By Rich Haridy

Over 30 years ago, a molecule with incredible anti-cancer properties was discovered in sea sponges. However, it was so structurally complex scientists have been unable to synthesize it in large enough quantities to be able to test it in humans. Now a team of scientists has finally made a landmark breakthrough, achieving total synthesis of the molecule in volumes large enough to proceed to clinical trials.

In 1986 a team of Japanese scientists isolated an organic compound called a polyether macrolide from the marine sponge, Halichondria okadai. The molecule was dubbed Halichondrin B and initial animal tests revealed it conferred extraordinary anti-cancer activity.

“At that time, they realized the halichondrins looked exceedingly potent,” recalls Takashi Owa, co-author of the new study. “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.”

In 1992 scientists finally figured out how to synthesize the halichondrin molecule. Unfortunately, the process was still incredibly complicated, and only very small quantities could be produced. A somewhat simplified iteration of the molecule, called Eribulin, was subsequently developed, and ultimately approved to treat breast cancer.

Three years ago a team of Harvard University chemists joined forces with scientists from Japanese pharmaceutical company Eisai to take another run at the problem. Harvard professor Yoshito Kishi, an expert in the synthesis of natural products, suggests a series of advances in convergent synthesis methods over the past few years paved the way for this significant breakthrough.

“In 1992, it was unthinkable to synthesize a gram quantity of a halichondrin, but three years ago we proposed it to Eisai,” Kishi explains. “Organic synthesis has advanced to that level, even with molecular complexity that was untouchable several years ago.”

A newly published paper outlines the incredible new achievement, synthesizing 11.5 grams of the halichondrin molecule, dubbed E7130. This mind-bindingly complex molecule has 31 chiral centers, with the researchers suggesting there are around 4 billion different incorrect ways this molecule could be orientated.

“It’s a really unprecedented achievement of total synthesis, a special one,” says Owa. “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.”

As Owa notes, a Phase 1 clinical trial is now underway in Japan, investigating the safety and efficacy of E7130 in human subjects, and the existence of this trial is solely due to the landmark breakthrough in synthesizing this complex molecule.

The new study was published in the journal Scientific Reports.

Source: Harvard University