Book of Abstracts - Ruhr-Universität Bochum
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Book of Abstracts - Ruhr-Universität Bochum

Book of Abstracts - Ruhr-Universität Bochum Book of Abstracts - Ruhr-Universität Bochum

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OP-27 ISBOMC `10 5.7 – 9.7. 2010 Ruhr-Universität Bochum Nitric Oxide Synthase Targeting with 99m Tc(I)/Re(I) Complexes João D. G. Correia,* a Bruno L. Oliveira, a Filipa Mendes, a Paula D. Raposinho, a Isabel Santos, a António Ferreira, b Carlos Cordeiro, b Ana P. Freire b a ITN, Unidade de Ciências Químicas e Radiofarmacêuticas, Estrada Nacional 10, 2686-953 Sacavém, Portugal. b Universidade de Lisboa, Faculdade de Ciências, Departamento de Química e Bioquímica, Lisbon, Portugal. E-mail: jgalamba@itn.pt Nitric oxide (NO), a key signaling mammalian mediator in several physiophatolological processes, is biosynthesized in vivo by oxidation of L-arginine to L-citrulline catalalyzed by Nitric Oxide Synthase (NOS). 1 This enzyme has two constitutive isoforms (neuronal, nNOS; endothelial, eNOS) and one inducible isoform (iNOS). Noninvasive imaging of NOS expression in vivo by nuclear techniques, namely by Single Photon Emission Tomography (SPECT) or Positron Emission Tomography (PET), holds great potential for providing new insights in understanding NO/NOS-related diseases, and may facilitate the development of novel therapeutic approaches. 2,3 Aiming to find 99m Tc(CO)3-based tracers for probing NOS levels in vivo, we will report on the synthesis and characterization of novel Re(I)/ 99m Tc(I) organometallic complexes containing pendant bioactive units for recognition of NOS active site. 4 The enzymatic studies with isolated murine iNOS have shown that some Re(I) compounds could inhibit the enzyme, being the first examples of organometallic complexes able to inhibit NOS. Such effect was also observed in LPS-stimulated murine macrophages. Interestingly, a few complexes could also be used as NOS substrates by the same cell model. The biological assessment of the 99m Tccomplexes in different cell lines and in mice will also be presented. References 1. S. Moncada, R. M. J. Palmer, E. A. Higgs, Pharmacol. Rev. 1991, 43, 109-142. 2. D. Zhou, H. Lee, J. M. Rothfuss, D. L. Chen, D. E. Ponde, M. J. Welch,R. H. Mach, J. Med. Chem.2009, 52, 2443–2453. 3. H. Hong, J. Sun, W. Cai, Free Radic. Biol. Med. 2009, 47, 684–698. 4. B. L. Oliveira, J. D. G. Correia, P. D. Raposinho, I. Santos, A. Ferreira, C. Cordeiro, A. P. Freire, Dalton Trans. 2009, 1, 152-162. Acknowledgements We thank the Fundação para a Ciência e Tecnologia (FCT) for financial support (POCI/SAU- FCF/58855/2004). Mallinkrodt-Tyco Inc. is acknowledged for providing the IsoLink® kits. B. L. O. thanks FCT for a BD grant (SFRH/BD/38753/2007). J. Marçalo is acknowledged for the ESI-MS analyses, which were run on a QITMS instrument (FCT Contract REDE/1503/REM/2005 - ITN). 43

OP-28 ISBOMC `10 5.7 – 9.7. 2010 Ruhr-Universität Bochum Mechanistic and Synthetic Studies of Bio-compatible Carbon Monoxide-Releasing Molecules Anthony J. Atkin, a Ian J. S. Fairlamb, a Jason M. Lynam, *a and Wei-Qiang Zhang a Department of Chemistry, University of York, Heslington, York, YO10 5DD, UK E-mail: jml12@york.ac.uk Carbon monoxide – releasing molecules (CO-RMs) have become an exciting target for therapeutic intervention. 1 CO generated in mammals is responsible for a variety of important physiological functions and is a fundamental signalling mediator. CO gas also elicits a range of beneficial therapeutic effects, although the associated toxicity and inherent poor selectivity of CO in its naked form is clearly not ideal. The method of choice for taking advantage of the beneficial role of CO is to utilise a CO-RM, such as a metal carbonyl complex, which act as a source of CO in biological systems. Although the biological effects of CO (and CO-RMs) are now well established, there is little understanding of the precise requirements needed for transition metal carbonyl compounds to act as effective therapeutic agents. We have therefore undertaken a systematic study in order to elucidate the factors that may control CO-release. 2 This has allowed us to determine which metal-carbonyl scaffolds have the greatest potential to act as CO-RMs which has in turn informed a synthetic programme designed to prepare a library of novel complexes with bio-compatible ligands. For example, we have prepared a range of Group 6 compounds which contain both natural and non-natural amino acids incorporated into the coordination sphere of the metal through a range of binding modes (Figure 1). This presentation will detail the key results from the findings of our synthetic and mechanistic studies into the CO-release process, as well as the behaviour of the new bio-compatible CO-RMs. For example, we have demonstrated how the CO-release behaviour of the amino ester derivatives 1 may be simply modulated by the choice of the substituent on the organic ligand. A mechanistic study has demonstrated that this process is controlled by loss of the amino ester and therefore supply of the “M(CO)5” (M = Cr, Mo, W) fragment is crucial to CO-release in aqueous systems. For the CO-RMs with structure 2 the rate of CO-release correlates with the electrophilicity of the carbene carbon, consistent with a mechanism in which nucleophilic attack of water initiates the CO-release process. The scope of biologically-relevant ligands which can be introduced into the coordination sphere of the metal will also be detailed. References 1. (a) T. T. Johnson, B. E. Mann, J. E. Clark, R. Foresti, C. J. Green, R. Motterlini, R. Angew. Chem. Int. Ed. 2003, 42, 3722-3729. (b) I. J. S. Fairlamb, A.-K. Duhme-Klair, J. M. Lynam, B. E. Moulton, C. T. O’Brien, P. Sawle, J. Hammad, R. Motterlini, Bioorg. & Med. Chem. Lett. 2006, 16, 995-998. (c) P. Sawle, J. Hammad, I. J. S. Fairlamb, B. E. Moulton, C. T. O'Brien, J. M. Lynam, A.-K. Duhme- Klair, R. Foresti, R. Motterlini, J. Pharmacol. Exp. Ther. 2006, 318, 403-410. (d) I. J. S. Fairlamb, J. M. Lynam, B. E. Moulton, I. E. Taylor, A. K. Duhme-Klair, P. Sawle, R. Motterlini, Dalton Trans. 2007, 3603-3605. 2. W.-Q. Zhang, A. J. Atkin, R. J. Thatcher, A. C. Whitwood, I. J. S. Fairlamb, J. M. Lynam, Dalton Trans. 2009, 4351-4358. 44

OP-27<br />

ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />

Nitric Oxide Synthase Targeting with 99m Tc(I)/Re(I) Complexes<br />

João D. G. Correia,* a Bruno L. Oliveira, a Filipa Mendes, a Paula D. Raposinho, a Isabel Santos, a<br />

António Ferreira, b Carlos Cordeiro, b Ana P. Freire b<br />

a ITN, Unidade de Ciências Químicas e Radi<strong>of</strong>armacêuticas, Estrada Nacional 10, 2686-953<br />

Sacavém, Portugal. b Universidade de Lisboa, Faculdade de Ciências, Departamento de Química e<br />

Bioquímica, Lisbon, Portugal. E-mail: jgalamba@itn.pt<br />

Nitric oxide (NO), a key signaling mammalian mediator in several physiophatolological processes, is<br />

biosynthesized in vivo by oxidation <strong>of</strong> L-arginine to L-citrulline catalalyzed by Nitric Oxide Synthase<br />

(NOS). 1 This enzyme has two constitutive is<strong>of</strong>orms (neuronal, nNOS; endothelial, eNOS) and one<br />

inducible is<strong>of</strong>orm (iNOS). Noninvasive imaging <strong>of</strong> NOS expression in vivo by nuclear techniques,<br />

namely by Single Photon Emission Tomography (SPECT) or Positron Emission Tomography (PET),<br />

holds great potential for providing new insights in understanding NO/NOS-related diseases, and may<br />

facilitate the development <strong>of</strong> novel therapeutic approaches. 2,3 Aiming to find 99m Tc(CO)3-based tracers<br />

for probing NOS levels in vivo, we will report on the synthesis and characterization <strong>of</strong> novel<br />

Re(I)/ 99m Tc(I) organometallic complexes containing pendant bioactive units for recognition <strong>of</strong> NOS<br />

active site. 4 The enzymatic studies with isolated murine iNOS have shown that some Re(I) compounds<br />

could inhibit the enzyme, being the first examples <strong>of</strong> organometallic complexes able to inhibit NOS.<br />

Such effect was also observed in LPS-stimulated murine macrophages. Interestingly, a few complexes<br />

could also be used as NOS substrates by the same cell model. The biological assessment <strong>of</strong> the 99m Tccomplexes<br />

in different cell lines and in mice will also be presented.<br />

References<br />

1. S. Moncada, R. M. J. Palmer, E. A. Higgs, Pharmacol. Rev. 1991, 43, 109-142.<br />

2. D. Zhou, H. Lee, J. M. Rothfuss, D. L. Chen, D. E. Ponde, M. J. Welch,R. H. Mach, J. Med.<br />

Chem.2009, 52, 2443–2453.<br />

3. H. Hong, J. Sun, W. Cai, Free Radic. Biol. Med. 2009, 47, 684–698.<br />

4. B. L. Oliveira, J. D. G. Correia, P. D. Raposinho, I. Santos, A. Ferreira, C. Cordeiro, A. P. Freire,<br />

Dalton Trans. 2009, 1, 152-162.<br />

Acknowledgements<br />

We thank the Fundação para a Ciência e Tecnologia (FCT) for financial support (POCI/SAU-<br />

FCF/58855/2004). Mallinkrodt-Tyco Inc. is acknowledged for providing the IsoLink® kits. B. L. O.<br />

thanks FCT for a BD grant (SFRH/BD/38753/2007). J. Marçalo is acknowledged for the ESI-MS<br />

analyses, which were run on a QITMS instrument (FCT Contract REDE/1503/REM/2005 - ITN).<br />

43

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