Article

Structure−Activity Relationships of the Estrogenic Sesquiterpene Ester Ferutinin. Modification of the Terpenoid Core

Giovanni AppendinoDipartimento di Scienze Chimiche, Alimentari, Farmaceutiche e Farmacologiche, Università del Piemonte Orientale, Via Bovio 6, 28100 Novara, Italy, Dipartimento di Scienza e Tecnologia del Farmaco, Università di Torino, Via Giuria 9, 10125 Torino, Italy, Department of Organic and Bioorganic Chemistry, Lund University, P.O. Box 124, 221 00 Lund, Sweden, and Endocrinology and Reproductive Research Group, Kings College, SE1 1 UL, London, U.KPaola SpagliardiDipartimento di Scienze Chimiche, Alimentari, Farmaceutiche e Farmacologiche, Università del Piemonte Orientale, Via Bovio 6, 28100 Novara, Italy, Dipartimento di Scienza e Tecnologia del Farmaco, Università di Torino, Via Giuria 9, 10125 Torino, Italy, Department of Organic and Bioorganic Chemistry, Lund University, P.O. Box 124, 221 00 Lund, Sweden, and Endocrinology and Reproductive Research Group, Kings College, SE1 1 UL, London, U.KOlov SternerDipartimento di Scienze Chimiche, Alimentari, Farmaceutiche e Farmacologiche, Università del Piemonte Orientale, Via Bovio 6, 28100 Novara, Italy, Dipartimento di Scienza e Tecnologia del Farmaco, Università di Torino, Via Giuria 9, 10125 Torino, Italy, Department of Organic and Bioorganic Chemistry, Lund University, P.O. Box 124, 221 00 Lund, Sweden, and Endocrinology and Reproductive Research Group, Kings College, SE1 1 UL, London, U.KStuart MilliganDipartimento di Scienze Chimiche, Alimentari, Farmaceutiche e Farmacologiche, Università del Piemonte Orientale, Via Bovio 6, 28100 Novara, Italy, Dipartimento di Scienza e Tecnologia del Farmaco, Università di Torino, Via Giuria 9, 10125 Torino, Italy, Department of Organic and Bioorganic Chemistry, Lund University, P.O. Box 124, 221 00 Lund, Sweden, and Endocrinology and Reproductive Research Group, Kings College, SE1 1 UL, London, U.K

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Abstract

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.

Identifiers

DOI: 10.1021/np049796w

Citations and references

Cited by 30 references

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