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Digital archive of theses discussed at the University of Pisa

 

Thesis etd-02262012-214651


Thesis type
Tesi di dottorato di ricerca
Author
NESI, GIULIA
URN
etd-02262012-214651
Thesis title
“Synthesis of new enzyme inhibitors as potential tools for the antineoplastic therapy”
Academic discipline
CHIM/08
Course of study
SCIENZA DEL FARMACO E DELLE SOSTANZE BIOATTIVE
Supervisors
tutor Dott.ssa Rapposelli, Simona
Keywords
  • Akt
  • inhibitor
  • PDK1
Graduation session start date
27/03/2012
Availability
Full
Summary
The phosphoinositide 3-kinase/3-phosphoinositide-dependent kinase 1 (PDK1)/Akt signaling pathway plays a key role in cancer cell growth, invasion, and survival. Moreover, its pivotal role in carcinogenesis and tumor progression has been definitely established. Aberrant activation of this pathway has been implicated in many cancers such as ovarian, lung, breast, colon cancer and glioblastoma, therefore it could be considered as an attractive target for cancer therapy.
Starting from an analysis of recent patented Akt pathway inhibitors chosen as lead structures, we designed and synthesised a new collection of oxyindolone derivatives (OXIDs). Although the 2-oxyindole nucleus has been widely investigated, and in particular as regards the effects induced by different type of substitutions in 3- position, only few cases regarded the insertion of electron reach groups in 5-position.The absence of a detailed study of this kind of modification prompted us to explore it. Then, we synthesised new OXIDs in which the C5 carbon was substituted by aromatic moieties anchored to the 2-oxyindole nucleus through different amidoalkyl chains.
A preliminary evaluation on human NSCLC showed a significant antiproliferative effects, and a marked suppression of Akt phosphorylation at P-Thr308. Finally a flow cytometry analysis showed that OXIDs lead to a G1 phase arrest associated to a reduction of G2/M phase and a relative loss of S-phase population, typical effect of Akt inhibitors.
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