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A more versatile way to build molecules
03-21-2017
by Jeffrey Bouley  |  Email the author
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LA JOLLA, Calif.—You know about those hard spots. That itch in the middle of your back. The light fixture or smoke alarm you can almost reach without a stool or chair. That home repair project that even your screwdriver and arm combined are an inch too short for.
 
Well, it turns out that potential drug molecules can have some hard-to-reach spots, too, and for that reason, chemists at The Scripps Research Institute (TSRI) have devised a new molecule-building tool for creating new drugs and other chemical products.
 
This tool, a small molecule known as a template, has a long, curved structure and functions, according to TSRI, “like a crane and wrecking-ball, anchoring itself temporarily to one part of a target molecule and swinging an atom of palladium to break a chemical bond at a distant part of the molecule.” Reportedly, using this process allows chemists to make relatively easy modifications to sites on organic molecules that are otherwise difficult or impossible to access.
 
More importantly, though, this new tool may help researchers achieve a challenging goal and realize a long-held ambition of using techniques of laboratory organic synthesis to make the highly selective transformations of molecules that enzymes catalyze in living cells—but without enzymes’ limitations.
 
“Enzymes that have evolved over millions of years are very good at making this type of modification of complex organic molecules, and here we’re showing that we can achieve a similar effect, with much greater versatility, using a small catalytic template,” said study senior author Jin-Quan Yu, the Frank and Bertha Hupp Professor in the Department of Chemistry at TSRI.
 
As noted in a paper published in the journal Nature, Yu and his colleagues demonstrated their new catalytic template by using it to modify—in a way that was previously impossible—molecules that are commonly found in drugs and other biologically active compounds.
 
At its core, the template is intended for the removal of a hydrogen (H) atom from the carbon (C) backbone of an organic molecule, “enabling the attachment of a more complex and reactive cluster of atoms,” TSRI notes—a process known as C-H activation.
 
This basic step in molecule-building is often what give a molecule the specific characteristics that make is useful as a drug, for example—or any other chemical product. With the new TSRI tool, the goal was to achieve C-H activation in particularly difficult-to-access locations of target molecules. Initial versions of remote C-H activation templates that were reported by the Yu laboratory in two previous papers in Nature, can anchor themselves to one side of a molecule and in effect swing a palladium atom around to selectively hit and break a C-H bond on the far side of the molecule.
 
As TSRI notes: “While these first-generation templates have been adopted by many chemists, they have some limitations: They anchor themselves to a target molecule using a very tight (covalent) bond, so that an extra reaction step is required to remove them. Moreover they often cannot attach to molecules called heterocycles, whose backbones contain a non-carbon such as nitrogen—yet more than half of modern drug molecules fall under this category.”
 
As Carmen Drahl noted in an article “Making Heterocycles Behave In C-H Activation” in 2014, “Heterocycles make great drugs, but they tend to be lousy substrates for C-H activation, a class of reactions that transform traditionally inert C-H bonds into more useful moieties.”
 
The new template from the TSRI team in Yu’s lab is meant to work with heterocycles and is designed to anchor in a reversible fashion. In this way, emulating “an enzyme, it lifts off naturally after doing its work and moves on to catalyze new C-H activations.” This cuts out an entire reaction step and doesn’t have to be supplied in quantities nearly as large as in earlier generations.
 
The template has two main parts: a long, U-shaped structure to hold the bond-breaking palladium atom, and a base structure that also holds a metal atom: either palladium or copper. The non-carbon parts of a heterocycle backbone tend to attract such metals, and the new template exploits that tendency by using a metal atom as its anchor.
 
“That tendency of metals to stick to heterocycles has been a notorious problem when trying to use metal catalysts, but in this case we’re turning that tendency to our advantage,” Yu said.
 
To demonstrate the breadth and utility of the new template design, the team used variants of it to attach different organic molecules to heterocycle structures including phenylpyridine and quinoline. These heterocycles are often found in drugs and other bioactive molecules but have not been modifiable via C-H activation using earlier templates.
 
The products of these new reactions, all potentially valuable commercially, included novel versions of a plant-derived molecule, camptothecin, which has promising antitumor properties.
 
“This approach provides a new way to rapidly modify the structures of complex organic molecules, and thus should be broadly useful in the pharmaceutical and other chemical industries,” Yu said.
 
Code: E03221701

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