TY - JOUR
T1 - Neuroactive and Anti-inflammatory Frankincense Cembranes
T2 - A Structure-Activity Study
AU - Pollastro, Federica
AU - Golin, Samantha
AU - Chianese, Giuseppina
AU - Putra, Masteria Yunovilsa
AU - Schiano Moriello, Aniello
AU - De Petrocellis, Luciano
AU - García, Victor
AU - Munoz, Eduardo
AU - Taglialatela-Scafati, Orazio
AU - Appendino, Giovanni
N1 - Publisher Copyright:
© 2016 The American Chemical Society and American Society of Pharmacognosy.
PY - 2016/7/22
Y1 - 2016/7/22
N2 - An expeditious isolation method for the cembrane diterpene alcohols incensol (1a) and serratol (2) has been developed from respectively African and Indian frankincense. The two native alcohols and a series of semisynthetic derivatives of incensol were evaluated for transient receptor potential vanilloid 3 (TRPV3) activation and the inhibition of NF-κB, the putative molecular targets underlying the psychotropic and anti-inflammatory activities of incensol acetate (IA, 1b). Serratol (2) was the most potent TRPV3 activator, outperforming by 2 orders of magnitude the reference agonist thymol and by 1 order of magnitude incensol acetate (1b). Acylation, epimerization, and oxidation did not significantly improve the affinity of incensol for TRPV3, while NF-κB inhibition, marginal for both natural alcohols, could be improved by esterification of incensol (1a) with lipophilic acids. Interestingly, incensol (1a) but not IA (1b) was a potent inhibitor of STAT3, raising the possibility that hydrolysis to incensol (1a) might be involved in the in vivo biological activity of IA (1b). Serratol was not amenable to chemical modification, but some marine cembranoids related to the frankincense diterpenoids showed a certain degree of TRPV3-activating properties, qualifying the aliphatic macrocyclic cembrane skeleton as a selective chemotype to explore the pharmacology of TRPV3, a thermo-TRP otherwise resistant to modulation by small molecules.
AB - An expeditious isolation method for the cembrane diterpene alcohols incensol (1a) and serratol (2) has been developed from respectively African and Indian frankincense. The two native alcohols and a series of semisynthetic derivatives of incensol were evaluated for transient receptor potential vanilloid 3 (TRPV3) activation and the inhibition of NF-κB, the putative molecular targets underlying the psychotropic and anti-inflammatory activities of incensol acetate (IA, 1b). Serratol (2) was the most potent TRPV3 activator, outperforming by 2 orders of magnitude the reference agonist thymol and by 1 order of magnitude incensol acetate (1b). Acylation, epimerization, and oxidation did not significantly improve the affinity of incensol for TRPV3, while NF-κB inhibition, marginal for both natural alcohols, could be improved by esterification of incensol (1a) with lipophilic acids. Interestingly, incensol (1a) but not IA (1b) was a potent inhibitor of STAT3, raising the possibility that hydrolysis to incensol (1a) might be involved in the in vivo biological activity of IA (1b). Serratol was not amenable to chemical modification, but some marine cembranoids related to the frankincense diterpenoids showed a certain degree of TRPV3-activating properties, qualifying the aliphatic macrocyclic cembrane skeleton as a selective chemotype to explore the pharmacology of TRPV3, a thermo-TRP otherwise resistant to modulation by small molecules.
UR - http://www.scopus.com/inward/record.url?scp=84979500133&partnerID=8YFLogxK
U2 - 10.1021/acs.jnatprod.6b00141
DO - 10.1021/acs.jnatprod.6b00141
M3 - Article
SN - 0163-3864
VL - 79
SP - 1762
EP - 1768
JO - Journal of Natural Products
JF - Journal of Natural Products
IS - 7
ER -