Skeletal Editing Advances: Oxygen-to-Nitrogen Swap Reprograms Natural Product Activity
核心洞察
Korean researchers used an oxygen-to-nitrogen atom swap to convert the furan group in natural products into pyrroles, dramatically altering biological activity.
The 15N-labeled limonin analog 15N-LIMO bound metabolic and mitochondrial proteins such as NNT instead of the kinases targeted by parent limonin.
Both limonin and 15N-LIMO showed antifibrotic activity through different mechanisms, with 15N-LIMO acting on mitochondrial redox systems and proving less cytotoxic.
A single-atom edit can redirect a natural product's biological function, according to researchers in Korea who swapped an oxygen atom for nitrogen in a furan ring and found that the resulting analogs engage entirely different protein targets than their parent compounds. The work, published in the Journal of the American Chemical Society (2026, DOI: 10.1021/jacs.6c14447), illustrates how skeletal-editing methods can reprogram molecules' activity without rebuilding them from scratch.
"Our question was, by changing that single atom in a very tiny portion of the compound, can we kind of change the fate of [its] biological function?" project leader Yoonsu Park of the Korea Advanced Institute of Science and Technology said in an interview with C&EN.
Atom-swapped analogs of drugs and natural products are not new, but chemists typically must backtrack many steps in a synthesis to produce them. Skeletal editing aims to give chemists tools to strategically alter molecules without such backtracking — an increasingly important goal as medicinal chemists seek to rapidly generate structurally diverse compounds.
Ammonium Chloride Enables Broader Substrate Scope
The Korean work extends chemistry Park's lab developed in 2024. The researchers updated their protocol to use ammonium chloride as the nitrogen source instead of organic amines or ammonium carbamate. The insoluble NH4Cl provides a slow release of ammonia so that it does not interfere with the photochemical oxidation step, making the reaction compatible with a broader range of molecules.
Switching the ammonia source also allowed the team to insert isotopically enriched nitrogen atoms into molecules to observe how they behave in biological systems. The researchers created a library of 15N-labeled molecules, including analogs of several commercially available natural products containing a furan group, and partnered with Ho Jeong Kwon's lab at Yonsei University to explore how the edited molecules interact with proteins.
Divergent Protein Binding and Antifibrotic Mechanisms
Using a thermal binding assay, the researchers found that 15N-LIMO, the pyrrole-bearing version of the citrus alkaloid limonin, engages with a very different set of proteins than its parent compound. Limonin prefers binding to kinases, while 15N-LIMO targets metabolic and mitochondrial proteins such as nicotinamide nucleotide transhydrogenase (搜索) (NNT).
"Just by changing a minimal portion of the whole molecule, we could change the binding affinity," Park said.
Further cell studies showed that both limonin and 15N-LIMO have antifibrotic activity, but via completely different mechanisms. Limonin inhibits a signaling pathway, while 15N-LIMO acts on mitochondrial redox systems to reduce reactive oxygen species. 15N-LIMO is also less cytotoxic than limonin.
A "Concrete Step" Toward Applications
"This is a very nice application of skeletal editing in a complex setting," said Mingji Dai, an organic chemist at Emory University who was not involved in the work. Skeletal editing is getting a lot of attention in the synthesis community, but "we really need to see some major applications," Dai said, adding that the paper represents a concrete step toward those applications. That the reaction works so well on molecules with such a high density of sensitive functional groups is "remarkable," he added.
Park cautioned that much more work would be needed to translate the findings to drug discovery, but said the study serves as proof of concept for how skeletal editing can reprogram molecules' activity. It also illustrates why synthetic chemists should collaborate more with chemical biologists. Park and his team plan to take their natural product alterations further by using multiple editing methods in sequence. "The value here is that we have an easy way to diversify preexisting libraries," he said.
A Complementary Approach: Chlorine-Guided Carbonyl Deletion
A separate team has reported a different skeletal-editing strategy that operates under unusually mild conditions. Researchers at Ritsumeikan University, led by Professor Toshifumi Dohi with Mr. Yusuke Yoto of Ritsumeikan University and Dr. Hideyasu China of Doshisha Women's College of Liberal Arts (搜索), developed a halogen-guided method for transforming accessible hydroxycoumarins into coumaranones, valuable heterocyclic structures in medicinal chemistry. Their study was made available online in JACS Au on July 26, 2026.
The approach deletes a carbonyl group through simultaneous C–C and C–O bond cleavage at room temperature without the need for transition metals. The team drew inspiration from halogenation-driven bond cleavage in natural product biosynthesis and from a "cut-to-fuse" concept, in which halogenation first "cuts" bonds in a cyclic compound to generate a reactive chain, before a subsequent intramolecular reaction "fuses" the chain into a new heterocyclic structure.
"We aimed to develop a new way of editing molecular skeletons for esters, one that could break difficult bonds under mild conditions and immediately reconstruct the molecule into a useful framework," Dohi said.
The initial experiments produced an unexpected result. The team had been investigating fluorine-induced carbon–carbon bond cleavage, but fluorination caused the hydroxycoumarin (搜索) to fragment into separate products. "Chlorine changed the reaction pathway completely," Dohi said. Treating a hydroxycoumarin with N-chlorosuccinimide (搜索) (NCS) led to formation of a chlorinated intermediate that underwent decarbonylative reconstruction, ultimately producing a coumaranone (搜索) rather than fragmenting the molecule.
Under optimized conditions — hydroxycoumarin (搜索) treated with NCS, water, and sodium acetate in ethyl acetate, followed by potassium phosphate — the method produced the model coumaranone (搜索) in more than 99% yield. According to the researchers, this represents the mildest nonenzymatic conditions reported to date for simultaneous cleavage of the C–C and C–O bonds involved in this type of carbonyl deletion.
The reaction proved broadly applicable. Hydroxycoumarins containing methoxy, halogen, azide, phenol, carboxylic acid, and boron-containing functionalities were tolerated, as were substrates bearing substituted aromatic rings, naphthalene, pyridine, thiophene, furan, and aliphatic groups. Several products were obtained in good to excellent yields. A related cyclic β-keto ester also underwent reconstruction, showing that the chemistry is not limited to a single substrate class.
Mechanistic experiments highlighted the importance of selective chlorination: when the chlorinating reagent was omitted, the starting material was recovered unchanged, and stepwise experiments showed that chlorination occurred first, followed by decarboxylation and intramolecular cyclization. On a gram scale, the model reaction produced the desired coumaranone (搜索) in 91% yield. The resulting scaffold could be further modified, including conversion to a benzofuran, introduction of a quaternary carbon center, and transition-metal-catalyzed coupling reactions; a coumaranone bearing a boron pinacol ester was directly applicable for palladium-catalyzed coupling without isolation.
Together, the two studies reflect a broader push in synthetic chemistry to edit molecular scaffolds rather than rebuild them, with the goal of streamlining access to structurally diverse compounds for medicinal chemistry.