Abstract
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.
Highlights
The structures of marine natural products continue to provide targets for total synthesis and new templates for biological evaluation
With propidium iodide staining and flow cytometry data indicating that the natural products increased the frequency of subdiploid cells caused by a rapid overproduction of intracellular reactive oxygen species (ROS) which in-turn led to a collapse of the mitochondrial transmembrane potential
It was originally reported that thiaplidiaquinones A and B displayed a strong accumulation of intracellular ROS in Jurkat cells, 97% of cells for 1 and 93% for 2, relative to untreated cells [4]
Summary
The structures of marine natural products continue to provide targets for total synthesis and new templates for biological evaluation. B (2), two thiazine-meroterpenoids, from Mediterranean specimens of Aplidium conicum (Figure 1) [4]. Both 1 and 2 exhibited cytotoxicity towards the human leukemia T cell line Jurkat with IC50 ~ 3 μM with propidium iodide staining and flow cytometry data indicating that the natural products increased the frequency of subdiploid (apoptotic) cells caused by a rapid overproduction of intracellular reactive oxygen species (ROS) which in-turn led to a collapse of the mitochondrial transmembrane potential. The interesting structures of thiaplidiaquinones A and B and their associated biological activities piqued the interest of ourselves and others, leading to reported biomimetic syntheses of 1 and 2 [5,6].
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