TY - JOUR
T1 - The dimerization of Δ9-tetrahydrocannabinolic acid A (THCA-A)
AU - Cuadari, Arben
AU - Pollastro, Federica
AU - Unciti-Broceta, Juan D.
AU - Caprioglio, Diego
AU - Minassi, Alberto
AU - Lopatriello, Annalisa
AU - Muñoz, Eduardo
AU - Taglialatela-Scafati, Orazio
AU - Appendino, Giovanni
N1 - Publisher Copyright:
© 2019 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences
PY - 2019/9
Y1 - 2019/9
N2 - 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.
AB - 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.
KW - Dimerization
KW - PPAR-γ
KW - Phytocannabinoids
KW - Δ-Tetrahydrocannabinol
KW - Δ-Tetrahydrocannabinolic acid A
UR - http://www.scopus.com/inward/record.url?scp=85068453234&partnerID=8YFLogxK
U2 - 10.1016/j.apsb.2019.06.007
DO - 10.1016/j.apsb.2019.06.007
M3 - Article
SN - 2211-3835
VL - 9
SP - 1078
EP - 1083
JO - Acta Pharmaceutica Sinica B
JF - Acta Pharmaceutica Sinica B
IS - 5
ER -