De Gregorio, Rosa (2025) Chemical synthesis and computational chemistry: a powerful combination for the identification of a new alternative approach to antitumoral therapy. [Tesi di dottorato]

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Abstract

The present work includes distinct research projects having as common platform the design and synthesis of biologically active small molecules, as tools for drug discovery and chemical biology studies. Cancer remains one of the leading causes of death worldwide, affecting millions of people every year. Despite significant advances in medical research and treatment, the fight against cancer remains a formidable challenge. Understanding the mechanisms of cancer and developing new therapeutic strategies are essential in the ongoing effort to transform cancer from a fatal prognosis to a manageable condition. In this context, recently LIF-LIFR pathway was identified as a plausible target in several cancers. Leukaemia inhibitory factor (LIF) belongs to the IL-6 family of cytokines, involved in immune regulation, morphogenesis and oncogenesis. In cancer tissues, LIF overexpression promotes epithelial mesenchymal transition and cell growth. Specifically, its over expression is correlated to the high mortality associated to pancreatic ductal adenocarcinoma (PDAC) and gastric cancer (GC). Since there are no LIFR inhibitors approved for clinical use, we decided to explore LIFR chemical space to identify new scaffold able to inhibit its pathway. In chapter 2, the study started from an in-silico screening of already FDA-approved drugs to select new putative LIFR inhibitors. The study led to the identification of mifepristone whose repositioning was then supported by computation and pharmacological studies. Then, to further explore LIFR chemical space, a small series of steroidal compound were designed starting from known LIFR inhibitors (EC359 and mifepristone), synthetised and tested in vitro. This led to the discovery of compound 4 as a new hit compound, even though its inhibitory activity was not significantly improved compared to the parent compounds. Consequently, a new series of 30 derivatives was designed, synthesized, and tested hoping to identify 2 better candidates. From this series, we identified two subsets of compounds: the first subset consists of selective LIFR inhibitors, while the second includes new LIFR antagonists and GPBAR1 agonists, thus presenting the 4,9-estradien-3-one scaffold for the first time as able to interact with GPBAR1. In Chapter 3, our study was focused on bile acids and their synthetic derivatives. To identify a new scaffold able to inhibit LIF/LIFR pathway and considering recent studies reporting the antitumor role of bile acids, a large library of natural and semisynthetic steroid compounds was evaluated in silico. The results identified BAR502 as a viable candidate for LIFR inhibition which was then confirmed by detailed in vitro analysis. Meanwhile, since BAR502 and BAR501 have been approved for clinical trial, we also focused on the synthesis of their biotransformation products. Indeed, the identification and the synthesis of metabolites of a drug are critical to describe in detail its bioavailability, pharmacokinetics, accumulation, distribution, and excretion. Therefore, in this chapter, we reported the synthetic protocol used for the synthesis of Phase I and Phase II metabolites as analytical standards. Finally, chapter 4 is about the project in which I was involved during my PhD period abroad. We worked on the development of a continuous flow approach for the generation of alkynes from isoxazolones under diazotisation conditions. In this case, I first reported the optimization process which led to the best reaction conditions, and then the substrate scope and the flow scale-up.

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