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DOI: https://doi.org/10.6023/A25050155

研究通讯

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

  • Fang ,
  • Xianfu ,
  • Ju ,
  • Yunzhu ,
  • Nie ,
  • Qigui ,
  • Fan ,
  • Xiaohong ,
  • Wang ,
  • Huihong ,
  • Li ,
  • Yangfeng ,
  • Zhang ,
  • Gong ,
  • Li ,
  • Yizhou
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  • 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

收稿日期: 2025-05-11

  网络出版日期: 2025-07-03

基金资助

项目受国家自然科学基金(Nos. 22222702, 22477011, 22407019)资助.

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

  • 方贤富 ,
  • 鞠昀竹 ,
  • 聂启桂 ,
  • 范晓红 ,
  • 王辉宏 ,
  • 李杨峰 ,
  • 张功 ,
  • 李亦舟
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  • 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
† These authors contributed equally to this work.

Received date: 2025-05-11

  Online published: 2025-07-03

Supported by

National Natural Science Foundation of China (Nos. 22222702, 22477011, and 22407019).

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摘要

在DNA编码分子库(DNA-encoded library, DEL)中引入杂环优势骨架的合成方法具有重要意义. 我们报道了一种DNA兼容的合成策略, 通过四氢吡咯促进的Knoevenagel缩合反应, 实现了5-亚芳基硫代乙内酰脲衍生物的合成. 在温和的反应条件下, 该方法表现出广泛的底物适用性, 大多数底物可实现中等至优异的转化率(50%~98%). 这种DNA兼容反应可用于DEL的构建, 从而进一步拓展其可及的化学空间.

关键词： DNA编码分子库; DNA兼容化学反应; 硫代乙内酰脲; Knoevenagel缩合; 醛类

本文引用格式

Fang , Xianfu , Ju , Yunzhu , Nie , Qigui , Fan , Xiaohong , Wang , Huihong , Li , Yangfeng , Zhang , Gong , Li , Yizhou . 通过DNA兼容的Knoevenagel缩合合成5-亚芳基硫代乙内酰脲衍生物★[J]. 化学学报, 0 : 25050155 -25050155 . DOI: 10.6023/A25050155

Abstract

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 µM in water), aldehyde (2500 nmol, 500 mM in DMSO), pyrrolidine (400 nmol, 200 mM in DMSO), total reaction volume of 20 μL, organic-to-aqueous phase ratio of 1:1, reaction temperature of 60 °C, and reaction time of 1 hour. 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 chemistry; thiohydantoin; Knoevenagel condensation; aldehydes

参考文献

[1] Brenner S.; Lerner R. A.Proc. Natl. Acad. Sci. U. S. A. 1992, 89, 5381.
[2] (a) Huang, Y.; Li, Y.; Li, X.Nat. Chem. 2022, 14, 129;(b) Peterson A. A.; Liu, D. R. Nat. Rev. Drug Discovery 2023, 22, 699; (c) Wu X.; Pan J.; Fan R.; Zhang Y.; Wang C.; Wang G.; Liu J.; Cui M.; Yue J.; Jin R.; Duan Z.; Zheng M.; Mei L.; Zhou L.; Tan M.; Ai J.; Lu, X. J. Am. Chem. Soc. 2025, 147, 15469; (d) Zhang J.; Liu J.; Li X.; Ju Y.; Li Y.; Zhang G.; Li, Y. J. Am. Chem. Soc. 2024, 146,2122; (e) Jiang, L.; Liu, S.; Jia, X.; Gong, Q.; Wen, X.; Lu, W.; Yang, J.; Wu, X.; Wang, X.; Suo, Y.; Li, Y.; Uesugi, M.; Qu, Z. B.; Tan, M.; Lu, X.; Zhou, L.J. Am. Chem. Soc. 2023, 145, 25283.
[3] (a) Dockerill, M.; Winssinger, N.Angew. Chem. Int. Ed. 2023, 62, e202215542;(b) Zhao, G.; Zhong, S.; Zhang, G.; Li, Y.; Li, Y. Angew. Chem. Int. Ed. 2022, 61, e202115157.
[4] (a) Ma, P.; Zhang, S.; Huang, Q.; Gu, Y.; Zhou, Z.; Hou, W.; Yi, W.; Xu, H.Acta Pharm. Sin. B 2024, 14, 492;(b) Nie, Q.; Sun, J.; Fang, X.; He, X.; Xiong, F.; Zhang, G.; Li, Y.; Li, Y. Chin. Chem. Lett. 2023, 34, 108132.
[5] Gironda-Martinez, A.; Donckele, E. J.; Samain, F.; Neri, D.ACS Pharmacol. Transl. Sci. 2021, 4, 1265.
[6] (a) Satz, A. L.; Brunschweiger, A.; Flanagan, M. E.; Gloger, A.; Hansen, N. J. V.; Kuai, L.; Kunig, V. B. K.; Lu, X.; Madsen, D.; Marcaurelle, L. A.; Mulrooney, C.; O’Donovan, G.; Sakata, S.; Scheuermann, J.Nat. Rev. Methods Primers 2022, 2, 3;(b) Wang, Y.; Li, X.; Cai, Y.; Li, X.; Shi, B. Chem. Res. Chin. Univ. 2023, 44, 130(in Chinese). (王盈盈, 李晓敏, 蔡雅慧, 李笑宇, 史兵兵, 高等学校化学学报, 2023, 44, 138.)
[7] Lessing A.; Petrov D.; Scheuermann J.Trends Pharmacol. Sci. 2023, 44, 817.
[8] (a) Fitzgerald, P. R.; Paegel, B. M.Chem. Rev. 2021, 121, 7155;(b) Song M.; Hwang, G. T. J. Med. Chem. 2020, 63,6578; (c) Liu, Z.; Mu, B.; Duan, Z.; Wang, X.; Lu, X.Synth. Biol. J. 2024, 5, 1102 (in Chinese). (刘子健, 穆柏杨, 段志强, 王璇, 陆晓杰, 合成生物学, 2024, 5#, 1102.)
[9] Li Y.; Gabriele E.; Samain F.; Favalli N.; Sladojevich F.; Scheuermann J.; Neri D.ACS Comb. Sci. 2016, 18, 438.
[10] (a) Oprea, I.; Smith, T. K.ACS Chem. Biol. 2024, 20, 19;(b) Fang, X.; Zhang, T.; Fang, W.; Zhang, G.; Li, Y.; Li, Y. Org. Lett. 2023, 25, 8326.
[11] Huang Q.; Gu Y.; Qin A.; Ma P.; Xu H.; Zhang S.ACS Med. Chem. Lett. 2024, 15, 1591.
[12] (a) Li, X.; Zhang, J.; Liu, C.; Sun, J.; Li, Y.; Zhang, G.; Li, Y.Chem. Sci. 2022, 13, 13100;(b) Xu H.; Ma F.; Wang N.; Hou W.; Xiong H.; Lu F.; Li J.; Wang S.; Ma P.; Yang G.; Lerner, R. A. Adv. Sci. 2019, 6, 1901551; (c) Sun Z.; Zhong Y.; Chen Y.; Xiao L.; Wang J.; Zeng F.; Yang K.; Duchemin N.; Hu, Y. J. Org. Lett. 2024, 26,4082; (d) Zhang, S.; Zhang, H.; Liu, X.; Qi, P.; Tan, T.; Wang, S.; Gao, H.; Xu, H.; Zhou, Z.; Yi, W.Adv. Sci. 2024, 11, e2307049.
[13] Ye Y.; Berry M.; Bock W. J.; Cheng K.; Nair S. K.; Park C. S.; Patman R. L.; Sakata S.; Tran-Dube, M.; Donaldson, J. S.; Yang, G.; Liu, G.Org. Lett. 2024, 26, 3338.
[14] (a) Matsuo, B.; Granados, A.; Levitre, G.; Molander, G. A.Acc. Chem. Res. 2023, 56, 385;(b) Fang, X.; Wang, Y.; He, P.; Liao, H.; Zhang, G.; Li, Y.; Li, Y. Org. Lett. 2022, 24, 3291.
[15] (a) Zhang, Y.; Xue, J. Y.; Su, X. C.; Xiao, W. J.; Lv, J. Y.; Shi, W. X.; Zou, Y.; Yan, M.; Zhang, X. J.Org. Lett. 2024, 26, 2212;(b) Wang G.; Tan Y.; Zou H.; Sui X.; Wang Z.; Satz A. L.; Kuai L.; Su W.; Zhang, Q. Org. Lett. 2024, 26,1353; (c) Fu, X.; Li, Y.; He, M.; Ren, J.; Wei, Z.; Kang, Z.; Hu, W.Org. Lett. 2024, 26, 10376;(d) Wang, G.; Zhang, X.; Zhu, H.; Shi, X.; Wen, Z.; Zhang, Q.; Satz, A. L.; Su, W.; Kuai, L.; Dai, D. J. Org. Chem. 2025, 90, 5460.
[16] Zhao G.; Zhu M.; He P.; Nie Q.; Li Y.; Zhang G.; Li Y.Angew. Chem.Int. Ed. 2025, 10.1002/anie.202507064.
[17] Wen X.; Wu X.; Jin R.; Lu X.Eur. J. Med. Chem. 2023, 248, 115079.
[18] Cho S.; Kim S.-H.; Shin D.Eur. J. Med. Chem. 2019, 164, 517.
[19] Whitely C.; Winburn H.; Li Y. ChemistrySelect2024, 9, e202304688.
[20] Fang X.; Ju Y.; Wang J.; Zhang G.; Li Y.; Li Y.Org. Lett. 2024, 26, 8916.
[21] Wang Y.; Fang X.; Liao H.; Zhang G.; Li Y.; Li Y.Org. Lett. 2023, 25, 4473.
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