Tesi etd-09302024-105808
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Tipo di tesi
Dottorato
Autore
UGOLINI, ALESSANDRA
URN
etd-09302024-105808
Titolo
Design, Synthesis and Biological Evaluation of Bactericidal- Autophagy Inhibitors
Settore scientifico disciplinare
CHIM/08
Corso di studi
Istituto di Scienze della Vita - PHD IN MEDICINA TRASLAZIONALE
Commissione
relatore Dott. GRIMALDI, BENEDETTO
Parole chiave
- autophagy
- bacteria
- cancer
- cloroquine
- structure-activity relationship
Data inizio appello
06/05/2025;
Disponibilità
parziale
Riassunto analitico
Dysregulation of autophagy flux has been linked to numerous pathological conditions, such as cancer and bacterial infections. Interestingly, established tumor cells are known to enhance autophagy to overcome chemotherapy-induced stress; therefore, a block of autophagy appears as a valuable strategy for improving the anticancer activity of several antineoplastic agents. Indeed, numerous clinical trials are exploring this possibility by using a combined therapy with diverse anticancer agents and chloroquine (CQ), which represents the only available clinical drug with autophagy inhibitory property. Nevertheless, one of the most common unfavorable consequence of this adjuvant chemotherapy remains the reduction in neutrophil count (chemotherapy-related neutropenia), which, increasing the susceptibility of patients to microbial infections, often leads to considerable morbidity and mortality. With the aim of identifying novel autophagy inhibitors, Dr Benedetto Grimaldi‘s Group has recently discovered that a previously characterized broad-spectrum antibiotic, named DCAP, also acts on human cell physiology by blocking autophagy process. These studies identified DCAP as a novel multi-target drug, inhibiting both the autophagy process and the bacterial growth, and supported further development studies for the identification of optimized bactericidal-autophagy inhibitor(s) with potential therapeutic applications for adjuvant therapy in cancer treatment and infection- related conditions. This PhD work describes the chemical exploration of DCAP series by reporting the structure-activity relationship (SAR) and structure- property relationship (SPR) studies around DCAP scaffold (carbazole series) with the goal of elucidating the crucial chemical and structural features within this series that are responsible for both the inhibition of bacteria growth and cytotoxicity (via autophagy inhibition). These medicinal chemistry efforts led to the identification of some potential issues within the carbazole-based DCAP series, which prompted this work to be directed to the design, synthesis and biological evaluation of a novel class of dual bactericidal-autophagy inhibitors– structurally differentiated from DCAP scaffold (confidential information).
Overall, this PhD work resulted in the identification of a novel and potent class of bioactive molecules with optimized dual biological profiles (antibacterial and cytotoxicity activities) and improved physicochemical and in vitro absorption, distribution, metabolism and excretion (ADME) properties compared to the carbazole series as valuable tools for future dedicated pharmacological investigations.
Overall, this PhD work resulted in the identification of a novel and potent class of bioactive molecules with optimized dual biological profiles (antibacterial and cytotoxicity activities) and improved physicochemical and in vitro absorption, distribution, metabolism and excretion (ADME) properties compared to the carbazole series as valuable tools for future dedicated pharmacological investigations.
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