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Accessing α-Ketoamides on DNA through a Coupling-Oxidation Strategy
Xianfu Fang1,2, Xin Wang2, Qigui Nie2,3
1Pharmaceutical Department, Chongqing University Three Gorges Hospital, Chongqing University, Chongqing 404100, China.
Organic Letters
|January 14, 2026
Summary
Researchers developed a novel on-DNA synthesis strategy to create α-ketoamides, crucial for drug discovery. This method expands DNA-encoded libraries (DELs) by enabling efficient synthesis of diverse α-ketoamide compounds.
Area of Science:
- Medicinal Chemistry
- Synthetic Chemistry
- Biotechnology
Background:
- α-Ketoamides are vital pharmacophores in drug discovery.
- Their incorporation into DNA-encoded libraries (DELs) is limited by a lack of efficient on-DNA synthetic methods.
Purpose of the Study:
- To develop a robust on-DNA synthetic strategy for α-ketoamide precursors.
- To expand the chemical diversity accessible within DNA-encoded libraries.
Main Methods:
- An on-DNA coupling-oxidation strategy was employed to synthesize DNA-conjugated α-hydroxyamides.
- Subsequent oxidation converted α-hydroxyamides into α-ketoamides.
Main Results:
- The protocol demonstrated broad substrate scope and excellent functional group tolerance, especially for mandelic acid derivatives.
- It enabled the collective transformation of α-hydroxyamide libraries into α-ketoamide libraries.
- This significantly increased the chemical space accessible for DELs.
Conclusions:
- A novel and efficient on-DNA synthetic route to α-ketoamides has been established.
- This method overcomes previous limitations, enabling broader application of DELs in drug discovery.
- The strategy facilitates the generation of diverse α-ketoamide libraries for screening.
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