CM – An important addition to a chemist’s toolkit for building new molecules

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June 25, 2021

by The Scripps Research Institute

Chemists at Scripps Research have solved a long-standing problem in their field by developing a method to perform a very useful and previously very difficult way of modifying organic molecules. The breakthrough facilitates the process of modifying a wide variety of existing molecules for valuable applications such as: B. improving the effectiveness and duration of drugs.

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The flexible new process for « directed C-H hydroxylation with molecular oxygen » does what previously only natural enzymes can do. It will be described in an article in Science this week.

« We expect this method to be widely used to build potential new drug molecules and to modify and even reuse existing drugs, » says research director Jin-Quan Yu, Ph .D., Bristol Myers Squibb Chair in Chemistry at Scripps Research. Yu is also Frank and Bertha Hupp Professor of Chemistry.

Most pharmaceuticals and countless other chemical products are small organic molecules based on backbone rings of carbon atoms. Sometimes the backbone ring contains a non-carbon atom such as nitrogen instead of carbon, in which case it is referred to as a heterocycle.

Chemists have made tremendous strides over the past century in finding ways to build such molecules through stepwise chemical reactions – a process they call organic synthesis. However, some highly desirable assembly steps have remained difficult or impossible with synthetic methods.

One of them is the replacement of a hydrogen atom, which adorns the carbons of the backbone by default, with a pairing of an oxygen and hydrogen atom called a hydroxyl. Chemists want to be able to make such a replacement anywhere on a carbon ring, using ordinary O2 as the source of oxygen atoms. However, it is very difficult to take an oxygen atom from O2, especially when modifying heterocyclic compounds. Although highly specialized and dedicated enzymes in animal cells known as cytochrome P450 enzymes have been developed to catalyze this type of reaction, no chemist with the more flexible tools of organic synthesis has yet succeeded.

Yu and his team , which included co-first authors Zhen Li and Zhen Wang, found a way to do this using an unusual reactive « catalyst ». The catalyst contains an atom of the noble metal palladium, which is widely used in organic synthesis because it can break the bonds that bind hydrogen atoms to the carbon backbone of organic molecules.

But the main component of the catalyst is a small organic molecule called pyridone which acts as a kind of handle – a « ligand » – on the palladium. This ligand essentially enables the palladium-driven removal of hydrogen and attachment of hydroxyls in a more flexible way than ever by changing its own identity – shape shifting between pyridone and a closely related molecule called pyridine. Chemists call such pairs of interconverting molecules « tautomers ».

Yu and colleagues demonstrated the simplicity and value of the new method by modifying a variety of existing drugs, including the antihypertensive telmisartan, the gout drug probenecid, and the anti-inflammatory meclofenamic acid .

« With this catalyst and its tautomeric ligand, we can bypass many of the traditional restrictions on where hydroxylation can occur when building new molecules or when modifying existing molecules, » says Yu.

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Keywords:

Chemistry,Molecule,Atom,Scripps Research,Chemistry, Molecule, Atom, Scripps Research,,

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