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Acta Chimica Sinica ›› 2025, Vol. 83 ›› Issue (10): 1119-1123.DOI: 10.6023/A25050155 Previous Articles     Next Articles

Communication

通过DNA兼容的Knoevenagel缩合合成5-亚芳基硫代乙内酰脲衍生物★

方贤富a,b,†, 鞠昀竹b,†, 聂启桂b, 范晓红a,b, 王辉宏a,b, 李杨峰b, 张功b,*(), 李亦舟b,*()   

  1. a 重庆大学 重庆大学附属三峡医院 药学部 重庆 404100
    b 重庆大学 药学院 创新药物研究中心 天然产物合成与创新药物研究重庆市重点实验室 重庆 401331
  • 投稿日期:2025-05-11 发布日期:2025-06-30
  • 通讯作者: 张功, 李亦舟
  • 作者简介:

    ★ “中国青年化学家”专辑.

  • 基金资助:
    国家自然科学基金(22222702); 国家自然科学基金(22477011); 国家自然科学基金(22407019)

Synthesis of 5-Arylidene Thiohydantoin Derivatives via DNA-Compatible Knoevenagel Condensation★

Xianfu Fanga,b, Yunzhu Jub, Qigui Nieb, Xiaohong Fana,b, Huihong Wanga,b, Yangfeng Lib, Gong Zhangb,*(), Yizhou Lib,*()   

  1. a Pharmaceutical Department, Chongqing University Three Gorges Hospital, Chongqing University, Chongqing 404100, China
    b Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, Innovative Drug Research Center, School of Pharmaceutical Sciences, Chongqing University, Chongqing 401331, China
  • Received:2025-05-11 Published:2025-06-30
  • Contact: Gong Zhang, Yizhou Li
  • About author:

    † These authors contributed equally to this work.

    ★ For the VSI “Rising Stars in Chemistry”.

  • Supported by:
    National Natural Science Foundation of China(22222702); National Natural Science Foundation of China(22477011); National Natural Science Foundation of China(22407019)

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Supporting Info.

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DNA-encoded library (DEL) technology has emerged as an important platform for drug development. It has attracted widespread attention from industry and academia due to its advantages such as short synthesis cycle, simple operation, high throughput and low cost. However, the advancement of DEL technology still faces challenges, such as the lack of DNA-compatible chemical reactions for constructing drug-like privileged scaffolds in DELs. Thiohydantoin is an important nitrogen-containing heterocycle widely present in natural products, bioactive molecules, and marketed drugs (e.g., enzalutamide and apalutamide). Among thiohydantoin compounds, the 5-arylidene thiohydantoin derivatives, which have demonstrated a wide range of biological effects, have attracted much attention. Additionally, aldehydes, as widely available building blocks, offer new synthetic approaches for expanding the chemical space of such thiohydantoin-focused DELs. Based on this, we aimed to develop a method for the efficient synthesis of 5-arylidene thiohydantoin DELs under DNA-compatible conditions. The method involves the Knoevenagel reaction between DNA-conjugated thiohydantoins and aldehydes. First, we optimized the reaction conditions and identified the optimal parameters: DNA-conjugated thiohydantoin (200 pmol, 100 µmol/L in water), aldehyde (2500 nmol, 500 mmol/L in dimethyl sulfoxide (DMSO)), pyrrolidine (400 nmol, 200 mmol/L in DMSO), total reaction volume of 20 μL, organic-to-aqueous phase volume ratio of 1∶1, reaction temperature of 60 ℃, and reaction time of 1 h. Subsequently, we evaluated the substrate scope using different aldehydes and DNA-conjugated thiohydantoins. The results demonstrated a broad substrate tolerance, with most reactions achieving moderate to excellent conversions (50%~98%). This study supports the practical construction of DELs focused on the drug-like 5-arylidene thiohydantoin scaffold and expands the accessible chemical space of DELs.

Key words: DNA-encoded library, DNA-compatible chemical reaction, thiohydantoin, Knoevenagel condensation, aldehydes