TY - JOUR
T1 - Iodine-mediated cyclization of cannabigerol (CBG) expands the cannabinoid biological and chemical space
AU - Lopatriello, Annalisa
AU - Caprioglio, Diego
AU - Minassi, Alberto
AU - Schiano Moriello, Aniello
AU - Formisano, Carmen
AU - De Petrocellis, Luciano
AU - Appendino, Giovanni
AU - Taglialatela-Scafati, Orazio
N1 - Publisher Copyright:
© 2018 Elsevier Ltd
PY - 2018/8/15
Y1 - 2018/8/15
N2 - Electrophilic attack to a double bond, the classic trigger of intramolecular isoprenoid cyclizations, is apparently silent in Cannabis and the diversity of the cannabinome can be ultimately traced to the oxidative cyclization of cannabigerolic acid (CBGA, 1a), a process triggered by the generation of an aromatic electrophilic species. To expand the chemical space of the cannabinoid chemotype, we have investigated an oxidative trigger based on the addition of iodine to the terminal isoprenyl double bond of cannabigerol (CBG, 1b), the decarboxylated and thermally stable version of CBGA (1a). Apart from the predictable product of an iodine-induced cascade cyclization (3), also a pair of unprecedented spiranes named spirocannabigerols (4a,b), derived from the formation of an edge-protonated cyclopropyl cation was also formed, along with a product (5) resulting from the incorporation, in a Friedel-Craft fashion, of the reaction solvent (toluene). Biological evaluation of these compounds on six thermo-transient receptor potential channels (TRPs) showed a remodeling of bioactivity compared to GBC, with emphasis on TRPA1 rather than TRPM8.
AB - Electrophilic attack to a double bond, the classic trigger of intramolecular isoprenoid cyclizations, is apparently silent in Cannabis and the diversity of the cannabinome can be ultimately traced to the oxidative cyclization of cannabigerolic acid (CBGA, 1a), a process triggered by the generation of an aromatic electrophilic species. To expand the chemical space of the cannabinoid chemotype, we have investigated an oxidative trigger based on the addition of iodine to the terminal isoprenyl double bond of cannabigerol (CBG, 1b), the decarboxylated and thermally stable version of CBGA (1a). Apart from the predictable product of an iodine-induced cascade cyclization (3), also a pair of unprecedented spiranes named spirocannabigerols (4a,b), derived from the formation of an edge-protonated cyclopropyl cation was also formed, along with a product (5) resulting from the incorporation, in a Friedel-Craft fashion, of the reaction solvent (toluene). Biological evaluation of these compounds on six thermo-transient receptor potential channels (TRPs) showed a remodeling of bioactivity compared to GBC, with emphasis on TRPA1 rather than TRPM8.
KW - Cannabigerol
KW - Cannabinoids
KW - Iodine
KW - Natural products
KW - Polyene cyclization
UR - http://www.scopus.com/inward/record.url?scp=85050820277&partnerID=8YFLogxK
U2 - 10.1016/j.bmc.2018.07.044
DO - 10.1016/j.bmc.2018.07.044
M3 - Article
SN - 0968-0896
VL - 26
SP - 4532
EP - 4536
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
IS - 15
ER -