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Acetylcholinesterase and antioxidant evaluation of C18-functionalized ferruginol analogues
Miguel A. González-Cardenete * 1 , Alberto Yuste 2 , Eva García-Martínez 2 , Marisa Nicolai 3 , Ramón J. Zaragozá 4 , Patricia Rijo 3
1  Instituto de Tecnologia Química, Universitat Politecnica de Valencia-Consejo Superior de Investigaciones Científicas, Valencia, Spain
2  Universitat Politècnica de València, Departamento de Tecnología de Alimentos, Grupo de Investigación e Innovación Alimentaria (CUINA), Camino de Vera s/n, 46022 Valencia, Spain.
3  Research Center for Biosciences & Health Technologies (CBIOS), Universidade Lusofona de Humanidades e Tecnologias, Campo Grande 376, 1749-024 Lisboa, Portugal
4  Departamento de Química Orgánica, Universidad de Valencia, Dr. Moliner 50, 46100 Burjassot, Valencia, Spain

Published: 30 October 2019 by MDPI AG in 5th International Electronic Conference on Medicinal Chemistry session ECMC-5
10.3390/ECMC2019-06313
Abstract:

Nearly 200 years ago, the study of the chemistry of terpenoids started with the analysis of turpentine oil, investigating the first resin acid, abietic acid from pine oleoresin.[1] Abietic acid occurs in plants of the genus Abies and is the first member of a class of plant metabolites, the abietane-type diterpenoids. They are characterized by a tricyclic ring system and have shown a wide range of chemical diversity and biological activity. [2,3] Medicinal chemists have studied derivatives of two readily available materials such as dehydroabietic acid and dehydroabietylamine. [3] To date, there is only one commercial drug, Ecabet® [ecabet sodium], based on abietanes, which is used for the treatment of reflux esophagitis and peptic ulcer disease. The simplest phenolic abietane, ferruginol, exhibits anticancer effects in human ovarian cancer and inhibition of cancer cell migration. It also has shown interesting properties in different models of Alzheimer’s disease, in particular, Zolezzi et al. reported neuroprotective effects of ferruginol against amyloid-b (Ab) oligomers-induced neurodegenerative alterations and Topçu et al. reported butyrylcholinesterase inhibition by ferruginol.[4]

During the last 10 years, we have synthesized several naturally occurring abietanes and derivatives, including ferruginol and other analogues for further biological study. Recently, the simultaneous isolation (in 2014) by Hua and co-workers of the new abietane liquiditerpenoic acid A, a sugiol analogue (7-oxoferruginol derivative), from the resin of Liquidambar formosana, [5] and from Pinus massoniana [6] by Kuo and co-workers named independently as abietopinoic acid prompted us to synthesize it and study its antitumor, GABAA modulation and antileishmanial properties along with some analogues.[7]

Further investigation of those synthesized ferruginol analogues in collaboration with Prof. Rijo at Universidade Lusofona has led to a study on anti-acetylcholinesterase activity, which we present in this communication including the most recent achievements of those molecules as potential antioxidant agents.

References:

[1] Bhat, S. V.; Terpenoids. In: Chemistry of Natural Products. Berlin: Springer; 2005, 131.

[2] For a review on this topic, see: González, M. A. Nat. Prod. Rep. 2015, 32, 684-704.

[3] For a review on this topic, see: González, M. A. Eur. J. Med. Chem. 2014, 87, 834-842.

[4] a) Zolezzi, J. M.; Schmeda-Hirschmann, G.; Inestrosa, N. C. et al. J. Alzheimers Dis., 2018, 63, 705-723; b) Topçu, G.; Öztürk, M.; Boga, M. et al. The Natural Products Journal, 2013, 3, 3-9.

[5] Shang, H.-J.; Li, D.-Y.; Wang, W.-J.; Li, Z.-L.; Hua, H.-M. Nat. Prod. Res. 2014, 28, 1-6.

[6] Mohamed, H. A.; Hsieh, C.-L.; Hsu, C.; Kuo, C.-C.; Kuo, Y.-H. Helv. Chim. Acta 2014, 97, 1146-1151.

[7] Hamulic, D.; Stadler, M.; González-Cardenete, M. A. et al. J. Nat.. Prod. 2019, 82, 823-831.

Keywords: Alzheimer; acetylcholinesterase; antioxidant; semisynthesis; diterpenoid; abietane
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