Structure-Activity Relationships of the Bioactive Thiazinoquinone Marine Natural Products Thiaplidiaquinones A and B.
In an effort to more accurately define the mechanism of cell death and to establish structure-activity relationship requirements for the marine meroterpenoid alkaloids thiaplidiaquinones A and B, we have evaluated not only the natural products but also dioxothiazine regioisomers and two precursor quinones in a range of bioassays. While the natural products were found to be weak inducers of ROS in Jurkat cells, the dioxothiazine regioisomer of thiaplidiaquinone A and a synthetic precursor to thiaplidiaquinone B were found to be moderately potent inducers. Intriguingly, and in contrast to previous reports, the mechanism of Jurkat cell death (necrosis vs. apoptosis) was found to be dependent upon the positioning of one of the geranyl sidechains in the compounds with thiaplidiaquinone A and its dioxothiazine regioisomer causing death dominantly by necrosis, while 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 tumor cells, with NCI sub-panel selectivity towards melanoma cell lines. The non-natural dioxothiazine regioisomers were also more active in antiplasmodial and anti-farnesyltransferase assays than their natural product counterparts. The results 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.
Malaghan Institute of Medical Research, PO Box 7060 Wellington South, New Zealand. jharper@malaghan.org.nz.
Jacquie L
JL
Harper
School of Chemical Sciences, University of Auckland, Private Bag 92019, 1142 Auckland, New Zealand. ikha019@aucklanduni.ac.nz.
Iman M
IM
Khalil
Malaghan Institute of Medical Research, PO Box 7060 Wellington South, New Zealand. l.shaw@centenary.org.au.
Lisa
L
Shaw
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. bourguet@mnhn.fr.
Marie-Lise
ML
Bourguet-Kondracki
Institut de Chimie des Substances Naturelles, CNRS UPR 2301, Centre de Recherche de Gif, Avenue de la Terrasse, 91198 Gif sur Yvette Cedex, France. joelle.dubois@icsn.cnrs-gif.fr.
Joëlle
J
Dubois
Université Paul Sabatier, PHARMA-DEV, UMR 152 IRD-UPS, Université de Toulouse, 118 Route de Narbonne, F-31062 Toulouse cedex 9, France. alexis.valentin@univ-tlse3.fr.
Alexis
A
Valentin
School of Chemical Sciences, University of Auckland, Private Bag 92019, 1142 Auckland, New Zealand. d.barker@auckland.ac.nz.
David
D
Barker
School of Chemical Sciences, University of Auckland, Private Bag 92019, 1142 Auckland, New Zealand. b.copp@auckland.ac.nz.
Brent R
BR
Copp
D017209:Apoptosis / Q000187:drug effects; D059001:Aquatic Organisms / Q000378:metabolism*; D001688:Biological Products / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D019169:Jurkat Cells; D011809:Quinones / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013729:Terpenes / Q000494:pharmacology*
D001688:Biological Products; D011809:Quinones; D013729:Terpenes; C500855:thiaplidiaquinone A; C500856:thiaplidiaquinone B
Aplidium; Jurkat; apoptosis; ascidian; cytotoxicity; farnesyltransferase; malaria; thiaplidiaquinone; thiazinoquinone