1.The dimerization of -tetrahydrocannabinolic acid A (THCA-A).
Arben CUADARI ; Federica POLLASTRO ; Juan D UNCITI-BROCETA ; Diego CAPRIOGLIO ; Alberto MINASSI ; Annalisa LOPATRIELLO ; Eduardo MUÑOZ ; Orazio TAGLIALATELA-SCAFATI ; Giovanni APPENDINO
Acta Pharmaceutica Sinica B 2019;9(5):1078-1083
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 -tetrahydrocannabinolic acid (THCA-A, ) 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 , that was next converted into the highly crystalline di-depsidic dimer upon treatment with DMAP. The mono-depsidic dimer 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 into the pre-cannabinoid amide . Both dimers showed excellent shelf stability and did not generate significant amounts of -THC upon heating. However, only the didepsidic dimer 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.
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