For years, drug discovery chemists have struggled to streamline a process that can boost a drug’s potency up to 2000-fold: “magic methylation.” The reaction sweeps out single hydrogen atoms and replaces them with methyl groups—reshaping the drug molecule to more easily interact with its biological targets. But carrying out this sleight of hand is so difficult that few researchers even try. Now, a team of chemists reports it has created a new catalyst that performs this delicate exchange with ease on a wide variety of druglike molecules, an advance that could lead to novel treatments for everything from cancer to infectious diseases.
“This paper is just stunning,” says Tim Cernak, an organic chemist at the University of Michigan, Ann Arbor, who was not involved in the research. The new catalyst manages the reaction in one easy step—a huge improvement on previous multistep methods that were expensive and time-consuming. “This is the wish [of] every drug hunter,” Cernak says. “It really is a dream reaction.”
To understand the dream, it helps to know one way chemists build drug molecules, explains M. Christina White, an organic chemist at the University of Illinois, Urbana-Champaign. Most drug molecules contain a skeleton of carbon atoms shaped as a rod or a ring, with multiple hydrogen atoms hanging off each carbon. Chemists act as molecular surgeons, cutting out specific carbon or hydrogen atoms and replacing them with oxygen or nitrogen atoms. If researchers want to add a magic methyl group (which consists of one carbon atom bonded to three hydrogen atoms), they often have to start over, building a new skeleton from scratch.
White wanted to find a way to add a methyl group at the end of the drug building process. To do that, she needed to surgically snip one carbon-hydrogen (C-H) bond at a time, without cleaving the other dozen or more C-H bonds in the molecule. Adding further difficulty, C-H bonds are among the strongest in organic molecules, which makes it harder to target just one bond without affecting others, White says.
Nature builds and reshapes molecules “in a totally different way,” White says. Chemical changes are made using large, complex enzymes that grasp hydrocarbon scaffolds so that just one C-H bond nuzzles up to the enzyme’s catalytic site—the point at which a reaction takes place. However, each enzyme typically works with only one specific molecule. “If I want to work on a different molecule, I need a new enzyme,” White says. “We want [a reagent that is] just as selective, but general.”
In an effort to find just such a catalyst, White and then–graduate student Mark Chen in 2007 devised a snowflake-shaped compound with an iron atom at its center that added oxygen atoms to desired spots in druglike molecules. The catalyst could work as selectively as an enzyme. But it simply didn’t work on a lot of molecular structures or when it was next to a nitrogen atom, which are common in drug molecules.
But White’s team kept at it. In 2015, she and her colleagues devised a set of conditions that allowed the iron catalyst and a variant to add oxygen atoms to druglike molecules. And in 2019, they created a similar manganese-based catalyst that performed the oxygen-for-hydrogen swap on druglike molecules containing nitrogen and other common add-ons.
But that was just the first step. Now, White’s team reports it has come up with chemical additives that help this latest catalyst complete the “magic methyl” process. After replacing a hydrogen with an oxygen, it steals a methyl group from a reagent known as trimethylaluminum and inserts it in oxygen’s place. White’s team carried out this molecular surgery on 41 different hydrocarbons, including 16 common druglike scaffolds, the researchers report today in Nature.
The upshot, White says, is that this reagent will now make it simple and cheap for drug hunters to insert “magic methyl” groups into their molecules. “We hope a lot more drugs with the magic methyl effect will be discovered,” White says.
This could help “across the board” in drug discovery, says David Rees, chief scientific officer of Astex Pharmaceuticals. Where adding a methyl group does increase a drug’s potency, doctors may be able to give their patients less of a drug. That could improve safety and reduce side effects. Among the drugmakers he knows, Rees says, “Everyone will jump on this.”