Planta Med 2016; 82(S 01): S1-S381
DOI: 10.1055/s-0036-1596124
Abstracts
Georg Thieme Verlag KG Stuttgart · New York

Structure-activity relationships of bioactive marine natural products leading to the identification of more potent non-natural analogues – the meroterpenoids, thiaplidiaquinones A and B

MM Cadelis
1   School of Chemical Sciences, University of Auckland, Private Bag 92019, 1142 Auckland, New Zealand
,
IM Khalil
1   School of Chemical Sciences, University of Auckland, Private Bag 92019, 1142 Auckland, New Zealand
,
JL Harper
2   Malaghan Institute of Medical Research, PO Box 7060 Wellington South, New Zealand
,
L Shaw
2   Malaghan Institute of Medical Research, PO Box 7060 Wellington South, New Zealand
,
J Dubois
3   Institut de Chimie des Substances Naturelles, CNRS UPR 2301, Centre de Recherche de Gif, Avenue de la Terrasse, 91198 Gif sur Yvette Cedex, France
,
A Valentin
4   Université Paul Sabatier, PHARMA-DEV, UMR 152 IRD-UPS, Université de Toulouse, 118 Route de Narbonne, F-31062 Toulouse cedex 9, France
,
ML Bourguet-Kondracki
5   Laboratoire Molécules de Communication et Adaptation des Micro-organismes, UMR 7245 CNRS, Muséum National d'Histoire Naturelle, 57 rue Cuvier (C.P. 54), 75005 Paris, France
,
D Barker
1   School of Chemical Sciences, University of Auckland, Private Bag 92019, 1142 Auckland, New Zealand
,
BR Copp
1   School of Chemical Sciences, University of Auckland, Private Bag 92019, 1142 Auckland, New Zealand
› Author Affiliations
Further Information

Publication History

Publication Date:
14 December 2016 (online)

Also available at
 

In an effort to define the mechanism of cell death and to establish structure-activity relationship requirements for the marine meroterpenoid alkaloids thiaplidiaquinones A (1) and B (2) [1], we have developed a bioinspired synthetic route to these complex natural products [2] and used it to prepare a library of natural and non-natural product analogues. Included in this library are novel prenyl and farnesylated analogues. Biological evaluation of this library has found that, in contrast to previous reports, the mechanism of Jurkat cell death (necrosis vs. apoptosis) was dependent upon the positioning of one of the terpenoid sidechains in the compounds with one natural product, thiaplidiaquinone A, and its dioxothiazine regioisomer causing death dominantly by necrosis, while the second natural product, thiaplidiaquinone B and its dioxothiazine isomer caused cell death via apoptosis. The dioxothiazine regioisomer of thiaplidiaquinone A exhibited more potent in vitro antiproliferative activity against human tumour cells, with NCI sub-panel selectivity towards melanoma cell lines. The non-natural dioxothiazine regioisomers were also more active inhibitors of parasitic and human farnesyltransferase (IC50 0.054 – 0.14µM) and were also growth inhibitors of Plasmodium falciparum (IC50 4.4 – 4.6µM).

This talk will present details of our biomimetic synthetic route to these natural products and the biological results, as summarised above [3]. These results will highlight the important role that natural product total synthesis can play in not only helping understand the structural basis of biological activity of natural products, but also the discovery of new bioactive scaffolds.

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Acknowledgements: Funding from The University of Auckland.

Keywords: Marine natural product, meroterpenoid, apoptosis, necrosis, Plasmodium falciparum.

References:

[1] Aiello A, Fattorusso E, Luciano P, Macho A, Menna M, Muñoz E. Antitumor effects of two novel naturally occurring terpene quinones isolated from the Mediterranean ascidian Aplidium conicum. J Med Chem 2005; 48: 3410 – 3416

[2] Khalil IM, Barker D, Copp BR. Biomimetic synthesis of thiaplidiaquinones A and B. J Nat Prod 2012; 75: 2256 – 2260

[3] Harper JL, Khalil IM, Shaw L, Bourguet-Kondracki M-L, Dubois J, Valentin A, Barker D, Copp BR. Structure-activity relationships of the bioactive thiazinoquinone marine natural products thiaplidiaquinones A and B. Mar Drugs 2015; 13: 5102 – 5110