Synthetic Fungal Compounds Show Potent Anticancer Potential

Recent advances in the chemical synthesis of rare fungal compounds have yielded an exciting new class of reagents with potent anticancer properties.

Investigators at the Massachusetts Institute of Technology (Cambridge, MA, USA) have been working with a class of fungal compounds called epipolythiodiketopiperazine (ETP) alkaloids. However, until recently the small amounts of these compounds that are produced naturally have made it difficult to do a comprehensive study of the relationship between the compounds' structure and their activity.

In a paper published in the January 24, 2013, online edition of the journal Chemical Science the investigators reported the development and application of a flexible and scalable synthetic technique, which allowed the construction of dozens of ETP derivatives.

Sixty of these compounds were tested against two different human cancer cell lines—cervical cancer and lymphoma. Many ETP derivatives demonstrated potent anticancer activity and killed cancer cells via induction of apoptosis. The most effective 25 compounds were tested against three additional lines, from lung, kidney, and breast tumors.

Overall, dimeric compounds appeared to be more effective at killing cancer cells than monomers, and compounds with at least two sulfur atoms were more effective than those with only one sulfur atom. Compounds lacking sulfur did not kill tumor cells efficiently. The active compounds were found to be approximately 1,000 times more toxic to cancer cells than they were to normal cells.

Several traits that bode well for the translational potential of the ETP class of natural products include concise and efficient synthetic access, potent induction of apoptotic cell death, activity against a wide range of cancer types, and a broad tolerance for modifications at multiple sites that should facilitate small-molecule drug development, mechanistic studies, and evaluation in vivo.

"What was particularly exciting to us was to see, across various cancer cell lines, that some of them are quite potent," said first author Dr. Mohammed Movassaghi, professor of chemistry at the Massachusetts Institute of Technology. "There is a lot of data out there, very exciting data, but one thing we were interested in doing is taking a large panel of these compounds, and for the first time, evaluating them in a uniform manner. We can go in with far greater precision and test the hypotheses we are developing in terms of what portions of the molecules are most significant at retaining or enhancing biological activity."

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Massachusetts Institute of Technology