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Digital archive of theses discussed at the University of Pisa

 

Thesis etd-08302021-154254


Thesis type
Tesi di laurea magistrale LM5
Author
GIANNESSI, LISA
URN
etd-08302021-154254
Thesis title
Developing new modifications of biologically active heterobicyclic scaffolds
Department
FARMACIA
Course of study
CHIMICA E TECNOLOGIA FARMACEUTICHE
Supervisors
relatore Prof. Pineschi, Mauro
relatore Dott.ssa Comparini, Lucrezia Margherita
Keywords
  • GLP-1
  • type 2 diabetes mellitus
  • neuroprotective agents
  • heterobicyclic scaffolds
Graduation session start date
04/10/2021
Availability
Withheld
Release date
04/10/2091
Summary
In 2017, Prof. Pineschi and coworkers have synthesized a novel molecular scaffold (1,3-diaza-4-oxa-[3.3.1]non-6-ene) which has demonstrated to be a secretagogue of GLP-1. It can increase the GLP-1 release both in vitro and in vivo, promoting the reduction of glycemia. Due to this biological activity, it is under preclinical evaluation as potential new per os type 2 diabetes treatment and as neuroprotective agent.
Although several analogues of this compound have been already synthesized in Prof. Pineschi’s laboratory, further modifications can still be developed. The aim of this thesis is the development of new modifications of this novel scaffold, following a well-established general four steps synthetic pathway:
1. Synthesis of 1,2-dihydropyridine
2. Nitroso Diels-Alder between 1,2-dihydropyridine and acyl nitroso derivative
3. Hetero-Cope rearrangement of Diels-Alder cycloadduct
4. Reduction using LiEt3BH
There are two moieties where modifications can be easily done: one deriving from the acyl nitroso derivative (step 2), and the other deriving from the aryl Grignard reagent (step 1).
Moreover, we performed the reductive N-O bond cleavage of this heterobicyclic scaffold. Several procedures of reductive N-O bond cleavage are reported in literature, but most of these resulted ineffective for our substrate. We have now found that Cp2TiCl can successfully cleave the N-O bond to give the corresponding tetrahydropyridine.
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