Citation: Shiqi Xu, Zi Ye, Shuang Shang, Fengge Wang, Huan Zhang, Lianguo Chen, Hao Lin, Chen Chen, Fang Hua, Chong-Jing Zhang. Pairs of thiol-substituted 1,2,4-triazole-based isomeric covalent inhibitors with tunable reactivity and selectivity[J]. Chinese Chemical Letters, ;2024, 35(7): 109034. doi: 10.1016/j.cclet.2023.109034 shu

Pairs of thiol-substituted 1,2,4-triazole-based isomeric covalent inhibitors with tunable reactivity and selectivity

Shiqi Xu ^{a, 1} ,
Zi Ye ^{a, 1} ,
Shuang Shang ^{b, 1} ,
Fengge Wang ^a ,
Huan Zhang ^b ,
Lianguo Chen ^c ,
Hao Lin ^a ,
Chen Chen ^a ,
Fang Hua ^{b, *,} ,
Chong-Jing Zhang ^{a, *,}

a.
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
b.
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study (BZ0150), Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, China
c.
The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China

huafang@imm.ac.cn

zhangchongjing@imm.ac.cn

Received Date: 18 July 2023
Revised Date: 28 August 2023
Accepted Date: 31 August 2023
Available Online: 3 September 2023

Figures(6)

Covalent bioactive compounds are successfully used in clinic and attracted intense research efforts in the fundamental study as well as drug development. The advantageous effects of covalent compounds compared with non-covalent ones are highly dependent on electrophilic warheads. Hence, electrophilic warheads with tunable reactivity and selectivity are highly demanded in fields of medicinal chemistry and chemical biology. Herein, we report a novel electrophilic warhead, chloromethyl group activated by thiol-substituted 1,2,4-triazole. Interestingly, a pair of regioisomers could be simultaneously occurred in the step of alkylation during the synthesis of this unique motif. This is a rare example that the alkylation could simultaneously generate these two separable regioisomers of 1,2,4-triazole at the nitrogen or sulfur atom. The covalent-working mechanism of this new warhead is confirmed by various chemoproteomics experiments including target identification and binding site mapping. Importantly, the reactivity and selectivity of this new electrophilic warhead could be efficiently tuned by virtue of stereo effect. Interestingly, one pair of regioisomers (19S and 19X) induced distinct modes of cell death. Isomer 19S could induce apoptosis of colon cancer cells while 19X could induce both apoptosis and ferroptosis. Together, this study provides pairs of novel electrophilic warheads that could be useful not only in supporting the design of covalent compounds for drug discovery but also in providing chemical probes for the fundamental biological study.
- Electrophilic warhead,
- Covalent inhibitor,
- 1,2,4-Triazole,
- Chemical proteomics,
- GSTO1
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