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The breakthrough of chemists in synthesis leads to a powerful anticancer agent

  "We spent decades of fundamental research, and we have made a lot of dramatic progress," says Yoshi Kishi, Maurice Loyb, a professor of chemistry honored at the Harvard Department of Chemistry and Chemical Biology. Sincerely: Stephanie Mitchell / Harvard Staff Photographer
It's a feat for three decades in creation: Harvard University chemists have achieved what a new book calls a "landmark in the discovery of drugs" with the total synthesis of halithrone. Known to be a powerful anti-cancer agent in mouse research and found naturally in marine mushrooms - albeit only in small quantities - the class of the halithindrine molecule is so damn complicated that it has never been synthesized on a significant scale in the laboratory.

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Emeritus at the Harvard Department of Chemistry and Chemical Biology have now synthesized a sufficient amount of halide-class drug candidate E71

30 in order to first enabled rigorous studies of its biological activity, pharmacological properties and efficacy, all conducted in collaboration with researchers from the Japanese pharmaceutical company Eisai

The molecule has undergone abnormally rapid development and has already been tested in clinical Phase I in Japan, licensed by Eisai's Harvard Technology Development Office (OTD). The company hopes to launch a second clinical trial in the United States in time.

Kishi Lab's results, aimed at completing an intensive, three-year collaboration with Eisai, have been published today in Scientific Reports Open Source Natural History Journal. The paper presents the overall synthesis of the highly potent molecule of chalichondrin E7130-11.5 grams of it, with a purity of 99.81% – and characterizes its mode of action. In preclinical studies, the research team identified it not only as an inhibitor of microtubule dynamics, as previously recognized, but also as a new agent targeting the tumor microenvironment.

"We spent decades of fundamental research, and we have made a lot of dramatic progress," says Kishi, whose 1978 laboratory has been receiving substantial and sustained support from the National Institute of Cancer (NCI) of the National Institutes of Health to study the synthesis of natural products

The structure of the full molecule E7130 is obtained by full synthesis is particularly difficult to replicate because it has 31 chiral centers, asymmetric points that have to be properly oriented, in other words, there are about 4 billion ways "When the natural product was identified 33 years ago by Japanese researchers, it provoked immediate interest." At that time, they realized that the halothinders looked extremely strong, "recalls Tahashi Ova, MD, Director General in Medicine and a senior expert on discovering Aesai's oncology business group and co-author of the newspaper. "Over time, NCI researchers who have studied small amounts of it recognize that this affects the formation of microtubules that are of particular concern importance for cell division. "Because of the very unique structure of the natural product, many people were interested in the mode of action and the investigators wanted to do a clinical study," Ova explains, "but the lack of supply of drugs prevented them from doing so. 30 years have passed, unfortunately, but Professor Kishi is a pioneer in this field. "

Over the years, Kishi Lab has advanced convergence synthesis methods that allow complex molecules to be assembled from subunits rather than linearly constructed. Another innovation, now known as the Nozaki-Hiyama-Kishi reaction, has strongly protected the reactive functional groups during their assembly. And in 1992, Kishi and colleagues achieved the first common synthesis of the halichondrin molecule (halithrin B). The process requires a sequence of more than 100 chemical reactions and produces less than 1% total yield. This was a great achievement, but the simplified version of this molecule, eribulin, has become a drug for the treatment of metastatic breast cancer and liposarcoma now sold by Eisai. Since then, Kishi's laboratory has been engaged in fundamental research on organic synthesis, including the discovery and development of new reactions that can be used at a later stage in synthesis. "In 1992, it was inconceivable to synthesize a gram-quantity of halichondrin," Kishi said, "but three years ago we offered it to Eisai, the organic synthesis progressed to this level, even with the molecular complexity that was untouchable a few years ago.We are very happy to see our basic discoveries on chemistry have already made it possible to synthesize this compound on a large scale. "

" This is a truly unprecedented achievement of total synthesis, special, "Ova says. "No one has been able to produce chalichondrin on a 10-gram scale – one milligram, that's all – they have completed a remarkable complete synthesis that allows us to begin a clinical trial of the E7130."

The report describes the results of studies conducted in vitro and in vivo in animal models that shed light on the complex mode of action of the molecule. The team has shown that the E7130 may increase intratumoral CD31-positive endothelial cells and reduce alpha-SMA-positive cancer associated fibroblasts, components of the tumor microenvironment, which can participate in the transformation to malignancy. with such an exciting and unique opportunity to test the molecule in our systems, "says Ova. "I have never experienced such a very effective and rapid successful collaboration, but only three years of collaboration has brought this from the discovery stage to the clinical development of such a complex molecule, having a very unique mechanism and mode of action."

"Eisai and Harvard is an example of the successful work of academia and industry to accelerate the development of a new class of therapists that may relate to important unsatisfied medical Vivian Berlin, managing director of Strategic Partnerships Harvard OTD. "The spirit of cooperation and the transparency of the relationship have greatly contributed to the success of the project."

"Without OTD," Ova said, "This collaboration could never happen." Harvard OTD is a core core of industry and researchers at Harvard and facilitates discussions on how to build mutually beneficial relationships.
Chemists are developing a new strategy to synthesize the molecule

More Information:
"Attraction in the discovery of drugs based on the complex synthesis of natural products" Scientific Reports (2019). DOI: 10.1038 / s41598-019-45001-9

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Harvard University

References :
The breakthrough of chemists in synthesis leads to a powerful anticancer agent (2019, June 17)
restored on June 17, 2019
by https://phys.org/news/2019-06-chemists-breakthrough-synthesis-advances-potent.html

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