白桦脂酸-三氮唑杂化物作为新型PTP1B抑制剂的合成与生物活性评价

doi:10.6023/cjoc202604010

摘要/Abstract

蛋白酪氨酸磷酸酶1B（PTP1B）是胰岛素和瘦素信号通路的关键负调控因子,已成为2型糖尿病（T2DM）的潜在治疗靶点。抑制PTP1B可增强胰岛素敏感性,为管理糖尿病和肥胖提供了一种潜在的策略。在这项研究中,35个白桦脂酸-三氮唑杂化物被合成,并评估了他们的PTP1B抑制活性。所合成的BA杂化物均表现出明显高于母体BA的PTP1B抑制活性。值得注意的是, BAT28表现出最强的活性,其IC₅₀值为1.06±0.06 μM。动力学分析表明,BAT28是一种混合型PTP1B抑制剂。CD光谱表明,BAT28与PTP1B结合并诱导酶的构象变化。分子对接研究进一步证实,BAT28与PTP1B的活性位点相互作用。使用口服葡萄糖耐量试验（OGTT）的体内实验表明,BAT28有效地降低了小鼠的餐后血糖水平。此外,ADME结果显示BAT28类药性良好。这些发现表明,BAT28可作为有前景的先导化合物,用于新型PTP1B抑制剂的开发。

关键词: 白桦脂酸, 三氮唑, PTP1B抑制

Protein tyrosine phosphatase 1B (PTP1B) is a key negative regulator of insulin and leptin signaling pathways and has emerged as a promising therapeutic target for the treatment of type 2 diabetes mellitus (T2DM). Inhibition of PTP1B enhances insulin sensitivity and offers a potential strategy for managing both diabetes and obesity. In this study, 35 betulinic acid (BA)-triazole hybrids (BAT1-BAT35) were synthesized and evaluated for their PTP1B inhibitory activities. All synthesized BA hybrids exhibited significantly higher PTP1B inhibitory activity than parent compound BA. Notably, BAT28 demonstrated the most potent activity, with an IC₅₀ value of 1.06 ± 0.06 μM. Kinetic analysis revealed that BAT28 acted as a mixed-type PTP1B inhibitor. CD spectra indicated that BAT28 bound to PTP1B and induced conformation changes in the enzyme. Molecular docking studies further confirmed that BAT28 interacted with the active site of PTP1B. In vivo experiments using an oral glucose tolerance test (OGTT) showed that BAT28 effectively reduced postprandial blood glucose levels in mice. Additionally, BAT28 exhibited favorable drug-like properties based on in silico predictions. These findings suggested that BAT28 represented a promising lead compound for the development of novel PTP1B inhibitors.

Key words: Betulinic acid, Triazole, PBP1B inhibitor

引用此文

张玉飞, 谭丽容, 钟月圆, 刘同征, 王少华. 白桦脂酸-三氮唑杂化物作为新型PTP1B抑制剂的合成与生物活性评价[J]. 有机化学, doi: 10.6023/cjoc202604010.

Yufei Zhang, Lirong Tan, Yueyuan Zhong, Tongzheng Liu, Shao-Hua Wang. Betulinic Acid-triazole Hybrids as Novel PTP1B Inhibitors: Synthesis and Bioactivity Evaluation[J]. Chinese Journal of Organic Chemistry, doi: 10.6023/cjoc202604010.

导出引用 EndNote|Reference Manager|ProCite|BibTeX|RefWorks

分享此文

参考文献

[1] (a) ElSayed, N.; Aleppo, G.; Aroda, V.; Bannuru, R.; Brown, F.; Bruemmer, D.; Collins, B.; Hilliard, M.; Isaacs, D.; Johnson, E.; Kahan, S.; Khunti, K.; Leon, J.; Lyons, S. K.; Perry, M.; Prahalad, P.; Pratley, R.; Seley, J.; Stanton, R.; Gabbay, R. Diabetes Care 2023, 46, S19-S40.
(b) Eleftheriou, P.; Geronikaki, A.; Petrou, A. Curr. Top.Med. Chem. 2019, 19, 246-263.
(c) Sun, J.; Xiao, D.; Lang, M.; Xu, X. Mol. Divers. 2025, 29, 1669-1681.
(d) Hu, C.; Liang, B.; Sun, J.; Li, J.; Xiong, Z.; Wang, S.; Xu, X. Eur. J. Med. Chem. 2024, 264, 115957.
[2] (a) Zhou, Y.; Liu, L.; Xiang, R.; Bu, X.; Qin, G.; Dai, J.; Zhao, Z.; Fang, X.; Yang, S.; Han, J.; Wang, G. Int. Immunopharmacol. 2023, 114, 109529.
(b) Kou, X.; Li, H.; Xu, X. Int. J. Biol. Macromol. 2025, 333, 148794.
(c) Li, M.; Sun, J.; Liang, B.; Min, X.; Hu, J.; Wu, R.; Xu, X. Bioorg. Chem. 2024, 144, 107177.
(d) Qian, S.; Zhang, M.; He, Y.; Wang, W.; Liu, S. Future Med. Chem. 2016, 8, 1239-1258.
[3] (a) Cole, J.; Florez, J. Nat. Rev. Nephrol. 2020, 16, 377-390.
(b) Min, X.; Guo, S.; Lu, Y.; Xu, X. J. Lumin. 2024, 269, 120437.
(c) Liang, B.; Xiao, D.; Wang, S.; Xu, X. Eur. J. Med. Chem. 2024, 275, 116595.
[4] (a) Byon, J.; Kusari, A.; Kusari, J. Mol. Cell. Biochem. 1998, 182, 101-108.
(b) Kenner, K.; Anyanwu, E.; Olefsky, J.; Kusari, J. J. Biol. Chem. 1996, 271, 19810-19816.
(c) Sharma, B.; Xie, L.; Yang, F.; Wang, W.; Zhou, Q.; Xiang, M.; Zhou, S.; Lv, W.; Jia, Y.; Pokhrel, L.; Shen, J.; Xiao, Q.; Gao, L. Eur. J. Med. Chem. 2020, 199, 112373.
[5] (a) Hussain, H.; Green, I. R.; Abbas, G.; Adekenov, S. M.; Hussain, W.; Ali, I. Expert Opin. Ther. Pat. 2019, 29, 689-702.
(b) Rath, P.; Ranjan, A.; Chauhan, A.; Verma, N. K.; Bhargava, A.; Prasad, R.; Jindal, T. Appl. Biochem. Biotechnol. 2022, 194, 4683-4710.
(c) Agrawal, N.; Dhakrey, P.; Pathak, S. Chem. Biol. Drug Des. 2023, 102, 921-938.
[6] (a) Lu, Y.; Xu, L.; Cong, Y.; Song, G.; Han, J.; Wang, G.; Zhang, P.; Chen, K. Carbohyd. Polym. 2019, 205, 63-71.
(b) Xu, C.; Shi, X.; Sun, H.; Yu, L.; Zhang, L.; Lan, D.; Wu, X.; Chen, M.; Cheng, N.; Pan, Y.; He, J.; Yin, R.; Zhou, L.; Gao, N.; Zhao, J. Carbohyd. Polym. 2025, 355, 123351.
(c) Cao, W.; Wu, J.; Zhao, X.; Li, Z.; Yu, J.; Shao, T.; Hou, X.; Zhou, L.; Wang, C.; Wang, G.; Han, J. Carbohyd. Polym. 2023, 325, 121565.
(d) Xu, L.; Lu, Y.; Cong, Y.; Zhang, P.; Han, J.; Song, G.; Wang, G.; Chen, K. Carbohyd. Polym. 2019, 206, 811-819.
(e) Wei, Z.; Chen, G.; Zhang, P.; Zhu, L.; Zhang, L.; Chen, K. Carbohyd. Polym. 2018, 198, 302-312.
[7] (a) Li, J.; Shen, B.; Nie, S.; Duan, Z.; Chen, K. Carbohyd. Polym. 2019, 206, 163-173.
(b) Wang, C.; Wang, R.; Chen, Y.; Wang, L.; Zhou, S.; Wang, H. Bioorg. Med. Chem. Lett. 2019, 29, 1282-1290.
(c) Zhou, J.; Yu, L.; Fan, Y.; Guo, C.; Lv, X.; Zhou, Z.; Huang, H.; Miao, D.; Zhang, S.; Li, X.; Zhao, P.; Liu, X.; Hu, W.; Zhang, C. Eur. J. Med. Chem. 2022, 245, 114860.
(d) He, L.; Zhu, Y.; Fan, Q.; Miao, D.; Zhang, S.; Liu, X.; Zhang, C. Bioorg. Med. Chem. Lett. 2019, 29, 549-555.
(e) Qin, L.; Cheng, X.; Wang, S.; Gong, G.; Su, H.; Huang, H.; Chen, T.; Damdinjav, D.; Dorjsuren, B.; Li, Z.; Qiu, Z.; Bian, J. J. Med. Chem. 2024, 67, 988-1007.
[8] (a) Paduch, R.; Kandefer-Szerszeń, M.; Trytek, M.; Fiedurek, J. Arch. Immunol. Ther. Exp. 2007, 55, 315-327.
(b) Sánchez-Quesada, C.; López-Biedma, A.; Warleta, F.; Campos, M.; Beltrán, G.; Gaforio, J. J. Agric. Food. Chem. 2013, 61, 12173-12182.
(c) Choi, Y.; Park, S.; Kim, J.; Won, K.; Kim, B.; Son, J.; Lee, S.; Kim, Y. J. Med. Food 2013, 16, 2-8.
(d) Hung, N. Vietnam Journal of Science and Technology 2018, 56, 69-69.
[9] (a) Wahab, H.; Dianita, R.; Rathnasamy, S.; Hsing, H.; Biomed. Res. Ther. 2020, 7, 3579-3592.
(b) Diaz-Rojas, M.; Gonzalez-Andrade, M.; Aguayo-Ortiz, R.; Rodriguez-Sotres, R.; Perez-Vasquez, A.; Madariaga-Mazon, A.; Mata, R. Front. Pharmacol. 2023, 14, 1281045.
[10] (a) Huang, J.; Su, J.; Wang, H.; Chen, J.; Tian, Y.; Zhang, J.; Feng, T.; Di, L.; Lu, X.; Sheng, H.; Zhu, Q.; Chen, X.; Wang, J.; He, X.; Yerkinkazhina, Y.; Xie, Z.; Shu, Y.; Kang, T.; Tang, H.; Qian, J.; Zhu, W. J. Med. Chem. 2024, 67, 17319-17349.
(b) Liu, D.; Yu, B.; Guan, X.; Song, B.; Pan, H.; Wang, R.; Feng, X.; Pan, L.; Huang, H.; Wang, Z.; Wu, H.; Qiu, Z.; Li, Z.; Bian, J. Chem. Sci. 2023, 14, 4174-4182.
(c) Qiu, X.; Li, Y.; Yu, B.; Ren, J.; Huang, H.; Wang, M.; Ding, H.; Li, Z.; Wang, J.; Bian, J. Eur. J. Med. Chem. 2021, 211, 113091.
(d) Ye, W.; Fan, C.; Fu, K.; Wang, X.; Lin, J.; Nian, S.; Liu, C.; Zhou, W. Eur. J. Med. Chem. 2022, 244, 114846.
(e) Xu, X.; Wang, J.; Wang, M.; Yuan, X.; Li, L.; Zhang, C.; Huang, H.; Jing, T.; Wang, C.; Tong, C.; Zhou, L.; Meng, Y.; Xu, P.; Kou, J.; Qiu, Z.; Li, Z.; Bian, J. J. Med. Chem. 2021, 64, 4588-4611.
[11] Kumar, S.; Misra,S.; Kashaw, S.; Kashaw, V.; Kumar, A. Talanta 2026, 305, 129543.
[12] Fermo, A.; Bisi, A.; Orioli, R.; Gobbi, S.; Belluti, F. Molecules 2026, 31, 355.
[13] (a) Liu, Z.; Bai, X.; Sheng, L.; Sun, L.; Li, J.; Zhang, T. Chem. Nat. Compd. 2023, 59, 508-511.
(b) Song, Z.; He, X.; Li, C.; Gao, L.; Wang, Z.; Tang, Y.; Xie, J.; Li, J.; Chen, G. Carbohyd. Res. 2011, 346, 140-145.
[14] (a) Zheng, P.; Xiong, Z.; Liao, C.; Zhang, X.; Feng, M.; Wu, X.; Lin, J.; Lei, L.; Zhang, Y.; Wang, S.; Xu, X. J. Enzym. Inhib. Med. Ch. 2021, 36, 1938-1951.
(b) Lin, J.; Xiao, D.; Lu, L.; Liang, B.; Xiong, Z.; Xu, X. J. Mol. Struct. 2023, 1283, 135279.
[15] (a) Zhang, X.; Zheng, Y.; Hu, C.; Wu, X.; Lin, J.; Xiong, Z.; Zhang, K.; Xu, X. Arab. J. Chem. 2022, 15, 104072.
(b) Wu, X.; Zhu, W.; Lu, L.; Hu, C.; Zheng, Y.; Zhang, X.; Lin, J.; Wu, J.; Xiong, Z.; Zhang, K.; Xu, X. Arab. J. Chem. 2023, 16, 104659.
[16] Zhang, Y.; Yu, X.; Li, J.; Liang, B.; Sun, J.; Min, X.; Xiong, Z.; Chen, W.; Xu, X. J. Mol. Struct. 2024, 1315, 138889.
[17] (a) Welte, S.; Baringhaus, K.; Schmider, W.; Müller, G.; Petry, S.; Tennagels, N. Anal. Biochem. 2005, 338, 32-38.
(b) Li, M.; Li, H.; Min, X.; Sun, J.; Liang, B.; Xu, L.; Li, J.; Wang, S.; Xu, X. J. Med. Chem. 2024, 67, 8406-8419.
(c) Zheng, Y.; Lu, L.; Li, M.; Xu, D.; Zhang, L.; Xiong, Z.; Zhou, Y.; Li, J.; Xu, X.; Zhang, K.; Xu, L. Bioorg. Chem. 2024, 143, 106985.
[18] (a) Wu, S.; Tang, J.; Zhou, Y.; Xu, X.; Zhang, H.; Wang, S. Chin. J. Org. Chem. 2024, 44, 613-621.
(b) Wen Y.; Yu Q.; Yang F.; Li J.; Lang M.; Yan J.; Xu X. Mol. Divers.2025.https://doi.org/10.1007/s11030-026-11487-5.
(c) Wu, Q.; Fang, W.; Liu, H.; Liu, Z.; Xu, X. Front. Pharmacol. 2024, 15, 1451452.
[19] (a) Feng, M.; Liang, B.; Sun, J.; Min, X.; Wang, S.; Lu, Y.; Xu, X. J. Mol. Struct. 2024, 1310, 138311.
(b) Liang, B.; Li, J.; Wu, S.; Kou, X.; Liu, T.; Xu, X. J. Mol. Struct. 2025, 1322, 140481.
(c) Zhou, H.; Wen, Y.; Wang, S.; Liu, Y.; Li, B.; Xu, X. Mol. Divers. 2025. DOI: 10.1007/s11030-025-11369-2.
[20] (a) Zhu, P.; Yang, Y.; Qian, J.; Han, J.; Kong, D.; Sun, B.; Zhang, J.; Wei, J.; Guo, Q.; Nian, S.; Zhou, L.; Wang, G.; Hou, S. J. Mol. Struct. 2025, 1321, 140125.
(b) Yang, X.; Huang, Z.; Ding, K.; Yang, H.; Wang, L.; Xia, Q.; Hu, R.; Shi, G.; Xu, B.; Qin, A. Sci. China Chem. 2025, 68, 1426-1433.
(c) Wei, W.; Xu, Q.; Wu, L.; Gong, G.; Tian, Y.; Huang, H.; Li, Z. Eur. J. Med. Chem. 2024, 270, 116333.
(d) Peng, J.; Liu, T.; Guan, L.; Xu, Z.; Xiong, T.; Zhang, Y.; Song, J.; Liu, X.; Yang, Y.; Hao, X. Talanta 2024, 273, 125938.
(e) Fan, Y.; Zhang, Y.; Zhang, G.; Ma, L.; Lv, Y.; Li, J.; Luan, Y.; Zhang, Y.; Chen, Y.; Ren, H.; Liu, W.; Li, M.; Wu, Y.; Chen, S.; Han, B.; Tang, Q.; Chen, L. Wesselius, A.; Su, W.; Zeegers, M.; Gu, Y.; Qin, Q.; Hao, H.; Xia, J.; Zhang, H.; Yu, E. Anal. Chem. 2025, 97, 12345-12355.
[21] (a) Su, L.; Zhu, X.; Ding, H.; Hu, L.; Chen, J.; Qi, S.; Luo, K.; Ling, W.; Tian, X. Sensor. Actuat. B-Chem. 2024, 412, 135792.
(b) Guo L.; Dai H.; Ma J.; Wang J.; Hua Y.; Zhou L. BMC Chem.2021, 15. https://doi.org/10.1186/s13065-021-00741-6.
(c) Ding, H.; Luo, L.; Su, L.; Chen, J.; Li, Y.; Hu, L.; Luo, K.; Tian, X. Biosens. Bioelectron. 2023, 247, 115939.
(d) Chang, X.; Gao, P.; Li, Q.; Liu, H.; Hou, H.; Wu, S.; Chen, J.; Gan, L.; Zhao, M.; Zhang, D.; Sun, S.; Wang, B. Sensor. Actuat. B-Chem. 2021, 345, 130363.
(e) Zeng, Y.; Liu, F.; Wang, J.; Shao, B.; He, T.; Xiang, Z.; Wang, Y.; Zhu, S.; Yang, T.; Yu, S.; Gong, C.; Liu, L. Chin. Chem. Lett. 2025, 36, 109734.