January 02, 2020

A new kind of molecular differentness Chemists' discovery of a small bacterial molecule with natural and inside-out' versions could have implications for future drug development

January 02, 2020

LA JOLLA, CA Chemists at Scripps Research have found a new way in which small organic molecules, despite having the same chemical formula and all the same chemical bonds, can differ in shape and therefore in their biological properties.

The chemists, who report their discovery in a paper in Science, found that a mysterious molecule called tryptorubin A, which is made only by certain bacteria that live in ant colonies, can be synthesized in the natural form or in a strange-looking alternative form that is essentially inside out.

This unusual type of shape variation, called non-canonical atropisomerism, has never been observed in a small molecule before. Small molecules are of special interest for chemists because most drugs are made of them their small size allows them to survive the digestion process when in pill form.

The ways in which a small molecule can vary in shape when it is synthesized are important too because often only one shape variant, or isomer, has the desired biological activity.

The Scripps Research chemists in this case were able to devise a technique to synthesize either the natural form of tryptorubin A or the unnatural, inside-out isomer.

I think our new awareness of this complex isomerism that can occur in small molecules, and the possible necessity of driving a synthesis towards one isomer or the other, are ultimately going to be relevant to the development of new drugs, says study lead author Solomon Reisberg, a graduate student in the laboratory of Phil Baran, PhD, the Darlene Shiley Chair in Chemistry at Scripps Research.

The study was a collaboration between the Baran Laboratory and the laboratory of chemist Jon Clardy, PhD, a professor of biological chemistry and molecular pharmacology at Harvard Medical School. Clardy and his colleagues isolated tryptorubin A in 2017 in the course of studying the symbiosis among ants, the fungus they farm for food, and the bacterial species that live on the fungus. The newly discovered compound, which has an oddly globular shape despite its small size, is produced by at least one species of fungus-associated Streptomyces bacteria.

No one yet understands tryptorubin A's natural function, Reisberg says. All that's known for sure is that it is found only when all three species ants, fungus, bacteria are around, so possibly it has a signaling role.

For the Baran lab, which specializes in finding new ways to make small molecules, tryptorubin A posed a more direct challenge: how to develop a set of organic chemistry reactions to make this natural compound with its highly strained, spherical, cage-like shape.

They eventually found a method to do that, but in analyzing the product they discovered that it existed in two alternative shapes, which they eventually recognized as roughly right side in and inside out. That type of isomerism has been considered impossible except in larger molecules that can fold into complex shapes with much less strain.

The discovery posed a new challenge: how to synthesize just the natural isomer of tryptorubin A, or alternatively the inside-out isomer. The solution that Reisberg and colleagues devised was to install a cluster of chemical bonds at the start of the synthetic process so as to force the structure to bend in one way or the other and then remove that guiding element once the structure closed on itself.

As chemists our job is to control the shapes of molecules in ever more sensitive ways to make better drugs and other products, Reisberg says. Here, we've shown that we can do that in a complex and unexpected context that may be pertinent for the development of some future drugs.

Total synthesis reveals atypical atropisomerism in a small-molecule natural product, tryptorubin A was written by Solomon Reisberg, Yang Gao, and Phil Baran, of Scripps Research; and Allison Walker, Eric Helfrich, and Jon Clardy of Harvard Medical School.

Funding was provided by the National Institutes of Health (GM-118176, R01AT009874).

Chemistry Baran, Phil

LINK:	https://www.scripps.edu/news-and-events/press-room/2020/20200102-baran...
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