title: Neuroactive and Anti-inflammatory Frankincense Cembranes: A Structure-Activity Study.
abstract: 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.
authors.affiliation: Dipartimento di Scienze del Farmaco, Università del Piemonte Orientale , Largo Donegani 2, 28100 Novara, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Pollastro
authors.affiliation: Dipartimento di Scienze del Farmaco, Università del Piemonte Orientale , Largo Donegani 2, 28100 Novara, Italy.
authors.forename: Samantha
authors.initials: S
authors.lastname: Golin
authors.affiliation: Dipartimento di Farmacia, Università di Napoli Federico II , Via Montesano 49, 80131 Napoli, Italy.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Chianese
authors.affiliation: Dipartimento di Farmacia, Università di Napoli Federico II , Via Montesano 49, 80131 Napoli, Italy.
authors.forename: Masteria Yunovilsa
authors.initials: MY
authors.lastname: Putra
authors.affiliation: Endocannabinoid Research Group, Institute of Biomolecular Chemistry, CNR , Via Campi Flegrei 34, 80078 Pozzuoli (NA), Italy.
authors.forename: Aniello
authors.initials: A
authors.lastname: Schiano Moriello
authors.affiliation: Endocannabinoid Research Group, Institute of Biomolecular Chemistry, CNR , Via Campi Flegrei 34, 80078 Pozzuoli (NA), Italy.
authors.forename: Luciano
authors.initials: L
authors.lastname: De Petrocellis
authors.affiliation: Maimonides Biomedical Research Institute of Córdoba, Reina Sofía University Hospital, Department of Cell Biology, Physiology and Immunology, University of Córdoba , Avenida Menéndez Pidal s/n, 14004 Córdoba, Spain.
authors.forename: Victor
authors.initials: V
authors.lastname: García
authors.affiliation: Maimonides Biomedical Research Institute of Córdoba, Reina Sofía University Hospital, Department of Cell Biology, Physiology and Immunology, University of Córdoba , Avenida Menéndez Pidal s/n, 14004 Córdoba, Spain.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Munoz
authors.affiliation: Dipartimento di Farmacia, Università di Napoli Federico II , Via Montesano 49, 80131 Napoli, Italy.
authors.forename: Orazio
authors.initials: O
authors.lastname: Taglialatela-Scafati
authors.affiliation: Dipartimento di Scienze del Farmaco, Università del Piemonte Orientale , Largo Donegani 2, 28100 Novara, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Appendino
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D004224:Diterpenes / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D065260:Frankincense / Q000737:chemistry; D007558:Italy; D015394:Molecular Structure; D018696:Neuroprotective Agents / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship; D050916:TRPV Cation Channels / Q000187:drug effects
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D004224:Diterpenes; D018696:Neuroprotective Agents; D050796:STAT3 Transcription Factor; D050916:TRPV Cation Channels; C459445:TRPV3 protein, human; C000618141:incensol; C530368:incensole acetate; C000618142:serratol; D065260:Frankincense