Tesi di laurea magistrale LM5
Design and synthesis of Imidazopyridine derivates as new drug candidates for the treatment of Glioblastoma Multiforme
Corso di studi
CHIMICA E TECNOLOGIA FARMACEUTICHE
relatore Prof.ssa La Motta, Concettina
relatore Dott. Quattrini, Luca
relatore Dott. Quattrini, Luca
- imidazopyridine derivates
- Glioblastoma multiforme
- stem cell
- tumor heterogeneity
Data inizio appello
Data di rilascio
The aim of this thesis work is the design and synthesis of novel imidazopyridine derivates, developed as drug candidates for the treatment of glioblastoma. Glioblastoma Multiforme (GBM) is the most common primary malignant brain tumor, with an average incidence rate of about 3.19 per 100,000 persons, and a prognosis of about 15 months of survival. GBM is an astrocytoma, and according to the World Health Organization (WHO) it is classified as a grade IV glioma (tumors that arise from glial or precursor cells). For this pathology, therapies are aimed at increasing patient survival time; the current standard of care are surgical resection, radiotherapy and chemotherapy, as Temozolomide. New therapies, like immunotherapy, are currently in clinical trials. The effectiveness of local therapies is limited by several factors like the growth of the tumor in a vital organ, the protection of the tumor cells by the blood-brain barrier, the dependence by various oncogenic pathways, and above all the tumor cellular heterogeneity. Indeed, tumor heterogeneity consists in different cancer cells that show distinct morphological and phenotypic profiles, such as gene expression, metabolism, proliferation, metastatic potential, and different response to therapies, even within a same tumor (intra-tumor heterogeneity). In glioblastoma there are also cancer stem cells (GSCs), which are similar to normal stem cells, as they separate asymmetrically and give birth to daughter cells equal to the cell of origin (a tumor stem cell), or are able to differentiate into different tumor cells. Among the markers for cancer stem cells, ALDH1, an isoform of aldehyde dehydrogenase, in one of the most important. Aldehyde dehydrogenases (ALDHs) are an enzyme superfamily composed of 19 human isoenzymes with 11 different families that have a different cellular localization, structure, and bond to the substrates. Indeed, they are localized in different tissues like uterus, brain, kidney, and liver. ALDHs oxidize endogenous and exogenous aldehydes to the corresponding carboxylic acids using either NAD+ or NADP+ as the coenzyme. ALDHs are involved in several biological functions, for example, they have a role in signaling pathway of retinoic acid, in ROS metabolism and in drug resistance. Since ALDH1 has different roles in GCSs, it is considered an important resistance factor against current therapies, making it a potential interesting target for glioblastoma treatment. <br>During my thesis period, I focused on the design and synthesis of new ALDH1 inhibitors by taking inspiration from the natural isoflavone Daidzin, which exhibits reversible inhibitory ability on ALDH by binding its active site. Therefore, starting from the structure of the Daidzin, 7-O-glucosyl-4'-hydroxy-isoflavone, changes were made to the main core of the molecule with the aim to improve its pharmacodynamic and pharmacokinetic properties. The modifications of Daidzin structure were thought to not affect important pharmacophoric moieties of the original molecule, maintaining a certain structural analogy, while giving to the new derivatives a better hydro-lipophilic profile, including a smaller polar surface area. Indeed, these characteristics are fundamental because these molecules have been designed to pass through the BBB and act on GSCs. The addition of aromatic, lipophilic and planar portions at positions 2 and 6 of the imidazopyridine nucleus allowed to obtain GA11, 2,6-diphenylimidazo[1,2-a]pyridine. Investigated in vitro, GA11 proved to inhibit ALDH1 efficiently. Moreover, it turned out to be active in an animal model of glioblastoma, thus standing out as a viable hit to develop.<br>Since crystallization of the protein with the imidazopyridine inhibitor is not yet available, we adopted a rational approach for the structural optimization of the hit compound GA11. New structural analogs have been synthesized, maintaining the 2,6 disubstituted central core of GA11, changing the nature of the substituents introduced to decorate the phenyl rings, which differ for electronic nature and steric hindrance.
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