Short Communication
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)[J]. Acta Pharmaceutica Sinica B, 2019, 9(5): 1078-1083

The dimerization of Δ9-tetrahydrocannabinolic acid A (THCA-A)
Arben Cuadaria, Federica Pollastroa, Juan D. Unciti-Brocetab, Diego Caprioglioa, Alberto Minassia, Annalisa Lopatrielloc, Eduardo Muñozd,e,f, Orazio Taglialatela-Scafatic, Giovanni Appendinoa
a Dipartimento di Scienze del Farmaco, Universitàdel Piemonte Orientale, Novara 28100, Italy;
b Emerald Health Biotechnology España, Calle Cecilia Payne, Córdoba 14014, Spain;
c Dipartimento di Farmacia, Universitàdi Napoli Federico Ⅱ, Napoli 80131, Italy;
d Maimonides Biomedical Research Institute of Córdoba, Cordoba 14004, Spain;
e Department of Cellular Biology, Physiology and Immunology, University of Córdoba, Cordoba 14004, Spain;
f University Hospital Reina Sofía, Avenida de Menendez Pidal s/n, Cordoba 14004, Spain
Abstract:
The renewed interest in dimeric salicylates as broad-spectrum anti-inflammatory and antidiabetic 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   
Received: 2019-03-18     Revised: 2019-05-04
DOI: 10.1016/j.apsb.2019.06.007
Funds: We are grateful to MIUR (Ministero Universita'e Ricerca) for financial support to the groups in Novara and Naples (PRIN2017, Project 2017WN73PL, bioactivity-directed exploration of the phytocannabinoid chemical space, Italy). Eduardo Muñoz, Juan D. Unciti-Broceta and Giovanni Appendino were also supported by Emerald Health Biotechnology España (Spain).
Corresponding author: Orazio Taglialatela-Scafati, Giovanni Appendino     Email:scatagli@unina.it;giovanni.appendino@uniupo.it
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Authors
Arben Cuadari
Federica Pollastro
Juan D. Unciti-Broceta
Diego Caprioglio
Alberto Minassi
Annalisa Lopatriello
Eduardo Muñoz
Orazio Taglialatela-Scafati
Giovanni Appendino

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