial factor for many biomedical and therapeutical applications (Posavec et al 2012.…”

Molecular devices based on reversible singlet oxygen binding in optical and photomedical applications

“…60 Singlet oxygen releasing naphthalene endoperoxide derivatives embedded in nanoparticles were shown to induce a very strong cytocidal effect on the proliferation of human breast cancer cells. 61 However, the use of endoperoxides in these biomedical applications is still in its infancy due to lack of carrier systems which can ensure: 1) selective targeting of diseased cells and, particularly, 2) prevent endoperoxide decomposition until the drug is delivered into cells. This contrasts with conventional PDT treatments, wherein a photosensitizer drug selectively accumulates in tumor tissue and generates singlet oxygen only if an external stimulus (light) is applied.…”