Dehydrofolate reductasi : a new molecular target for gold(I) drugs? R. Galassi,a A. Burini,a D. Micozzi,a A. Dolmella,b S. Pucciarellic a School of Science and Technology, Chemistry Division, University of Camerino, 62032 Camerino (Italy); b Department of Pharmaceutical Sciences, University of Padova, 35131 Padova (Italy); c School of Biosciences and Biotechnology, University of Camerino, 62032 Camerino (Italy). daniela.micozzi@unicam.it DHFR is an important enzyme mainly involved in the synthesis of pyrimidine and thymine basilar for the DNA replication and hence the cell proliferation. To perform its functions the DHFR enzyme needs the presence of a substrate and a cofactor such as NADPH and H2F.[1] Despite its fundamental importance in the cell’s metabolism this enzyme has never been tested as molecular target for gold(I) compounds which anti-proliferative action was ascertained. In fact, it is generally accepted that gold compounds act as multi-target drug and the proposed mechanisms mainly involve enzymes. Moreover, their action is function of their overall structure and of the nature of the ligands around the central metal atom. Some pyrazolyl and imidazolyl gold(I) phosphane complexes synthesized by us have shown anticancer properties and they successfully inhibit some seleno-dependent enzymes such as thioredoxina reductase and glutathione peroxidase.[2] To investigate in depth their action on the regards of enzyme, inhibitory studies on DHFR have been carried out. Moreover, appropriate modifications in their structure have been performed in order to get information about the structure/properties relationship. DTNB assays, stability studies in solution and affinity constant determinations have been performed too. Some conclusions about the possible mechanism of action may be taken accordingly. Acknowledgements Authors are grateful to CIRCSMB for Daniela Micozzi fellowship. References [1] M. Brandsch, I. Knütter, E. Bosse-Doenecke, J. Pharm. Pharmacol. 2008, 60, 543. [2] R. Galassi, A. Burini, S. Ricci, M. Pellei, M. P. Rigobello, A. Citta, A. Dolmella, V. Gandin, C Marzano. Dalton Trans., 2012, 41, 5307
Dihydrofolate reductase: a new molecular target for gold(I) drugs?
R. Galassi;A. Burini;D. Micozzi;S. Pucciarelli
2012-01-01
Abstract
Dehydrofolate reductasi : a new molecular target for gold(I) drugs? R. Galassi,a A. Burini,a D. Micozzi,a A. Dolmella,b S. Pucciarellic a School of Science and Technology, Chemistry Division, University of Camerino, 62032 Camerino (Italy); b Department of Pharmaceutical Sciences, University of Padova, 35131 Padova (Italy); c School of Biosciences and Biotechnology, University of Camerino, 62032 Camerino (Italy). daniela.micozzi@unicam.it DHFR is an important enzyme mainly involved in the synthesis of pyrimidine and thymine basilar for the DNA replication and hence the cell proliferation. To perform its functions the DHFR enzyme needs the presence of a substrate and a cofactor such as NADPH and H2F.[1] Despite its fundamental importance in the cell’s metabolism this enzyme has never been tested as molecular target for gold(I) compounds which anti-proliferative action was ascertained. In fact, it is generally accepted that gold compounds act as multi-target drug and the proposed mechanisms mainly involve enzymes. Moreover, their action is function of their overall structure and of the nature of the ligands around the central metal atom. Some pyrazolyl and imidazolyl gold(I) phosphane complexes synthesized by us have shown anticancer properties and they successfully inhibit some seleno-dependent enzymes such as thioredoxina reductase and glutathione peroxidase.[2] To investigate in depth their action on the regards of enzyme, inhibitory studies on DHFR have been carried out. Moreover, appropriate modifications in their structure have been performed in order to get information about the structure/properties relationship. DTNB assays, stability studies in solution and affinity constant determinations have been performed too. Some conclusions about the possible mechanism of action may be taken accordingly. Acknowledgements Authors are grateful to CIRCSMB for Daniela Micozzi fellowship. References [1] M. Brandsch, I. Knütter, E. Bosse-Doenecke, J. Pharm. Pharmacol. 2008, 60, 543. [2] R. Galassi, A. Burini, S. Ricci, M. Pellei, M. P. Rigobello, A. Citta, A. Dolmella, V. Gandin, C Marzano. Dalton Trans., 2012, 41, 5307I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
