Unit:
Department of ChemistryLibrary of the School of Science
Author:
Mavrikaki Vasiliki
Dissertation committee:
Δημήτριος Γεωργιάδης, Καθηγητής, Τμήμα Χημείας, ΕΚΠΑ
Γεώργιος Κόλλιας, Καθηγητής, Τμήμα Ιατρικής, ΕΚΠΑ
Σκαρλάτος Ντέντος, Αναπληρωτής Καθηγητής, Τμήμα Βιολογίας, ΕΚΠΑ
Βασιλική Σαρλή, Αναπληρώτρια Καθηγήτρια, Τμήμα Χημείας, ΑΠΘ
Αγγελική Κουρουνάκη, Καθηγήτρια, Τμήμα Φαρμακευτικής, ΕΚΠΑ
Παναγιώτης Μαράκος, Καθηγητής, Τμήμα Φαρμακευτικής, ΕΚΠΑ
Βικτωρία Μαγκριώτη, Αναπληρώτρια Καθηγήτρια, Τμήμα Χημείας, ΕΚΠΑ
Original Title:
Ανάπτυξη Βιοδραστικών Ενώσεων έναντι Χρόνιων Φλεγμονωδών Νόσων Στοχεύοντας την Ενεργοποίηση Παθογόνων Ινοβλαστών
Translated title:
Development of Bioactive Compounds against Chronic Inflammatory Diseases Targeting the Activation of Pathogenic Fibroblasts
Summary:
Fibroblasts play a crucial role in regulating inflammation, fibrosis, and cancer. Today, more than 50% of all deaths are attributed to inflammation-related diseases, while fibrotic diseases contributed to 17.8% in 2019. In terms of cancer, there were 9.7 million cancer-related deaths worldwide in 2022. Targeting fibroblast activation in these complex diseases has recently emerged as a novel approach to restore tissue homeostasis. In this study, we present a multidisciplinary approach for the discovery of small molecule lead compounds that inhibit pathogenic fibroblast activation. Our research involves initially the design and synthesis of novel bioactive compounds through exploration of extensive structure-activity relationship (SAR) and bioisosterism studies. The resulting benzamide derivatives were initially screened for their anti-inflammatory activity using phenotypic assays, while the biopharmaceutical properties (ADMET) of the most promising compounds were evaluated in vitro. To this end, robust synthetic procedures which are amenable to the parallel synthesis of derivatives were designed and applied, while our screening pipeline allowed us to discriminate key structural components against deactivating fibroblasts, to refine atoms or groups that favor a desirable ADMET profile, as well as to identify metabolic “hot-spots” of the new pharmacophore. Furthermore, the mechanism of action of the compounds was investigated by employing innovative cutting-edge techniques, such as chemoproteomics and RNA sequencing, followed by target validation experiments. In addition, preliminary pharmacokinetic and in vivo evaluation studies were performed for the most optimized derivatives. Notably, the current PhD thesis brings to light the first-in-class inhibitors for HYOU1 protein, a member of the HSP70 family linked to cellular stress responses. Therefore, targeting HYOU1 could offer a tractable approach to modulate fibroblast activation and address chronic inflammatory and fibrotic conditions.
Main subject category:
Science
Keywords:
Chronic inflammatory diseases, activated fibroblasts, small molecules, benzamides, click chemistry, hypoxia-upregulated protein 1 (HYOU1)
Number of index pages:
17
Number of references:
105
File:
File access is restricted until 2027-10-26.
ΔΔ_Μαυρικάκη.pdf
20 MB
File access is restricted until 2027-10-26.