New Glycoconjugates for the Treatment of Diseases related to Metal Dyshomeostasis

Abstract

Metal dyshomeostasis has been involved in the etiology of a great number of pathologies such as Wilson s, Alzheimer s, Parkinson s and Niemann-Pick diseases and cancer. The precise mechanisms responsible for triggering these disorders remain unclear; however, they share multifactorial pathogenic mechanisms related to metal dyshomeostasis and, as a consequence, oxidative stress. Considering the multifactorial nature of these diseases, it is becoming more and more evident that the next generation of therapies must have multiple functions to combat the multiple mechanisms of disease progression and metal ions represent a promising therapeutic target as they could be a starting point to hit multiple targets. On the other hand, especially in the treatment of cancer, drugs may be directed to the site of action in order to reduce their side effects on healthy tissues. This PhD thesis centers on the synthesis and evaluation of multifunctional molecules to interfere with different key target points of neurodegeneration and cancer. 8-hydroxyquinoline, a metal chelator, has been chosen as a basic molecular scaffold to build selective prodrugs and multifunctional metal-binding compounds on the basis of the rekindled interest in this compound and its derivatives for the treatment of Alzheimer s disease and cancer. The synthesis, characterization and biological evaluation of new covalent glycoconjugates with 8-hydroxyquinolines are reported here. Glycosylation has been a successful strategy for improving several features of these systems. Apart from the increase in solubility, sugar moiety confers selectivity and multifunctionality. In this thesis, glucosylated and galactosylated prodrugs of hydroxyquinolines were designed and synthetized in order to exploit unique and frequent features of cancer cells such as the high expression of certain proteins (e.g. glucosidases and glucose transporters) and the high levels of Cu2+. The main advantages of these glycosylated compounds are targeting and prevention of side effects due to systemic chelation. The chelating function of these compounds is masked and they must be subject to hydrolysis through specific beta-glucosidases or beta-galactosidases to liberate the active aglycone in targeted cells. The obtained results suggest that glucose- and galactose-bearing 8-hydroxyquinoline prodrugs could be suitable for prodrug monotherapy and antibody-directed enzyme prodrug therapy, respectively. Chelating 8-hydroxyquinoline conjugates with monosaccharides and disaccharides have also been synthetized in order to compare their properties to those of the glycosylated prodrugs. Unlike these latter compounds, they are able to complex Cu2+ and Zn2+ ions with high stability constants. These systems are promising compounds for the treatment of diseases related to metal dyshomeostasis. Finally, the synthetized cyclodextrin conjugates are promising multifunctional molecules that combine antioxidant, SOD-like activity, chelating, antiaggregant and inclusion abilities into one compound as demonstrated in this thesis. Cyclodextrin-hydroxyquinoline conjugates have significant antioxidant capacity and the possibility to form inclusion complexes with coformulating drugs and/or endogenous compounds such as cholesterol. The compounds can complex Cu2+ and Zn2+ ions with high conditional stability constants. Moreover, these derivatives are also able to strongly inhibit metal-induced protein aggregation and the formation of amyloid fibrils. The antiproliferative studies, carried out for this class of compounds, bode well for administering relatively high concentrations of these derivatives, for use as antioxidant and antiaggregant drugs, if necessary, without damage to healthy tissues. Overall, these conjugates compounds have great potential as therapeutic agents in the treatment of neurodegenerative diseases related to oxidative stress and metal dyshomeostasis, such as Alzheimer s and Niemann-Pick C diseases.