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Tesi etd-02182010-105452

Thesis type
Tesi di laurea specialistica
email address
Design and synthesis of novel Acadesine analogues as Adenosine Monophosphate-activated Protein Kinase (AMPK) activators
Corso di studi
relatore Dott.ssa La Motta, Concettina
correlatore Dott.ssa Sartini, Stefania
Parole chiave
  • AMPK activators
Data inizio appello
Data di rilascio
Riassunto analitico
AMPK (5&#39; AMP-activated protein kinase or 5&#39; adenosine monophosphate-activated protein kinase) is an enzyme that plays a key role in cellular energy homeostasis. It consists of three subunits that together make a functional enzyme. It is expressed in a number of tissues, including liver, brain, and skeletal muscle. The ultimate effect of AMPK activation is the stimulation of hepatic fatty acid oxidation and ketogenesis, inhibition of cholesterol synthesis, lipogenesis, triglyceride synthesis, inhibition of adipocyte lipolysis and lipogenesis, stimulation of skeletal muscle fatty acid oxidation, muscle glucose uptake and modulation of insulin secretion by pancreatic beta-cells.<br>Mammalian AMPK is activated by binding to AMP, but this activation is inhibited by ATP with a ratio 1:3. Because cellular ADP/ATP ratios remain nearly constant due to the equilibrium maintained by adenylate kinase, it is thought that AMPK activity in vivo depends primarily on the ATP/AMP ratio, the primary determinant of cellular energy charge. Lowered cellular energy charge can arise either from inhibition of ATP synthesis, for example, in hypoxia, or by increased ATP consumption, as happens in skeletal muscle during exercise. When energy charge is low, active AMPK inhibits numerous ATP consuming pathways and also activates mobilization of intracellular energy stores to produce ATP. <br>On the contrary, when energy charge is high, AMPK inactivation is favored, leading to enhancement of energy storage and use. AMPK also functions in organism-level energy homeostasis by responding to systemically circulating hormones, including leptin, adiponectin, and resistin.<br>The development of novel AMPK activators started from an accurate study of acadesine chemical structure (AICAR or 5-aminoimidazole-4-carboxamide-1-╬▓-D-ribofuranoside), the most important AMPK-activator known in literature, that showed positive results in the treatment of type 2 diabetes, obesity, ischemic injury and inflammation. The lead compound was subjected to structural optimization through rational chemical modifications, in order to improve its potency and bioavailability.