The dimerization of Δ9-tetrahydrocannabinolic acid A (THCA-A)
The renewed interest in dimeric salicylates as broad-spectrum anti-inflammatory and anti-diabetic agents provided a rationale to investigate the dimerization of the substituted salicylate Δ9-tetrahydrocannabinolic acid (THCA-A, 3a) as a strategy to solve its instability to decarboxylation and to gen...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2019-09-01
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| Series: | Acta Pharmaceutica Sinica B |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S221138351930379X |
| _version_ | 1817982957157089280 |
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| author | Arben Cuadari Federica Pollastro Juan D. Unciti-Broceta Diego Caprioglio Alberto Minassi Annalisa Lopatriello Eduardo Muñoz Orazio Taglialatela-Scafati Giovanni Appendino |
| author_facet | Arben Cuadari Federica Pollastro Juan D. Unciti-Broceta Diego Caprioglio Alberto Minassi Annalisa Lopatriello Eduardo Muñoz Orazio Taglialatela-Scafati Giovanni Appendino |
| author_sort | Arben Cuadari |
| collection | DOAJ |
| description | The renewed interest in dimeric salicylates as broad-spectrum anti-inflammatory and anti-diabetic agents provided a rationale to investigate the dimerization of the substituted salicylate Δ9-tetrahydrocannabinolic acid (THCA-A, 3a) as a strategy to solve its instability to decarboxylation and to generate analogues and/or pro-drugs of this native pre-cannabinoid. Activation of the carboxylic group with the DCC-HOBt-DMAP protocol afforded a high yield of the OBt ester 4, that was next converted into the highly crystalline di-depsidic dimer 5 upon treatment with DMAP. The mono-depsidic dimer 6 was also formed when the reaction was carried out with partially decarboxylated THCA-A samples. The structure of the depsidic dimers was established by spectroscopic methods and by aminolysis of 5 into the pre-cannabinoid amide 7. Both dimers showed excellent shelf stability and did not generate significant amounts of Δ9-THC upon heating. However, only the didepsidic dimer 5 activated PPAR-γ, the major target of pre-cannabinoids, but strong binding to serum proteins abolished this activity, also shielding it from the action of esterases. Key words: Phytocannabinoids, Dimerization, Δ9-Tetrahydrocannabinolic acid A, Δ9-Tetrahydrocannabinol, PPAR-γ |
| first_indexed | 2024-04-13T23:27:45Z |
| format | Article |
| id | doaj.art-3dc4172bc9674dbfa7e1c6c40f0ff5ba |
| institution | Directory Open Access Journal |
| issn | 2211-3835 |
| language | English |
| last_indexed | 2024-04-13T23:27:45Z |
| publishDate | 2019-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Acta Pharmaceutica Sinica B |
| spelling | doaj.art-3dc4172bc9674dbfa7e1c6c40f0ff5ba2022-12-22T02:25:00ZengElsevierActa Pharmaceutica Sinica B2211-38352019-09-019510781083The dimerization of Δ9-tetrahydrocannabinolic acid A (THCA-A)Arben Cuadari0Federica Pollastro1Juan D. Unciti-Broceta2Diego Caprioglio3Alberto Minassi4Annalisa Lopatriello5Eduardo Muñoz6Orazio Taglialatela-Scafati7Giovanni Appendino8Dipartimento di Scienze del Farmaco, Università del Piemonte Orientale, Novara 28100, ItalyDipartimento di Scienze del Farmaco, Università del Piemonte Orientale, Novara 28100, ItalyEmerald Health Biotechnology España, Calle Cecilia Payne, Córdoba 14014, SpainDipartimento di Scienze del Farmaco, Università del Piemonte Orientale, Novara 28100, ItalyDipartimento di Scienze del Farmaco, Università del Piemonte Orientale, Novara 28100, ItalyDipartimento di Farmacia, Università di Napoli Federico II, Napoli 80131, ItalyMaimonides Biomedical Research Institute of Córdoba, Cordoba 14004, Spain; Department of Cellular Biology, Physiology and Immunology, University of Córdoba, Cordoba 14004, Spain; University Hospital Reina Sofía, Avenida de Menendez Pidal s/n, Cordoba 14004, SpainDipartimento di Farmacia, Università di Napoli Federico II, Napoli 80131, Italy; Corresponding authors.Dipartimento di Scienze del Farmaco, Università del Piemonte Orientale, Novara 28100, Italy; Corresponding authors.The renewed interest in dimeric salicylates as broad-spectrum anti-inflammatory and anti-diabetic agents provided a rationale to investigate the dimerization of the substituted salicylate Δ9-tetrahydrocannabinolic acid (THCA-A, 3a) as a strategy to solve its instability to decarboxylation and to generate analogues and/or pro-drugs of this native pre-cannabinoid. Activation of the carboxylic group with the DCC-HOBt-DMAP protocol afforded a high yield of the OBt ester 4, that was next converted into the highly crystalline di-depsidic dimer 5 upon treatment with DMAP. The mono-depsidic dimer 6 was also formed when the reaction was carried out with partially decarboxylated THCA-A samples. The structure of the depsidic dimers was established by spectroscopic methods and by aminolysis of 5 into the pre-cannabinoid amide 7. Both dimers showed excellent shelf stability and did not generate significant amounts of Δ9-THC upon heating. However, only the didepsidic dimer 5 activated PPAR-γ, the major target of pre-cannabinoids, but strong binding to serum proteins abolished this activity, also shielding it from the action of esterases. Key words: Phytocannabinoids, Dimerization, Δ9-Tetrahydrocannabinolic acid A, Δ9-Tetrahydrocannabinol, PPAR-γhttp://www.sciencedirect.com/science/article/pii/S221138351930379X |
| spellingShingle | Arben Cuadari Federica Pollastro Juan D. Unciti-Broceta Diego Caprioglio Alberto Minassi Annalisa Lopatriello Eduardo Muñoz Orazio Taglialatela-Scafati Giovanni Appendino The dimerization of Δ9-tetrahydrocannabinolic acid A (THCA-A) Acta Pharmaceutica Sinica B |
| title | The dimerization of Δ9-tetrahydrocannabinolic acid A (THCA-A) |
| title_full | The dimerization of Δ9-tetrahydrocannabinolic acid A (THCA-A) |
| title_fullStr | The dimerization of Δ9-tetrahydrocannabinolic acid A (THCA-A) |
| title_full_unstemmed | The dimerization of Δ9-tetrahydrocannabinolic acid A (THCA-A) |
| title_short | The dimerization of Δ9-tetrahydrocannabinolic acid A (THCA-A) |
| title_sort | dimerization of δ9 tetrahydrocannabinolic acid a thca a |
| url | http://www.sciencedirect.com/science/article/pii/S221138351930379X |
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