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Scalable synthesis of withanolides: A significant development in cancer research

Researchers at Moffitt Cancer Center have developed a novel method for the scalable synthesis of withanolides, a class of naturally occurring compounds with significant potential in cancer treatment. This groundbreaking approach, published in Science Advances [1], could revolutionise cancer research by providing a reliable and efficient means of producing these vital compounds in large quantities.

Withanolides have long been a focus of cancer research due to their ability to inhibit cancer cell growth, induce cell death, and prevent metastasis. However, the difficulty of obtaining enough of these compounds from plants has hindered research and therapeutic development. The new synthesis route developed by the Moffitt team addresses this challenge, enabling the production of withanolides on a gram scale.

A bioinspired approach

The key to this innovative synthesis is a bioinspired photooxygenation-allylic hydroperoxide rearrangement sequence. This approach facilitates the introduction of functional groups at the late stages of the synthesis, ensuring scalability and allowing for the concise preparation of numerous different withanolides from the same synthesis. Dr Justin M. Lopchuk, lead author and associate member of the Drug Discovery Department at Moffitt, said: “Our new synthesis route represents a major step forward in the field of withanolide chemistry. By enabling the diversifiable production of these compounds on a gram scale, we can now support more extensive biological research and medicinal chemistry efforts.”

Withaferin A

Implications for cancer research and treatment

The scalable synthesis of withanolides opens up new avenues for cancer research and treatment development. Unlike conventional treatments targeting a single pathway, withanolides act on multiple cellular pathways. They can:

1. Interfere with cancer cell division
2. Damage the cellular structures of cancer cells
3. Modulate the immune system to enhance the body’s ability to fight cancer
4. Potentially enhance the effectiveness of cancer treatments by making cancer cells more sensitive to chemotherapy and radiation

Efficacy across multiple cancer types

Withanolides have shown efficacy against a range of cancer types, including breast, lung, colon, and prostate. This broadspectrum activity makes them particularly promising candidates for cancer treatment research.

A critical aspect of withanolides’ potential is their ability to overcome drug resistance. Cancer cells can develop resistance to conventional treatments over time, but withanolides, due to their unique mechanisms of action, may help overcome this resistance and remain effective where other treatments fail.

1. Lopchuk, J. M., et al. (2024). Divergent synthesis of complex withanolides enabled by a scalable route and late-stage functionalization. Science Advances.