The renewed interest in dimeric salicylates as broad-spectrum anti-inflammatory and anti-diabetic agents provided a rationale to investigated the dimerization of the substituted salicylate 9-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 in high yield the OBt ester 4, 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 9-THC upon heating. However, only the didepsidic dimer 5 activated PPAR-, the major target of pre-cannabinoids, but strong binding to serum proteins abolished this activity, also shielding it from the action of esterases.
The dimerization of Δ9-tetrahydrocannabinolic acid A (THCA-A) / Cuadari, A.; Pollastro, F.; Unciti-Broceta, J. D.; Caprioglio, D.; Minassi, A.; Lopatriello, A.; Munoz, E.; Taglialatela-Scafati, O.; Appendino, G.. - In: ACTA PHARMACEUTICA SINICA B. - ISSN 2211-3835. - 9:5(2019), pp. 1078-1083. [10.1016/j.apsb.2019.06.007]
The dimerization of Δ9-tetrahydrocannabinolic acid A (THCA-A)
Lopatriello A.Membro del Collaboration Group
;Taglialatela-Scafati O.
;
2019
Abstract
The renewed interest in dimeric salicylates as broad-spectrum anti-inflammatory and anti-diabetic agents provided a rationale to investigated the dimerization of the substituted salicylate 9-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 in high yield the OBt ester 4, 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 9-THC upon heating. However, only the didepsidic dimer 5 activated PPAR-, the major target of pre-cannabinoids, but strong binding to serum proteins abolished this activity, also shielding it from the action of esterases.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
