Abstract
Photodynamic therapy (PDT) is a therapeutic approach mainly used in the treatment of cancer, based on the combination of light, oxygen and a PS. The action of light at a specific wavelength on the PS in the presence of oxygen results in the formation of reactive oxygen species (ROS), inducing cell death. During the PDT process, two types of photo-induced reactions occur, type I and type II. The type I reaction involves electron transfer, leading to the production of ROS. The type II process, on the other hand, leads to the formation of 1O2 due to energy transfer. PDT can lose its effectiveness because of tumor hypoxia, a feature frequently found in most solid tumors. The effects induced by low oxygen levels are orchestrated by hypoxia-inducible Factor (HIF), that regulate many genes involved in cancer progression. One of the adaptive responses of tumor cells to hypoxia involves increased expression and functional activation of carbonic anhydrase IX (hCA IX), a membrane enzyme catalyzing the reversible conversion of carbon dioxide to bicarbonate ion and a proton, it is considered as marker of hypoxia and therapeutic target, due to its mode of expression and its functional implications in tumor biology.The aim of this thesis is to develop new functional PSs incorporating selective inhibitors of hCA IX /XII for the therapy and imaging of hypoxic tumors.Firstly, the synthesis, characterization and study of the optical properties of new tetrafunctionalized zinc (II) porphyrins linked to CAi of sulfonamide or coumarin family. This approach showed the potential of combining PSs and selective CAi for hCA IX and hCA XII, more specifically the CAi introduction, allow to the porphyrin specifically targeting the Capan-1 membrane and, alter cell proliferation. In addition, the effective properties of the PS linked to coummarin moieties make this PS a promising candidate for PDT. In the second approach the development of series of CAi-PS hybrid systems, which combine a classic CAi from the sulfonamide family, coumarin or sulfocoumarin units are discussed. The thiochromenocarbazole imide (CTI) has been used as a PS. The optical properties of the PSs obtained, their ability to generate 1O2 were then evaluated. Subsequently, hCA inhibition assays on four human isoforms were carried out. These PSs showed significant optical properties, and excellent efficiency in generating 1O2, PSs with the coumarin sulfocoumarin fragments showed high selectivity, giving them the possibility of targeting cancer cells membrane, studies are currently underway to examine their biological activity in more detail.Finally, the synthesis of three PS with AIE properties (Aggregation-induced emission), linked with selective hCA IX and hCA XII inhibitors was discussed. the architecture of these PSs is based on a Donor-Acceptor system. CAi of sulfonamide or coumarin sries, have been linked in different ways to the TPE, either directly, or by separating them from the TPE core with alkyl chains. Their preparation, optical properties, CA inhibition and 1O2 production were described. The TPEs showed excellent 1O2 generation with interesting AIE properties, and then their hCA inhibition assays reported that TPES linked to coumarin units are selective towards hCA membrane isoforms IX and XII. Afterwards biological studies, which are currently underway to test their photocytoxicity and their ability to be used as agents for PDT and imaging.