When a person consumes a pharmaceutical drug, liver enzymes break down the substance into water-soluble metabolites, so that the body can get rid of it more easily. In some cases, the resulting metabolites can have powerful effects that can be good or bad.
Medicinal chemists have to test drug candidates for these potential side effects, and the only way is with large quantities of metabolites that they create “from scratch” in a long sequence of chemical reactions, which requires a lot of time, labor, and materials.
Now, a research team, at the University of Illinois Urbana-Champaign led by M. Christina White, William H. and Janet G. Lycan Professor of Chemistry, and graduate students Rachel Chambers and Jake Weaver and visiting scholars Jinho Kim, has collaborated with Merck & Co scientists to develop a fast and efficient method to produce many metabolites directly from a drug or drug precursor through carbon-hydrogen oxidation catalysis.
The critical component of the method is the White-Gormisky-Zhao catalyst [Mn(CF3-PDP)] which mimics the natural function of the CYP450 liver enzyme to oxidize drugs and break them down into metabolites.
Their study, “A preparative small-molecule mimic of liver CYP450 enzymes in aliphatic CH oxidation of carbocyclic N-heterocycles,” was published in PNAS and details the catalyst’s ability to oxidize drugs and drug-like molecules such as CYP450 enzymes in the liver, yielding metabolites on a large scale in just one to two steps from drug or drug precursor.
In the study, researchers demonstrated this process on large scales with pharmaceutical compounds such as the antipsychotic blonanserin, COX-2 inhibitors, and the fungicide penconazole.
White said the White-Gormisky-Zhao catalyst is like a “P450 mimic in a bottle.”
Chambers said this work has important implications for the study of metabolism, because carbon-hydrogen oxidation is one of the key steps the human body takes when it eliminates drugs in the metabolic process.
“Understanding and being able to mimic these processes with chemical reactions can lead to the development of new drugs or modification of existing ones to improve their effectiveness and reduce side effects,” said Chambers.
The researchers say that the key to this discovery is to greatly expand the ability of their catalyst to introduce oxygen to a wide range of heterocycle-containing molecules, which are very common structures in synthetics. human drugs. Nitrogen containing heterocycles are present in 59% of FDA approved pharmaceuticals, according to the study.
The researchers report that their catalyst works in the presence of 25 nitrogen heterocycles, including 14 of the 27 most frequent N-heterocycles in man-made drugs. The researchers said that the expansion of the scope was guided and quantitatively evaluated by chemoinformatics analysis that supports their catalyst’s potential for significantly expanding the pharmaceutical chemical space now available in small molecule carbon-hydrogen oxidation catalysis.
Weaver said prior to this work, the oxidation of CH bonds in the presence of many types of nitrogen heterocycles had rarely been demonstrated.
“Because of this, many types of pharmaceuticals are considered ‘untouchable’ for the CH oxidation reaction. Our reaction opens the door for many new types of nitrogen-containing drugs compatible with the oxidation of CH,” Weaver said.
An emerging trend in small molecule pharmaceuticals often composed of N-heterocycles is the incorporation of aliphatic fragments that improve their potency and solubility. But this makes it more challenging to study metabolite effects. The reason, said White, is that the production of drug metabolites where oxidation occurs in aliphatic fragments is difficult due to the tendency of most reactions to oxidize the nitrogen heterocycle.
In general, Weaver explained, nitrogen-containing molecules have less tolerance for CH oxidation catalysts. To address that problem, the team used their catalyst together with an HBF4 protonation strategy that deactivates nitrogen from being oxidized while allowing the desired distant aliphatic carbon-hydrogen oxidation to occur.
White said the strategy showed no selectivity for oxidizing the aliphatic fragments of the drugs while leaving the nitrogen heterocycles untouched.
Rachel K. Chambers et al, A preparative small molecule mimic of liver CYP450 enzymes in aliphatic CH oxidation of carbocyclic N-heterocycles, Proceedings of the National Academy of Sciences (2023). DOI: 10.1073/pnas.2300315120
Awarded by the University of Illinois at Urbana-Champaign
Citation: Catalyst’s ability to mimic liver enzyme could expand scope of drug discovery (2023, July 13) retrieved 13 July 2023 from https://phys.org/news/2023-07-catalyst- ability-mimic-liver-enzyme.html
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