A powerful anti-cancer agent that was found in scarce quantities in sea sponges has finally been synthesized in a laboratory in sufficient quantities that it can undergo serious studies.

Chemists at Harvard University, working with researchers at Japanese pharmaceutical company Eisai, have totally synthesized E7130, from the halichondrin class, which had been used in mouse studies. According to The Harvard Gazette, “The molecule has undergone unusually rapid development and is already being tested in a Phase I clinical trial in Japan …The company hopes to begin a second clinical trial in the U.S. in due course.”

The scientific paper noting the achievement states, “Despite their extraordinarily potent and unique anticancer activities, to date, intact halichondrins have not been studied as anticancer drugs in humans because the material could not be secured via either isolation from natural sources or chemical synthesis13. Nonetheless, its exceptional in vivo antitumour activity in mouse xenograft models may suggest that halichondrins are not simply microtubule-targeted drugs, thereby having encouraged us to undertake drug development efforts using intact halichondrins.”

Yoshito Kishi, who led the Harvard team, told The Harvard Gazette, “We spent decades on basic research and made very dramatic progress.” His laboratory has worked for decades examining the synthesis of natural products.

The Gazette noted, “The structure of the complete E7130 molecule derived by total synthesis is particularly challenging to replicate because it has 31 chiral centers, asymmetrical points that must each be correctly oriented. In other words, there are roughly 4 billion ways to get it wrong.”

The natural product was first noted by Japanese researchers more than three decades ago. Takashi Owa, chief medicine creation officer and chief discovery officer for Eisai’s oncology business group and a co-author of the paper, recalled, “At that time, they realized the halichondrins looked exceedingly potent … Due to 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. But a lack of drug supply prevented them from doing it. So 30 years have passed, very unfortunately, but Professor Kishi is a pioneer in this field.”

Kishi added, “In 1992, it was unthinkable to synthesize a gram quantity of a halichondrin. but three years ago we proposed it to Eisai. Organic synthesis has advanced to that level, even with molecular complexity that was untouchable several years ago. We are very delighted to see our basic chemistry discoveries have now made it possible to synthesize this compound at large scale.”

Owa concluded, “It’s a really unprecedented achievement of total synthesis, a special one. No one has been able to produce halichondrins on a 10-gram scale. One milligram, that’s it. They have completed a remarkable total synthesis, enabling us to initiate a clinical trial of E7130.”

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