Thursday, 8 Jun 2023

Chemists achieve molecular editing feat

Chemists from Scripps Research and the University of California, Los Angeles, have developed methods for the precise, flexible modification of a broad class of chemical compounds called bicyclic aza-arenes, which are commonly used to build drug molecules.

The landmark achievement, reported August 9, 2022, in Nature, reflects a powerful new approach that generally offers much easier and more flexible molecular design, enabling chemists to synthesize innumerable chemical products — including potential blockbuster drugs — that were previously out of reach.

“These new methods effectively give chemists a unified, practical, late-stage ‘molecular editing’ toolkit for modifying bicyclic aza-arenes at desired sites in any desired order — greatly expanding the diversity of drugs and other useful molecules that could be built from these popular starting compounds,” says study co-leader Jin-Quan Yu, PhD, the Bristol Myers Squibb Endowed Chair in Chemistry and Frank and Bertha Hupp Professor of Chemistry at Scripps Research.

Yu and his lab collaborated on the research with the lab of Kendall Houk, PhD, Distinguished Research Professor in the Department of Chemistry and Biochemistry at UCLA. The first authors of the study were postdoctoral researchers Zhoulong Fan, PhD, and Xiangyang Chen, PhD, of the Yu and Houk labs respectively.

Building organic molecules with laboratory chemistry techniques, a practice known as organic synthesis, has always been more challenging than building things at macro scale. Down at the molecular scale, how sets of atoms move and bond to each other is governed by a highly complex mix of forces. Although chemists have developed hundreds of reactions that can transform starting compounds into other compounds, they have lacked toolkits for modifying widespread carbon centers containing carbon-hydrogen bonds only.

The ambitious goal, or “Holy Grail,” of many synthetic chemists has been to develop flexible and universal molecular editing methods that modify as many carbon atoms as possible at any site by breaking carbon-hydrogen bonds in the starting molecules. Specifically, synthetic chemists have wanted to, in a streamlined and easy way, modify the atom of their choice — typically carbon — on the backbone of a given organic molecule, and to modify more than one of these carbon atoms on the molecule, and in any order. This ability would make the construction of new molecules as straightforward as creating a sentence by changing individual words at will. But the difficulty of devising reactions that can direct a modification to one specific atom, and not others that may be virtually identical in traditional chemical terms, has tended to make the concept of molecular editing seem like an impossible dream.

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