Tumor drug targeting is one of the most promising therapeutic strategies in oncology. The aim of this PhD work was the study of the essential features required for the assembly of tumor targeting conjugates.This work was focused on the deveploment of ligands for the GRP receptor that should function as carrier molecules for the targeting of tumor cells overexpressing this receptor. For this purpose, non-peptide GRP mimetics were designed, using a computer-based drug design technique, synthesized and tested. Two analogue compounds based on a bicyclic scaffold exerted an antagonist behaviour on the GRP receptor. Synthetic studies have been performed to optimize their production as well as biological tests to determine their potential as carrier molecules. Apart from the targeting moiety, we also studied the antineoplastic part of tumor targeting conjugates. Akt is a proto-oncogenic kinase that has been associated to cancer development. Therefore, the Akt inhibitory activity of phosphatidylinositol phosphate analogues was exploited. A small library of iminosugar-based phosphatidylinositol phosphate analogues was designed and synthesized. During the biological evaluation, target compounds displayed low to moderate inhibitory activity for Akt, which suggests their feasibility for the development of new and more potent Akt inhibitors.

(2011). Studies on tumor drug targeting. (Tesi di dottorato, Università degli Studi di Milano-Bicocca, 2011).

Studies on tumor drug targeting

ORSATO, ALEXANDRE
2011-02-10

Abstract

Tumor drug targeting is one of the most promising therapeutic strategies in oncology. The aim of this PhD work was the study of the essential features required for the assembly of tumor targeting conjugates.This work was focused on the deveploment of ligands for the GRP receptor that should function as carrier molecules for the targeting of tumor cells overexpressing this receptor. For this purpose, non-peptide GRP mimetics were designed, using a computer-based drug design technique, synthesized and tested. Two analogue compounds based on a bicyclic scaffold exerted an antagonist behaviour on the GRP receptor. Synthetic studies have been performed to optimize their production as well as biological tests to determine their potential as carrier molecules. Apart from the targeting moiety, we also studied the antineoplastic part of tumor targeting conjugates. Akt is a proto-oncogenic kinase that has been associated to cancer development. Therefore, the Akt inhibitory activity of phosphatidylinositol phosphate analogues was exploited. A small library of iminosugar-based phosphatidylinositol phosphate analogues was designed and synthesized. During the biological evaluation, target compounds displayed low to moderate inhibitory activity for Akt, which suggests their feasibility for the development of new and more potent Akt inhibitors.
NICOTRA, FRANCESCO
LA FERLA, BARBARA
Drug targeting, Cancer, Gastrin-Releasing Peptide, Peptidomimetics, Computer-based drug design, Synthesis, Akt, Phosphatidylinositol phosphate analogues
CHIM/06 - CHIMICA ORGANICA
English
Scuola di dottorato di Scienze
SCIENZE CHIMICHE - 18R
23
2009/2010
(2011). Studies on tumor drug targeting. (Tesi di dottorato, Università degli Studi di Milano-Bicocca, 2011).
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/10281/19200
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