Synthesizing A Natural Compound That Hunts Down Cancer Stem Cells

Scientists in China have synthesized a natural cyclic compound that targets pancreatic cancer stem cells.

AsianScientist (Oct. 30, 2017) – Scientists have successfully synthesized a natural cyclic compound that could be used to treat pancreatic cancer by targeting cancer stem cells. Their results have been published in Angewandte Chemie.

Pancreatic cancer stem cells are resistant to even the most aggressive treatments. A class of naturally occurring compounds called cyclic depsipeptides are known to have anti-cancer properties but are so rare that they cannot be isolated in sufficient quanity. Cyclic depsipeptides are peptide rings that contain one or more ester bonds in addition to peptidic amide bonds, and are found in a variety of organisms such as fungi, bacteria, and marine organisms.

Due to their complicated chemical structures, it has been difficult to synthesize cyclic depsipeptides in the lab. Furthermore, scientists are unsure of which parts of the molecule contain therapeutically active sites, and their mechanism of action remains unknown.

In this study, a team of scientists led by Professor Chen Yue from the Tianjin Key Laboratory of Molecular Drug Research at Nankai University, China, have synthesized a depsipeptide, BE-43547A2, that exhibited anticancer properties. The compound has a structure containing three chiral centers and two double bonds, synthesized over 15 linear steps.

The researchers were able to produce a relatively large quantity—more than one-third of a gram—of pure material. This amount was enough to perform preliminary laboratory tests on its anticancer properties in comparison with other drugs, as well as investigate its structure–activity relationship.

The scientists found that the compound’s anticancer activity was far better than that of several established drugs, including two components that are already in clinical trial against pancreatic cancer stem cells. BE-43547A2 reduced the percentage of cancer stem cells within a population of pancreatic cancer cells by 21-fold relative to the control. The compound also abolished the tumor-initiating capability of the pancreatic cancer stem cells.

“All of the biological assays indicate that BE-43547A2 can selectively ablate pancreatic cancer stem cells,” the scientists reported.

Furthermore, because molecules synthesized with slight differences in structure were not active, the researchers were able to establish which sites in the molecule were pharmacologically relevant. For future studies, the researchers intend to identify the mechanism by which BE-43547A2 kills pancreatic stem cells.

The article can be found at: Sun et al. (2017) Cyclic Depsipeptide BE-43547A2: Synthesis and Activity against Pancreatic Cancer Stem Cells.

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Source: Nankai University; Photo: Shutterstock.
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