Antileishmanial Activity and Cytotoxicity of ent-Beyerene Diterpenoids
We describe the in vitro and in vivo leishmanicidal activity of two diterpenes of the ent-beyerene type, as well as several derivatives. The results indicate that the 18-hydroxymethyl group is essential for the activity. Using in vitro assays, two compounds, 10 and 11, exhibited an EC50 of 1.1 and 1...
- Autores:
-
Murillo Mosquera, Jilmar Andrés
Gil Romero, Juan Fernando
Upegui Zapata, Yulieth Alexandra
Restrepo Agudelo, Adriana María
Robledo Restrepo, Sara María
Quiñones Fletcher, Winston
Echeverri López, Luis Fernando
Escobar Peláez, Gustavo
San Martin, Aurelio
Olivo, Horacio F.
- Tipo de recurso:
- Article of investigation
- Fecha de publicación:
- 2019
- Institución:
- Universidad de Antioquia
- Repositorio:
- Repositorio UdeA
- Idioma:
- eng
- OAI Identifier:
- oai:bibliotecadigital.udea.edu.co:10495/47253
- Acceso en línea:
- https://hdl.handle.net/10495/47253
- Palabra clave:
- Línea Celular
Cell Line
Diterpenos
Diterpenes
Leishmania braziliensis
Leishmaniasis Cutánea
Leishmaniasis, Cutaneous
Macrófagos - efectos de los fármacos
Macrophages - drug effects
Mesocricetus
https://id.nlm.nih.gov/mesh/D008647
Tripanocidas
Trypanocidal Agents
https://id.nlm.nih.gov/mesh/D002460
https://id.nlm.nih.gov/mesh/D004224
https://id.nlm.nih.gov/mesh/D007892
https://id.nlm.nih.gov/mesh/D016773
https://id.nlm.nih.gov/mesh/D008264
https://id.nlm.nih.gov/mesh/D014344
ODS 3: Salud y bienestar. Garantizar una vida sana y promover el bienestar de todos a todas las edades
- Rights
- openAccess
- License
- http://creativecommons.org/licenses/by-nc-nd/4.0/
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Antileishmanial Activity and Cytotoxicity of ent-Beyerene Diterpenoids |
| title |
Antileishmanial Activity and Cytotoxicity of ent-Beyerene Diterpenoids |
| spellingShingle |
Antileishmanial Activity and Cytotoxicity of ent-Beyerene Diterpenoids Línea Celular Cell Line Diterpenos Diterpenes Leishmania braziliensis Leishmaniasis Cutánea Leishmaniasis, Cutaneous Macrófagos - efectos de los fármacos Macrophages - drug effects Mesocricetus https://id.nlm.nih.gov/mesh/D008647 Tripanocidas Trypanocidal Agents https://id.nlm.nih.gov/mesh/D002460 https://id.nlm.nih.gov/mesh/D004224 https://id.nlm.nih.gov/mesh/D007892 https://id.nlm.nih.gov/mesh/D016773 https://id.nlm.nih.gov/mesh/D008264 https://id.nlm.nih.gov/mesh/D014344 ODS 3: Salud y bienestar. Garantizar una vida sana y promover el bienestar de todos a todas las edades |
| title_short |
Antileishmanial Activity and Cytotoxicity of ent-Beyerene Diterpenoids |
| title_full |
Antileishmanial Activity and Cytotoxicity of ent-Beyerene Diterpenoids |
| title_fullStr |
Antileishmanial Activity and Cytotoxicity of ent-Beyerene Diterpenoids |
| title_full_unstemmed |
Antileishmanial Activity and Cytotoxicity of ent-Beyerene Diterpenoids |
| title_sort |
Antileishmanial Activity and Cytotoxicity of ent-Beyerene Diterpenoids |
| dc.creator.fl_str_mv |
Murillo Mosquera, Jilmar Andrés Gil Romero, Juan Fernando Upegui Zapata, Yulieth Alexandra Restrepo Agudelo, Adriana María Robledo Restrepo, Sara María Quiñones Fletcher, Winston Echeverri López, Luis Fernando Escobar Peláez, Gustavo San Martin, Aurelio Olivo, Horacio F. |
| dc.contributor.author.none.fl_str_mv |
Murillo Mosquera, Jilmar Andrés Gil Romero, Juan Fernando Upegui Zapata, Yulieth Alexandra Restrepo Agudelo, Adriana María Robledo Restrepo, Sara María Quiñones Fletcher, Winston Echeverri López, Luis Fernando Escobar Peláez, Gustavo San Martin, Aurelio Olivo, Horacio F. |
| dc.contributor.researchgroup.none.fl_str_mv |
Programa de Estudio y Control de Enfermedades Tropicales (PECET) Química Orgánica de Productos Naturales |
| dc.subject.decs.none.fl_str_mv |
Línea Celular Cell Line Diterpenos Diterpenes Leishmania braziliensis Leishmaniasis Cutánea Leishmaniasis, Cutaneous Macrófagos - efectos de los fármacos Macrophages - drug effects Mesocricetus https://id.nlm.nih.gov/mesh/D008647 Tripanocidas Trypanocidal Agents |
| topic |
Línea Celular Cell Line Diterpenos Diterpenes Leishmania braziliensis Leishmaniasis Cutánea Leishmaniasis, Cutaneous Macrófagos - efectos de los fármacos Macrophages - drug effects Mesocricetus https://id.nlm.nih.gov/mesh/D008647 Tripanocidas Trypanocidal Agents https://id.nlm.nih.gov/mesh/D002460 https://id.nlm.nih.gov/mesh/D004224 https://id.nlm.nih.gov/mesh/D007892 https://id.nlm.nih.gov/mesh/D016773 https://id.nlm.nih.gov/mesh/D008264 https://id.nlm.nih.gov/mesh/D014344 ODS 3: Salud y bienestar. Garantizar una vida sana y promover el bienestar de todos a todas las edades |
| dc.subject.meshuri.none.fl_str_mv |
https://id.nlm.nih.gov/mesh/D002460 https://id.nlm.nih.gov/mesh/D004224 https://id.nlm.nih.gov/mesh/D007892 https://id.nlm.nih.gov/mesh/D016773 https://id.nlm.nih.gov/mesh/D008264 https://id.nlm.nih.gov/mesh/D014344 |
| dc.subject.ods.none.fl_str_mv |
ODS 3: Salud y bienestar. Garantizar una vida sana y promover el bienestar de todos a todas las edades |
| description |
We describe the in vitro and in vivo leishmanicidal activity of two diterpenes of the ent-beyerene type, as well as several derivatives. The results indicate that the 18-hydroxymethyl group is essential for the activity. Using in vitro assays, two compounds, 10 and 11, exhibited an EC50 of 1.1 and 1.3 g/mL, with SI 3.1 and 3.5 respectively, while cure was obtained in 50% of hamsters with natural diterpenoids 1 and 2, both topically applied as cream at 0.81 and 2.6% (w/w). Because of the low abundance of these diterpenoids in nature, one of them was prepared from stevioside. These results suggest that ent-beyerene diterpenoids 1 and 2 as potential candidates for cutaneous leishmaniasis chemotherapy by topical application. However, further studies should be conducted to optimize this biological activity, specially dose and therapeutic scheme. |
| publishDate |
2019 |
| dc.date.issued.none.fl_str_mv |
2019 |
| dc.date.accessioned.none.fl_str_mv |
2025-09-01T00:56:13Z |
| dc.type.none.fl_str_mv |
Artículo de investigación |
| dc.type.coar.none.fl_str_mv |
http://purl.org/coar/resource_type/c_2df8fbb1 |
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http://purl.org/redcol/resource_type/ART |
| dc.type.content.none.fl_str_mv |
Text |
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info:eu-repo/semantics/article |
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info:eu-repo/semantics/acceptedVersion |
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http://purl.org/coar/resource_type/c_2df8fbb1 |
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acceptedVersion |
| dc.identifier.issn.none.fl_str_mv |
0968-0896 |
| dc.identifier.uri.none.fl_str_mv |
https://hdl.handle.net/10495/47253 |
| dc.identifier.doi.none.fl_str_mv |
10.1016/j.bmc.2018.11.030 |
| dc.identifier.eissn.none.fl_str_mv |
1464-3391 |
| identifier_str_mv |
0968-0896 10.1016/j.bmc.2018.11.030 1464-3391 |
| url |
https://hdl.handle.net/10495/47253 |
| dc.language.iso.none.fl_str_mv |
eng |
| language |
eng |
| dc.relation.ispartofjournalabbrev.none.fl_str_mv |
Bioorg. Med. Chem. |
| dc.relation.citationendpage.none.fl_str_mv |
160 |
| dc.relation.citationissue.none.fl_str_mv |
1 |
| dc.relation.citationstartpage.none.fl_str_mv |
153 |
| dc.relation.citationvolume.none.fl_str_mv |
27 |
| dc.relation.ispartofjournal.none.fl_str_mv |
Bioorganic and Medicinal Chemistry |
| dc.rights.uri.none.fl_str_mv |
http://creativecommons.org/licenses/by-nc-nd/4.0/ |
| dc.rights.accessrights.none.fl_str_mv |
info:eu-repo/semantics/openAccess |
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Attribution-NonCommercial-NoDerivatives 4.0 International |
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http://purl.org/coar/access_right/c_abf2 |
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http://creativecommons.org/licenses/by-nc-nd/4.0/ Attribution-NonCommercial-NoDerivatives 4.0 International http://purl.org/coar/access_right/c_abf2 |
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8 páginas |
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application/pdf |
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Elsevier |
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Oxford, Inglaterra |
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Elsevier |
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Universidad de Antioquia |
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Murillo Mosquera, Jilmar AndrésGil Romero, Juan FernandoUpegui Zapata, Yulieth AlexandraRestrepo Agudelo, Adriana MaríaRobledo Restrepo, Sara MaríaQuiñones Fletcher, WinstonEcheverri López, Luis FernandoEscobar Peláez, GustavoSan Martin, AurelioOlivo, Horacio F.Programa de Estudio y Control de Enfermedades Tropicales (PECET)Química Orgánica de Productos Naturales2025-09-01T00:56:13Z20190968-0896https://hdl.handle.net/10495/4725310.1016/j.bmc.2018.11.0301464-3391We describe the in vitro and in vivo leishmanicidal activity of two diterpenes of the ent-beyerene type, as well as several derivatives. The results indicate that the 18-hydroxymethyl group is essential for the activity. Using in vitro assays, two compounds, 10 and 11, exhibited an EC50 of 1.1 and 1.3 g/mL, with SI 3.1 and 3.5 respectively, while cure was obtained in 50% of hamsters with natural diterpenoids 1 and 2, both topically applied as cream at 0.81 and 2.6% (w/w). Because of the low abundance of these diterpenoids in nature, one of them was prepared from stevioside. These results suggest that ent-beyerene diterpenoids 1 and 2 as potential candidates for cutaneous leishmaniasis chemotherapy by topical application. However, further studies should be conducted to optimize this biological activity, specially dose and therapeutic scheme.COL0015099COL00153398 páginasapplication/pdfengElsevierOxford, Inglaterrahttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessAttribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://purl.org/coar/access_right/c_abf2Antileishmanial Activity and Cytotoxicity of ent-Beyerene DiterpenoidsArtículo de investigaciónhttp://purl.org/coar/resource_type/c_2df8fbb1http://purl.org/redcol/resource_type/ARTTextinfo:eu-repo/semantics/articleinfo:eu-repo/semantics/acceptedVersionLínea CelularCell LineDiterpenosDiterpenesLeishmania braziliensisLeishmaniasis CutáneaLeishmaniasis, CutaneousMacrófagos - efectos de los fármacosMacrophages - drug effectsMesocricetushttps://id.nlm.nih.gov/mesh/D008647TripanocidasTrypanocidal Agentshttps://id.nlm.nih.gov/mesh/D002460https://id.nlm.nih.gov/mesh/D004224https://id.nlm.nih.gov/mesh/D007892https://id.nlm.nih.gov/mesh/D016773https://id.nlm.nih.gov/mesh/D008264https://id.nlm.nih.gov/mesh/D014344ODS 3: Salud y bienestar. Garantizar una vida sana y promover el bienestar de todos a todas las edadesBioorg. Med. 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