Design, synthesis and biological evaluation of buthutin derivatives as cardioprotective agents

doi:10.1007/s13659-025-00497-9

应用天然产物 ›› 2025, Vol. 15 ›› Issue (2): 14-14.DOI: 10.1007/s13659-025-00497-9

Design, synthesis and biological evaluation of buthutin derivatives as cardioprotective agents

Yuan Liu¹, Fa-Qi Wang¹, Xin-Hao Hua¹, Shu-Han Yang¹, Li-Ning Wang², Yun-Sheng Xu¹, Chen-Yue Shao¹, Xiang-Bo Gou¹, Yu-Ming Liu¹

1. Department of Pharmacy Engineering, Tianjin University of Technology, Tianjin, 300384, People's Republic of China;
2. College of Traditional Chinese Medicine, Tianjin Univerisity of Traditional Chinese Medicine, Tianjin, 300193, People's Republic of China

收稿日期:2024-10-15 接受日期:2025-01-13 出版日期:2025-04-25 发布日期:2025-05-17
通讯作者: Xiang-Bo Gou, E-mail:gouxiangbo@163.com;Yu-Ming Liu, E-mail:coumarin1968@hotmail.com
基金资助:
This work was financially supported by the National Natural Science Foundation of China (NSFC) Youth Project (No. 82204397).

Design, synthesis and biological evaluation of buthutin derivatives as cardioprotective agents

Yuan Liu¹, Fa-Qi Wang¹, Xin-Hao Hua¹, Shu-Han Yang¹, Li-Ning Wang², Yun-Sheng Xu¹, Chen-Yue Shao¹, Xiang-Bo Gou¹, Yu-Ming Liu¹

1. Department of Pharmacy Engineering, Tianjin University of Technology, Tianjin, 300384, People's Republic of China;
2. College of Traditional Chinese Medicine, Tianjin Univerisity of Traditional Chinese Medicine, Tianjin, 300193, People's Republic of China

Received:2024-10-15 Accepted:2025-01-13 Online:2025-04-25 Published:2025-05-17
Contact: Xiang-Bo Gou, E-mail:gouxiangbo@163.com;Yu-Ming Liu, E-mail:coumarin1968@hotmail.com
Supported by:
This work was financially supported by the National Natural Science Foundation of China (NSFC) Youth Project (No. 82204397).

摘要/Abstract

摘要： Natural products are the important sources in cardiovascular drug development. In this study, twenty-nine buthutin derivatives were designed, synthesized, and evaluated for their NHE-1 inhibition and protective effects on cardiomyocyte injury. The structure of the newly synthesized compounds had been confirmed by ¹H-NMR, ¹³C-NMR, and HR-ESI-MS spectra. Among all target compounds at 1 μM, compounds 9d, 9f, 9k, 9m, and 9n, with a protection ratio exceeding 30%, exerted stronger protective effects on H9c2 cardiomyocyte than positive control dexrazoxane and buthutin A. Meanwhile, compounds 9k, 9m, and 9o showed the significant NHE-1 inhibitory activities on H9c2 cardiomyocyte, all with a dpHi/min value less than 0.23. What is more, compounds 9k, 9m, 9o and buthutin A all exhibited the specificity on NHE-1 inhibition. Molecular modelling studies suggested the ability of compounds 9m and 9o to establish interactions with three hydrogen bonds to Asp267 and Glu346 of NHE-1, but also the ability with much lower CDOCKER energies than positive control cariporide and buthutin A. The structure-activity relationship (SAR) studies suggested that the presences of amide group, four-carbon linker, and para hydroxyl benzene ring were advantageous pharmacophores for above two pharmacological actions. This research would open new avenues for developing amide-guanidine-based cardioprotective agents.

关键词: Buthus martensii, Amide-guanidine derivatives, Cardioprotective agents, NHE-1

Abstract: Natural products are the important sources in cardiovascular drug development. In this study, twenty-nine buthutin derivatives were designed, synthesized, and evaluated for their NHE-1 inhibition and protective effects on cardiomyocyte injury. The structure of the newly synthesized compounds had been confirmed by ¹H-NMR, ¹³C-NMR, and HR-ESI-MS spectra. Among all target compounds at 1 μM, compounds 9d, 9f, 9k, 9m, and 9n, with a protection ratio exceeding 30%, exerted stronger protective effects on H9c2 cardiomyocyte than positive control dexrazoxane and buthutin A. Meanwhile, compounds 9k, 9m, and 9o showed the significant NHE-1 inhibitory activities on H9c2 cardiomyocyte, all with a dpHi/min value less than 0.23. What is more, compounds 9k, 9m, 9o and buthutin A all exhibited the specificity on NHE-1 inhibition. Molecular modelling studies suggested the ability of compounds 9m and 9o to establish interactions with three hydrogen bonds to Asp267 and Glu346 of NHE-1, but also the ability with much lower CDOCKER energies than positive control cariporide and buthutin A. The structure-activity relationship (SAR) studies suggested that the presences of amide group, four-carbon linker, and para hydroxyl benzene ring were advantageous pharmacophores for above two pharmacological actions. This research would open new avenues for developing amide-guanidine-based cardioprotective agents.

Key words: Buthus martensii, Amide-guanidine derivatives, Cardioprotective agents, NHE-1

Yuan Liu, Fa-Qi Wang, Xin-Hao Hua, Shu-Han Yang, Li-Ning Wang, Yun-Sheng Xu, Chen-Yue Shao, Xiang-Bo Gou, Yu-Ming Liu. Design, synthesis and biological evaluation of buthutin derivatives as cardioprotective agents[J]. 应用天然产物, 2025, 15(2): 14-14.

参考文献

[1] Medina AJ, Pinilla OA, Portiansky EL, Caldiz CI, Ennis IL, et al. Silencing of the Na⁺/H⁺ exchanger 1 (NHE-1) prevents cardiac structural and functional remodeling induced by angiotensin II. Exp Mol Pathol. 2019;107:1-9.
[2] Pan G, Cui B, Han M, Lin L, Li Y, Wang L, et al. Puerarin inhibits NHE1 activity by interfering with the p38 pathway and attenuates mitochondrial damage induced by myocardial calcium overload in heart failure rats: Puerarin inhibits NHE1 activity. Acta Biochim Biophys Sin. 2024;56(2):270-9.
[3] Yeves AM, Ennis IL. Na⁺/H⁺ exchanger and cardiac hypertrophy. Hipertens Riesgo Vasc. 2020;37(1):22-32.
[4] Chen S, Overberg K, Ghouse Z, Hollmann MW, Weber NC, Coronel R, et al. Empagliflozin mitigates cardiac hypertrophy through cardiac RSK/NHE-1 inhibition. Biomed Pharmacother. 2024;174: 116477.
[5] Jaballah M, Mohamed IA, Alemrayat B, Al-Sulaiti F, Mlih M, Mraiche F. Na⁺/H⁺ exchanger isoform 1 induced cardiomyocyte hypertrophy involves activation of p90 ribosomal s6 kinase. PLoS ONE. 2015;10(4): e0122230.
[6] Mohamed IA, Gadeau AP, Fliegel L, Lopaschuk G, Mlih M, Abdulrahman N, et al. Na⁺/H⁺ exchanger isoform 1-induced osteopontin expression facilitates cardiomyocyte hypertrophy. PLoS ONE. 2015;10(4): e0123318.
[7] Carvalho C, Santos RX, Cardoso S, Correia S, Oliveira PJ, Santos MS, Moreira PI. Doxorubicin: the good, the bad and the ugly effect. Curr Med Chem. 2009;16:3267-85.
[8] Carvalho FS, Burgeiro A, Garcia R, Moreno AJ, Carvalho RA, Oliveira PJ. Doxorubicin-induced cardiotoxicity: From bioenergetic failure and cell death to cardiomyopathy. Med Res Rev. 2014;34:106-35.
[9] Rawat PS, Jaiswal A, Khurana A, Bhatti JS, Navik U. Doxorubicin-induced cardiotoxicity: An update on the molecular mechanism and novel therapeutic strategies for effective management. Biomed Pharmacother. 2021;139: 111708.
[10] Wenningmann N, Knapp M, Ande A, Vaidya TR, Ait-Oudhia S. Insights into doxorubicin-induced cardiotoxicity: molecular mechanisms, preventive strategies, and early monitoring. Mol Pharmacol. 2019;96:219-32.
[11] Zhang P-P, Lu H, Wu Y, Lu D-B, Li C-G, Yang X-D, et al. COX5A alleviates doxorubicin-induced cardiotoxicity by suppressing oxidative stress, mitochondrial dysfunction and cardiomyocyte apoptosis. Int J Mol Sci. 2023;24:10400.
[12] Sangweni NF, Moremane M, Riedel S, van Vuuren D, Huisamen B, Mabasa L, et al. The prophylactic effect of pinocembrin against doxorubicin-induced cardiotoxicity in an in vitro H9c2 cell model. Front Pharmacol. 2020;11:1172.
[13] Yin Y, Niu Q, Hou H, Que H, Mi S, Yang J, et al. PAE ameliorates doxorubicin-induced cardiotoxicity via suppressing NHE1 phosphorylation and stimulating PI3K/AKT phosphorylation. Int Immunopharmacol. 2022;113: 109274.
[14] Tebbi CK, London WB, Friedman D, Villaluna D, De Alarcon PA, Constine LS, et al. Dexrazoxane-associated risk for acute myeloid leukemia/myelodysplastic syndrome and other secondary malignancies in pediatric Hodgkin’s disease. J Clin Oncol. 2007;25:493-500.
[15] Lee BH, Seo HW, Yi KY, Lee S, Lee S, Yoo SE. Effects of KR-32570, a new Na⁺/H⁺ exchanger inhibitor, on functional and metabolic impairments produced by global ischemia and reperfusion in the perfused rat heart. Eur J Pharmacol. 2005;511:175-82.
[16] Avkiran M, Cook AR, Cuello F. Targeting Na⁺/H⁺ exchanger regulation for cardiac protection: a RSKy approach? Curr Opin Pharmacol. 2008;8:133-40.
[17] Cuadrado I, Oramas-Royo S, González-Cofrade L, Amesty Á, Hortelano S, Estévez-Braun A. Labdane conjugates protect cardiomyocytes from doxorubicin-induced cardiotoxicity. Drug Dev Res. 2023;84:84-95.
[18] Alzahrani AM, Rajendran P, Veeraraghavan VP, Hanieh H. Cardiac protective effect of kirenol against doxorubicin-induced cardiac hypertrophy in H9c2 cells through Nrf2 signaling via PI3K/AKT pathways. Int J Mol Sci. 2021;22(6):3269.
[19] Gao H, Yang X, Gu X, Zhu YZ. Synthesis and biological evaluation of the codrug of leonurine and aspirin as cardioprotective agents. Bio Med Chem Lett. 2016;26:4650-4.
[20] Zhu YZ, Wu W, Zhu Q, Liu X. Discovery of Leonuri and therapeutical applications: from bench to bedside. Pharmacol Therapeut. 2018;188:26-35.
[21] Li C, Gou X, Gao H. Doxorubicin nanomedicine based on ginsenoside Rg1 with alleviated cardiotoxicity and enhanced antitumor activity. Nanomedicine. 2021;16(29):2587-604.
[22] Wan M, Yin K, Yuan J, Ma S, Xu Q, Li D, et al. YQFM alleviated cardiac hypertrophy by apoptosis inhibition and autophagy regulation via PI3K/AKT/mTOR pathway. J Ethnopharmacol. 2022;285: 114835.
[23] Liu YM, Fan JJ, Wang LN. Discovery of guanidine derivatives from Buthus martensii Karsch with metal-binding and cholinesterase inhibition properties. Molecules. 2021;26:6737.
[24] Salamouni NSE, Buckley BJ, Lee R, Ranson M, Kelso MJ, Yu H. Ion transport and inhibitor binding by human NHE1: Insights from molecular dynamics simulations and free energy calculations. J Phys Chem B. 2024;128:440-50.
[25] Dong Y, Gao Y, Ilie A, Kim D, Boucher A, Li B, et al. Structure and mechanism of the human NHE1-CHP1 complex. Nat Commun. 2021;12:3474.
[26] Roosterman D. Agonist-dependent and -independent dopamine-1-like receptor signalling differentially regulates downstream effectors. FEBS J. 2014;281:4792-804.
[27] Beloto-Silva O, Machado UF, Oliveira-Souza M. Glucose-induced regulation of NHEs activity and SGLTs expression involves the PKA signaling pathway. J Membrane Biol. 2011;239:157-65.
[28] Nolte AP, Chodisetti G, Yuan Z, Busch F, Riederer B, Luo M, et al. Na⁺ /H⁺ exchanger NHE1 and NHE2 have opposite effects on migration velocity in rat gastric surface cells. J Cell Physiol. 2017;232(7):1669-80.
[29] Cardoso VG, Gonçalves GL, Costa-Pessoa JM, Thieme K, Lins BB, Casare FAM, et al. Angiotensin II-induced podocyte apoptosis is mediated by endoplasmic reticulum stress/PKC-δ/p38 MAPK pathway activation and trough increased Na⁺/H⁺ exchanger isoform 1 activity. BMC Nephrol. 2018;19:179.

Design, synthesis and biological evaluation of buthutin derivatives as cardioprotective agents

Design, synthesis and biological evaluation of buthutin derivatives as cardioprotective agents

PDF (PC)

可视化

摘要/Abstract

引用本文

使用本文

参考文献

相关文章 0

编辑推荐

Metrics

本文评价