A powerful new approach for the precise, flexible modification of a broad class of chemical compounds called bicyclic aza-arenes—which are commonly used to build drug molecules—has been developed. The approach is expected to be readily adopted by the pharmaceutical industry because it enables chemists to more readily design and synthesize novel structures, including potential blockbuster drugs.

Specifically, the approach allows chemists to selectively modify multiple carbon atoms, when they are bound to simple hydrogen atoms, at various sites on bicyclic aza-arenes. Bicyclic aza-arenes are relatively simple organic molecules that include two ring-like backbones, mostly made of carbon atoms but with at least one nitrogen atom.

“We also expect soon to broaden this approach to other classes of starting compounds,” said Jin-Quan Yu, PhD, a professor of chemistry at Scripps Research, who teamed up with Kendall Houk, PhD, professor of chemistry and biochemistry at the University of California, Los Angeles, on the work. They reported their achievement in Nature (“Molecular Editing of Aza-arene C–H Bonds by Distance, Geometry and Chirality”).

Myriad existing drugs and medically relevant natural compounds are built from bicyclic aza-arene scaffolds. Although chemists have developed hundreds of reactions that can transform starting compounds into other compounds, they have long sought flexible and universal molecular editing methods that modify specific atoms—typically carbon—in starting molecules.

This concept of molecular editing has seemed like an impossible dream because it is difficult to devise reactions that can direct a modification to one specific atom and not others with similar chemical properties.

The new approach is a variant of C-H (carbon-hydrogen) functionalization, which involves removing a hydrogen atom from a carbon atom and replacing it with a more complex set of atoms. “Direct molecular editing of [C-H] bonds through consecutive selective C-H functionalization has the potential to grant rapid access into diverse chemical space,” the researchers wrote in their article.

Their approach employs specially designed helper molecules called directing templates that become reversibly anchored to the starting molecule and efficiently direct C-H functionalization at the desired sites. “A key aspect of our new approach is that the templates direct C-H functionalization not based on traditional electronic criteria, but instead on the distance and geometry of the path to the target,” Yu explained.

The templates direct the reactions but are not consumed by them, and thus continue to work without the need for constant replenishment.

The new approach is expected to be useful for pharmaceutical chemists because of its ease and versatility. With this in mind, the researchers demonstrated the feasibility of their approach for drug discovery.

“The applicability of this method in a drug discovery context was first exemplified by the divergent late-stage site-selective C-H functionalization of the anticancer natural product camptothecin,” wrote the researchers. “Subjecting camptothecin to our C6-selective template generated [a] novel analogue…in 63% yield, while the corresponding C7-selective template generated its regioisomer…in 25% yield. Successful C-H editing of key pharmacophores was also demonstrated, providing novel analogues of anticancer agent cabozantinib…and antimalarial agent chloroquine.”

“Finally, we were eager to address the ultimate challenge of executing sequential site-selective late-stage ‘molecular editing’ in any desired order on a quinoline scaffold; its feasibility [was] demonstrated by successful iterative CH activations to access products…bearing diverse substitutions,” they wrote.

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