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Author Spotlight: In Silico Creation and Impact of Carbonylated Amino Acids on Protein Structure and Function
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Carbonyl-to-Sulfur Skeletal Editing: A Transformative Strategy for Drug Scaffold Diversification
1State Key Laboratory of Chemical Biology, Research Center of Chemical Kinomics, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai, 200032, China.
Current Medicinal Chemistry
|April 2, 2026
Summary
A new two-step method converts carbonyl compounds to sulfur-bearing analogs using mild radical conditions. This breakthrough offers a practical approach for drug discovery and development, overcoming limitations of older thiolation techniques.
Area of Science:
- Medicinal Chemistry
- Organic Synthesis
- Drug Discovery
Background:
- Sulfur-containing motifs are crucial in ~25% of FDA-approved drugs.
- Existing methods for carbonyl-to-sulfur conversion are often toxic, multi-step, or have limited compatibility.
Purpose of the Study:
- To dissect the mechanism of a novel two-step Carbonyl- to-Sulfur (CO-to-S) skeletal transformation.
- To highlight the utility of this method in late-stage drug derivatization and scaffold diversification.
Main Methods:
- Utilized a two-step sequence involving Nitrogen-Assisted Homolytic Activation (NAHA) reagent and Tosyl Disulfide (Ts-S-Ts) mediator.
- Employed mild radical conditions for C-C bond cleavage and sulfur incorporation.
Main Results:
- Established a concise and practical CO-to-S skeletal transformation.
- Demonstrated potential for late-stage derivatization, scaffold diversification, and metabolic profile optimization.
Conclusions:
- The NAHA and Ts-S-Ts mediated CO-to-S transformation represents a significant advancement in sulfur-centered chemistry.
- Future directions include developing enantioselective variants and exploring bioconjugation applications.
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