Structure--activity relationships of the estrogenic sesquiterpene ester ferutinin. Modification of the terpenoid core.
Esterification of p-hydroxybenzoic acid, a very weak estrogenic compound, with the daucane alcohol jaeschkeanadiol (1b) leads to a spectacular magnification of the estrogenic activity. To identify the structural elements responsible for this effect, the terpenoid core of jaeschkeanadiol p-hydroxybenzoate (ferutinin, 1a) was modified, capitalizing on the presence of two functionalities, the monoacylated, hydrogen-bonded 1,3-diol system and the double bond. The hydrogen bonding, while possibly useful, was not critical for activity, while hydrogenation and cyclopropanation of the double bond were tolerated. Conversely, oxidative modifications of the double bond that placed a hydroxyl on the alpha-face of the molecule proved detrimental. Taken together, these observations identified the substitution at C-8/C-9 as critical for activity.
Appendino
Giovanni
G
Dipartimento di Scienze Chimiche, Alimentari, Farmaceutiche e Farmacologiche, Università del Piemonte Orientale, Via Bovio 6, 28100 Novara, Italy. Giovanni.Appendino@pharm.unipmn.it
Spagliardi
Paola
P
Sterner
Olov
O
Milligan
Stuart
S
D001565:Benzoates / Q000737:chemistry* / Q000494:pharmacology*; D001643:Bridged Bicyclo Compounds; D002384:Catalysis; D003508:Cycloheptanes; D004305:Dose-Response Relationship, Drug; D004952:Esters / Q000737:chemistry / Q000494:pharmacology; D004968:Estrogens, Non-Steroidal / Q000737:chemistry* / Q000494:pharmacology*; D005309:Ferula / Q000737:chemistry; D007202:Indicators and Reagents; D015394:Molecular Structure; D010084:Oxidation-Reduction; D010946:Plants, Medicinal / Q000737:chemistry; D011960:Receptors, Estrogen / Q000378:metabolism*; D012717:Sesquiterpenes / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D001565:Benzoates; D001643:Bridged Bicyclo Compounds; D003508:Cycloheptanes; D004952:Esters; D004968:Estrogens, Non-Steroidal; D007202:Indicators and Reagents; D011960:Receptors, Estrogen; D012717:Sesquiterpenes; C493118:jaeschkeanadiol; C111068:4-oxy-6-(4-oxybezoyloxy)dauc-8,9-en