Alkoxyamine 1 is selectively hydrolyzed by chymotrypsin and substilisin A into alkoxyamine 2H+ for which C–ON bond homolysis occurred with a 4-fold increase in rate constants compared to 1 while non-specific proteases had no effect.
Photodynamic therapy (PDT) is a promising technique to treat different kinds of disease especially cancer. PDT requires three elements: molecular oxygen, a photo-activatable molecule called the photosensitizer (PS) and appropriate light. Under illumination, the PSs generate, in the presence of oxygen, the formation of reactive oxygen species including singlet oxygen, toxic, which then destroys the surrounding tissues. Even if PDT is used with success to treat actinic keratosis or prostate cancer for example, PDT suffers from two major drawbacks: the lack of selectivity of most of the PSs currently used clinically as well as the need for oxygen to be effective. To remedy the lack of selectivity, targeting the tumor neovessels is a promising approach to destroy the vascularization and cause asphyxia of the tumor. KDPPR peptide affinity for the NRP-1 receptor overexpressed on endothelial cells has already been proven. To compensate for the lack of oxygen, we focused on photoactivatable alkoxyamines, molecules capable of generating toxic radicals by light activation. In this paper we describe the synthesis of a multifunctional platform combining three units: a PS for an oxygen-dependent PDT, a peptide to target tumor neovessels and an alkoxyamine for an oxygen-independent activity. The synthesis of the compound was successfully carried out, the study of the photophysical properties showed that the PS retained its capacity to form singlet oxygen, the affinity tests confirmed the affinity of the compound for NRP-1. Thanks to the Electron Paramagnetic Resonance (EPR) spectroscopy, a technique of choice for radical investigation, the radicals generated by the illumination of the alkoxyamine could be detected. The proof of concept was thus successfully established.
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