Abstract
A cell-based high-throughput screen that assessed the cellular stability of a tumor suppressor protein PDCD4 (Programmed cell death 4) was used to identify a new guanidine-containing marine alkaloid mirabilin K (3), as well as the known compounds mirabilin G (1) and netamine M (2). The structures of these tricyclic guanidine alkaloids were established from extensive spectroscopic analyses. Compounds 1 and 2 inhibited cellular degradation of PDCD4 with EC50 values of 1.8 μg/mL and 2.8 μg/mL, respectively. Mirabilin G (1) and netamine M (2) are the first marine natural products reported to stabilize PDCD4 under tumor promoting conditions.
Highlights
Tumor suppressor proteins can prevent or repress malignant cell growth by regulating progression of the cell cycle or by promoting apoptosis via alteration in gene expression patterns
PDCD4-luciferase signal from TPA-induced degradation; b Values presented as the minimum concentration required for total luciferase signal loss, relative to TPA treated control cells; c Not active; d Positive control, concentration in μM
Stabilization of PDCD4 was assessed as previously described [14], using HEK-293 cells that could be readily transfected with appropriate PDCD4-luciferase plasmids
Summary
Tumor suppressor proteins can prevent or repress malignant cell growth by regulating progression of the cell cycle or by promoting apoptosis via alteration in gene expression patterns. The screening assay was used to test natural product extracts sourced from a diverse collection of marine invertebrates, terrestrial plants, and microbial isolates from the Natural Products Repository of the US National Cancer Institute. These metabolites belong to a class of tricyclic guanidine alkaloids exemplified by the ptilocaulins, [21,22,23] netamines, [20,24] and mirabilins [18,19,25]
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