Cytidine triphosphate synthetase (CTPS), a glutamine amidotransferase (GAT) responsible for the de novo synthesis of CTP, was recently suggested as a potential drug target for the treatment of Human African Trypanosomiasis, a parasitic disease caused by Trypanosoma brucei. Acivicin, a natural antitumor antibiotic, is a well-known inhibitor of enzymes belonging to the GAT family. Its CTPS inhibitory activity has been related to the observed trypanocidal activity in bloodstream T. brucei cell cultures. The aim of this project was the design and synthesis of Acivicin analogues characterized by an increased affinity and selectivity for CTPS, as potential new trypanocidal agents with low toxicity against human cells. The results obtained have shown that substituting the 3-Cl- with a 3-Br-isoxazoline increased the inhibitory potency of Acivicin against the target enzyme CTPS three fold, while the substitution with a 3-MeO- group produced a complete loss of the activity, confirming the important role played by the leaving group in the C-3 position of the isoxazoline ring. Interestingly, the three-fold increase of the CTPS inhibitory potency translates into a twelve fold increase of the in vitro anti-trypanosomal activity with a concomitant increase of the selectivity index relative to human cells. Another important finding of the present research project is that the inhibitory activity against CTPS can be increased by applying a molecular complication approach, that means inserting groups able to establish additional interaction with the binding pocket of the enzyme. This strategy has been pursued thanks to the synthesis of N1-substituted-pyrazoline analogues of acivicin. The analysis of the enzymatic activity and the in vitro anti-trypanosomal activity of all the derivatives under study shows that an increased inhibitory activity towards CTPS may produce a great increase of the anti-trypanosomal activity but this cannot be taken as a general rule, since other important factors may play a role, notably the ability of the molecules to penetrate into the target cells.
SYNTHESIS AND BIOLOGICAL EVALUATION OF NEW CTP SYNTHETASE INHIBITORS AS NEW POTENTIAL AGENTS FOR THE TREATMENT OF AFRICAN TRYPANOSOMIASIS. / M.c. Iannuzzi ; tutor: P. Conti ; coordinatore: E. Valoti. - Milano : Università degli studi di Milano. Universita' degli Studi di Milano, 2012 Feb 13. ((24. ciclo, Anno Accademico 2011.
|Titolo:||SYNTHESIS AND BIOLOGICAL EVALUATION OF NEW CTP SYNTHETASE INHIBITORS AS NEW POTENTIAL AGENTS FOR THE TREATMENT OF AFRICAN TRYPANOSOMIASIS.|
|Supervisori e coordinatori interni:||VALOTI, ERMANNO|
|Data di pubblicazione:||13-feb-2012|
|Parole Chiave:||African Trypanosomiasis ; CTP synthetase ; Acivicin ; isoxazoline ; pyrazoline|
|Settore Scientifico Disciplinare:||Settore CHIM/08 - Chimica Farmaceutica|
|Citazione:||SYNTHESIS AND BIOLOGICAL EVALUATION OF NEW CTP SYNTHETASE INHIBITORS AS NEW POTENTIAL AGENTS FOR THE TREATMENT OF AFRICAN TRYPANOSOMIASIS. / M.c. Iannuzzi ; tutor: P. Conti ; coordinatore: E. Valoti. - Milano : Università degli studi di Milano. Universita' degli Studi di Milano, 2012 Feb 13. ((24. ciclo, Anno Accademico 2011.|
|Appare nelle tipologie:||Tesi di dottorato|