Studies on the Chemical Modulation of Neuroprotective Agents Related to CR-6 Addressed to Improve the Delivery through the Blood-Brain Barrier

Tesi realitzada a l'Institut de Química Avançada de Catalunya (IQAC-CSIC) Oxidative stress is one of the most important factors in degenerative diseases like cancer, Alzheimer or in episodes like ischemia. During these processes, reactive species of oxygen (ROS) and nitrogen (RNS) are generated. This fact can cause the chemical modification of important biomolecules, in particular lipids and proteins. The strategy that involves the use of antioxidants and neuroprotective agents to fight against the lesive effects of these species stumbles over the blood-brain-barrier (BBB). This barrier protects the brain from the action of a wide variety of organic molecules and drugs. Thus, it is important to develop novel antioxidant agents with good delivery through the BBB. In our group it was discovered the antioxidant agent 3,4-dihydro-2,2-dimethyl-7-metoxy-1-(2H)-benzopyran (CR-6), an analogue of alpha- and gamma-tocopherols (Figure 1), which is currently used in dermopharmacy and it is also in a phase II trials for anticancer treatment (combined with other drugs). In our present project, one of the main goals is the synthesis of a short library of CR-6 analogues that could improve the pass through the BBB. Accordingly, fourteen novel CR-6 analogues have been synthesized introducing essential nutrients for brain that work as BBB-shuttles at C2 of CR-6 scaffold. The antioxidant activity was evaluated to assure that it does not change by the incorporation of variability at C2 position (the DPPH assay and the in vitro CAA were used). In addition, the BBB permeability was evaluated to compare the BBB bioavailability of these new antioxidant agents with the references CR-6 and Trolox (PAMPA, Caco-2 and BBCEC assays were used). El estrés oxidativo es uno de los factores etiológicos más importantes en las enfermedades degenerativas como el cáncer, el Alzheimer o en episodios de isquemia. Durante estos procesos, se generan especies reactivas de oxigeno (ROS) y de nitrógeno (RNS) que provocan modificaciones de las biomoléculas como los lípidos, las proteínas y el ADN. El uso de agentes antioxidantes y neuroprotectores ayudan a reducir los efectos lesivos que el estrés oxidativo tiene en el cerebro, por ejemplo. La barrera hematoencefálica o BBB protege al cerebro de la acción de una amplia variedad de moléculas orgánicas y fármacos. Por ello, existe un gran interés en el desarrollo de nuevos agentes antioxidantes con un buen transporte a través de la BBB. En nuestro grupo d