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Digital archive of theses discussed at the University of Pisa

 

Thesis etd-03062024-092523


Thesis type
Tesi di dottorato di ricerca
Author
COMPARINI, LUCREZIA MARGHERITA
URN
etd-03062024-092523
Thesis title
Development of new approaches to the synthesis of heterocycles of medicinal interest
Academic discipline
CHIM/06
Course of study
SCIENZA DEL FARMACO E DELLE SOSTANZE BIOATTIVE
Supervisors
tutor Prof. Pineschi, Mauro
Keywords
  • Diabetes
  • GLP-1
  • Grignard reagents
  • Quinagolide
  • Ring-opening reactions
  • spiro-cyclization
Graduation session start date
14/03/2024
Availability
Withheld
Release date
14/03/2094
Summary
Summary
Small molecules are organic compounds with the capacity to influence a wide range of molecular pathways. They typically have a low molecular weight and can be created through intentional design or extracted from natural sources. Small molecules have played a vital role in the advancement of medicine, with their effectiveness often stemming from their inherent properties. Their potential for oral absorption is a significant advantage, and their compact size allows for straightforward synthesis and structural modifications, enabling the creation of extensive compound libraries. Specific designs can be formulated to produce pro-drugs or drugs that target specific sites in the body. Their cost-effective production and extended shelf life, in comparison to biological drugs, make small molecules a highly practical choice in various contexts. The core theme connecting the different chapters of this thesis is the development of small molecules, particularly those containing heterocyclic frameworks. This Ph.D. program encompassed four projects, with each one focusing on the synthesis of small molecules and the methodological study for their synthesis.
Chapter 1 concentrates on the formation of a compound library featuring a 1,3-diaza-4-oxa [3.3.1] bicyclic scaffold with GLP-1 secretagogue properties. These compounds exhibit favorable attributes for oral administration and could potentially offer a novel treatment for type-2 diabetes mellitus. The project involved the synthesis of numerous compounds, followed by biological testing to assess their effectiveness. A highly active lead compound was identified, and an enantioselective synthesis method was developed to produce both enantiomers of the molecule. Additionally, late-stage modifications were performed on the scaffolds using various methodologies.
Chapter 2 discusses the project undertaken during an international internship as part of the Ph.D. program at LEO Pharma A/S in Denmark. The project centered on analyzing the reaction mechanism of the spiro-cyclization step in the production of Delgocitinib, a small molecule used topically to treat atopic dermatitis. Through the use of NMR, HPLC, and IR analysis, the study identified all the reaction intermediates and two distinct reaction pathways, depending on the base used to initiate the reaction.
Chapter 3 differs from the others, as its primary focus was on identifying and developing a new synthetic approach for the ring-opening alkylation of cyclic gem-diamines using Grignard reagents and copper salt catalysis. Cyclic gem-diamines are commonly found in medicinal chemistry, agrochemicals, and natural products. Ring-opening with Grignard reagents can lead to the formation of substituted 1,2- and 1,3-diamines with high purity and yield, a result not easily achievable through other protocols.
Chapter 4 addresses the development of an enantioselective strategy for the synthesis of (-)-Quinagolide, a project conducted in collaboration with Ferring Pharmaceuticals. Noprolac® is the brand name of the racemic mixture of quinagolide, a D2 receptor agonist small molecule used to treat hyperprolactinemia. However, the dopaminergic activity resides in only one of the stereoisomers. Consequently, an enantioselective synthesis of the eutomer was devised through an enzymatic kinetic resolution and stereoselective reduction of an iminium ion, building upon the industrially established synthetic protocol with minor adjustments.
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