Design, synthesis, and biological evaluation of phosphinopeptides against Trypanosoma cruzi targeting trypanothione biosynthesis
As a part of our project aimed at the search for new safe chemotherapeutic and chemoprophylactic agents against American trypanosomiasis (Chagas's disease); a series of phosphinopeptides structurally related to glutathione was designed, synthesized, and evaluated as antiproliferative agents aga...
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| Acceso en línea: | http://hdl.handle.net/20.500.12110/paper_00222623_v49_n1_p426_Ravaschino |
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todo:paper_00222623_v49_n1_p426_Ravaschino2023-10-03T14:30:15Z Design, synthesis, and biological evaluation of phosphinopeptides against Trypanosoma cruzi targeting trypanothione biosynthesis Ravaschino, E.L. Docampo, R. Rodriguez, J.B. 1 butyl [[(gamma glutamylleucyl)amino]methyl]phosphinate 1 pentyl [[(gamma glutamylleucyl)amino]methyl]phosphinate phosphinic acid derivative trypanothione unclassified drug amastigote antiprotozoal activity article Chagas disease drug design drug efficacy drug structure drug synthesis myoblast pharmacophore Trypanosoma cruzi Amide Synthases Animals Antiprotozoal Agents Cell Proliferation Drug Design Glutathione Molecular Structure Parasitic Sensitivity Tests Peptides Phenyl Ethers Phosphinic Acids Spermidine Structure-Activity Relationship Thiocyanates Trypanosoma cruzi As a part of our project aimed at the search for new safe chemotherapeutic and chemoprophylactic agents against American trypanosomiasis (Chagas's disease); a series of phosphinopeptides structurally related to glutathione was designed, synthesized, and evaluated as antiproliferative agents against the parasite responsible for this disease, the hemoflagellated protozoan Trypanosoma cruzi. The rationale for the synthesis of these compounds was supported on the basis that the presence of the phosphinic acid moiety would mimic the tetrahedral transition state of trypanothione synthase (TryS), a typical C:N ligase, and the molecular target of these drugs. Of the designed compounds, 53 and 54 were potent growth inhibitors against the clinically more relevant form of T. cruzi (amastigotes) growing in myoblasts. The efficacy for these drugs was comparable to that exhibited by the well-known antiparasitic agent WC-9. The simple phosphinopeptide structure found as a pharmacophore in the present study constitutes a starting point for the development of straightforward optimized drugs. © 2006 American Chemical Society. Fil:Ravaschino, E.L. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Rodriguez, J.B. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. JOUR info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/2.5/ar http://hdl.handle.net/20.500.12110/paper_00222623_v49_n1_p426_Ravaschino |
| institution |
Universidad de Buenos Aires |
| institution_str |
I-28 |
| repository_str |
R-134 |
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Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
1 butyl [[(gamma glutamylleucyl)amino]methyl]phosphinate 1 pentyl [[(gamma glutamylleucyl)amino]methyl]phosphinate phosphinic acid derivative trypanothione unclassified drug amastigote antiprotozoal activity article Chagas disease drug design drug efficacy drug structure drug synthesis myoblast pharmacophore Trypanosoma cruzi Amide Synthases Animals Antiprotozoal Agents Cell Proliferation Drug Design Glutathione Molecular Structure Parasitic Sensitivity Tests Peptides Phenyl Ethers Phosphinic Acids Spermidine Structure-Activity Relationship Thiocyanates Trypanosoma cruzi |
| spellingShingle |
1 butyl [[(gamma glutamylleucyl)amino]methyl]phosphinate 1 pentyl [[(gamma glutamylleucyl)amino]methyl]phosphinate phosphinic acid derivative trypanothione unclassified drug amastigote antiprotozoal activity article Chagas disease drug design drug efficacy drug structure drug synthesis myoblast pharmacophore Trypanosoma cruzi Amide Synthases Animals Antiprotozoal Agents Cell Proliferation Drug Design Glutathione Molecular Structure Parasitic Sensitivity Tests Peptides Phenyl Ethers Phosphinic Acids Spermidine Structure-Activity Relationship Thiocyanates Trypanosoma cruzi Ravaschino, E.L. Docampo, R. Rodriguez, J.B. Design, synthesis, and biological evaluation of phosphinopeptides against Trypanosoma cruzi targeting trypanothione biosynthesis |
| topic_facet |
1 butyl [[(gamma glutamylleucyl)amino]methyl]phosphinate 1 pentyl [[(gamma glutamylleucyl)amino]methyl]phosphinate phosphinic acid derivative trypanothione unclassified drug amastigote antiprotozoal activity article Chagas disease drug design drug efficacy drug structure drug synthesis myoblast pharmacophore Trypanosoma cruzi Amide Synthases Animals Antiprotozoal Agents Cell Proliferation Drug Design Glutathione Molecular Structure Parasitic Sensitivity Tests Peptides Phenyl Ethers Phosphinic Acids Spermidine Structure-Activity Relationship Thiocyanates Trypanosoma cruzi |
| description |
As a part of our project aimed at the search for new safe chemotherapeutic and chemoprophylactic agents against American trypanosomiasis (Chagas's disease); a series of phosphinopeptides structurally related to glutathione was designed, synthesized, and evaluated as antiproliferative agents against the parasite responsible for this disease, the hemoflagellated protozoan Trypanosoma cruzi. The rationale for the synthesis of these compounds was supported on the basis that the presence of the phosphinic acid moiety would mimic the tetrahedral transition state of trypanothione synthase (TryS), a typical C:N ligase, and the molecular target of these drugs. Of the designed compounds, 53 and 54 were potent growth inhibitors against the clinically more relevant form of T. cruzi (amastigotes) growing in myoblasts. The efficacy for these drugs was comparable to that exhibited by the well-known antiparasitic agent WC-9. The simple phosphinopeptide structure found as a pharmacophore in the present study constitutes a starting point for the development of straightforward optimized drugs. © 2006 American Chemical Society. |
| format |
JOUR |
| author |
Ravaschino, E.L. Docampo, R. Rodriguez, J.B. |
| author_facet |
Ravaschino, E.L. Docampo, R. Rodriguez, J.B. |
| author_sort |
Ravaschino, E.L. |
| title |
Design, synthesis, and biological evaluation of phosphinopeptides against Trypanosoma cruzi targeting trypanothione biosynthesis |
| title_short |
Design, synthesis, and biological evaluation of phosphinopeptides against Trypanosoma cruzi targeting trypanothione biosynthesis |
| title_full |
Design, synthesis, and biological evaluation of phosphinopeptides against Trypanosoma cruzi targeting trypanothione biosynthesis |
| title_fullStr |
Design, synthesis, and biological evaluation of phosphinopeptides against Trypanosoma cruzi targeting trypanothione biosynthesis |
| title_full_unstemmed |
Design, synthesis, and biological evaluation of phosphinopeptides against Trypanosoma cruzi targeting trypanothione biosynthesis |
| title_sort |
design, synthesis, and biological evaluation of phosphinopeptides against trypanosoma cruzi targeting trypanothione biosynthesis |
| url |
http://hdl.handle.net/20.500.12110/paper_00222623_v49_n1_p426_Ravaschino |
| work_keys_str_mv |
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| _version_ |
1807316333881196544 |