Uptake of NO-releasing drugs by the P2 nucleoside transporter in trypanosomes
Nitric oxide (NO·) has been identified as a principal regulatory molecule of the immune system and the major cytotoxic mediator of activated immune cells. NO· can also react rapidly with a variety of biological species, particularly with the superoxide radical anion O2·- at almost diffusion-limited...
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| Format: | Article |
| Language: | English |
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Associação Brasileira de Divulgação Científica
1999-11-01
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| Series: | Brazilian Journal of Medical and Biological Research |
| Subjects: | |
| Online Access: | http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0100-879X1999001100016 |
| _version_ | 1818188926690525184 |
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| author | L. Soulère P. Hoffmann F. Bringaud J. Périé |
| author_facet | L. Soulère P. Hoffmann F. Bringaud J. Périé |
| author_sort | L. Soulère |
| collection | DOAJ |
| description | Nitric oxide (NO·) has been identified as a principal regulatory molecule of the immune system and the major cytotoxic mediator of activated immune cells. NO· can also react rapidly with a variety of biological species, particularly with the superoxide radical anion O2·- at almost diffusion-limited rates to form peroxynitrite anion (ONOO-). ONOO- and its proton-catalyzed decomposition products are capable of oxidizing a great diversity of biomolecules and can act as a source of toxic hydroxyl radicals. As a consequence, a strategy for the development of molecules with potential trypanocidal activities could be developed to increase the concentration of nitric oxide in the parasites through NO·-releasing compounds. In this way, the rate of formation of peroxynitrite from NO· and O2·- would be faster than the rate of dismutation of superoxide radicals by superoxide dismutases which constitute the primary antioxidant enzymatic defense system in trypanosomes. The adenosine transport systems of parasitic protozoa, which are also in certain cases implicated in the selective uptake of active drugs such as melarsoprol or pentamidine, could be exploited to specifically target these NO·-releasing compounds inside the parasites. In this work, we present the synthesis, characterization and biological evaluation of a series of molecules that contain both a group which would specifically target these drugs inside the parasites via the purine transporter, and an NO·-donor group that would exert a specific pharmacological effect by increasing NO level, and thus the peroxynitrite concentration inside the parasite. |
| first_indexed | 2024-12-11T23:34:41Z |
| format | Article |
| id | doaj.art-072d73c665b74c31bba3992f8eb9f089 |
| institution | Directory Open Access Journal |
| issn | 0100-879X 1414-431X |
| language | English |
| last_indexed | 2024-12-11T23:34:41Z |
| publishDate | 1999-11-01 |
| publisher | Associação Brasileira de Divulgação Científica |
| record_format | Article |
| series | Brazilian Journal of Medical and Biological Research |
| spelling | doaj.art-072d73c665b74c31bba3992f8eb9f0892022-12-22T00:45:54ZengAssociação Brasileira de Divulgação CientíficaBrazilian Journal of Medical and Biological Research0100-879X1414-431X1999-11-0132111447145210.1590/S0100-879X1999001100016Uptake of NO-releasing drugs by the P2 nucleoside transporter in trypanosomesL. SoulèreP. HoffmannF. BringaudJ. PériéNitric oxide (NO·) has been identified as a principal regulatory molecule of the immune system and the major cytotoxic mediator of activated immune cells. NO· can also react rapidly with a variety of biological species, particularly with the superoxide radical anion O2·- at almost diffusion-limited rates to form peroxynitrite anion (ONOO-). ONOO- and its proton-catalyzed decomposition products are capable of oxidizing a great diversity of biomolecules and can act as a source of toxic hydroxyl radicals. As a consequence, a strategy for the development of molecules with potential trypanocidal activities could be developed to increase the concentration of nitric oxide in the parasites through NO·-releasing compounds. In this way, the rate of formation of peroxynitrite from NO· and O2·- would be faster than the rate of dismutation of superoxide radicals by superoxide dismutases which constitute the primary antioxidant enzymatic defense system in trypanosomes. The adenosine transport systems of parasitic protozoa, which are also in certain cases implicated in the selective uptake of active drugs such as melarsoprol or pentamidine, could be exploited to specifically target these NO·-releasing compounds inside the parasites. In this work, we present the synthesis, characterization and biological evaluation of a series of molecules that contain both a group which would specifically target these drugs inside the parasites via the purine transporter, and an NO·-donor group that would exert a specific pharmacological effect by increasing NO level, and thus the peroxynitrite concentration inside the parasite.http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0100-879X1999001100016nitric oxideperoxynitritethionitriteS-nitrosothioladenosine |
| spellingShingle | L. Soulère P. Hoffmann F. Bringaud J. Périé Uptake of NO-releasing drugs by the P2 nucleoside transporter in trypanosomes Brazilian Journal of Medical and Biological Research nitric oxide peroxynitrite thionitrite S-nitrosothiol adenosine |
| title | Uptake of NO-releasing drugs by the P2 nucleoside transporter in trypanosomes |
| title_full | Uptake of NO-releasing drugs by the P2 nucleoside transporter in trypanosomes |
| title_fullStr | Uptake of NO-releasing drugs by the P2 nucleoside transporter in trypanosomes |
| title_full_unstemmed | Uptake of NO-releasing drugs by the P2 nucleoside transporter in trypanosomes |
| title_short | Uptake of NO-releasing drugs by the P2 nucleoside transporter in trypanosomes |
| title_sort | uptake of no releasing drugs by the p2 nucleoside transporter in trypanosomes |
| topic | nitric oxide peroxynitrite thionitrite S-nitrosothiol adenosine |
| url | http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0100-879X1999001100016 |
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