Synthesis and antitumor activity evaluation of glycoconjugates derived from natural product harmine

LIU Xiaohan; TAN Yunying; LI Qiang; CHEN Xu; FU Junjie; YIN Jian

doi:10.11665/j.issn.1000-5048.2023041101

Journal of China Pharmaceutical University > 2023 > 54(6): 729-742. > DOI: 10.11665/j.issn.1000-5048.2023041101

LIU Xiaohan, TAN Yunying, LI Qiang, CHEN Xu, FU Junjie, YIN Jian. Synthesis and antitumor activity evaluation of glycoconjugates derived from natural product harmine[J]. Journal of China Pharmaceutical University, 2023, 54(6): 729-742. DOI: 10.11665/j.issn.1000-5048.2023041101

Citation:

PDF (3760 KB)

Synthesis and antitumor activity evaluation of glycoconjugates derived from natural product harmine

1.
Key Laboratory of Carbohydrate Chemistry and Biotechnology (Ministry of Education), School of Biotechnology, Jiangnan University, Wuxi 214122
2.
School of Life Sciences and Health Engineering, Jiangnan University, Wuxi 214122, China

Funds: This study was supported by the Open Project of Key Laboratory of Carbohydrate Chemistry and Biotechnology (Ministry of Education), Jiangnan University (No.KLCCB-KF202003)

More Information

Received Date: April 10, 2023
Revised Date: December 11, 2023

Graphical Abstract

Abstract

Abstract

Based on our previous work, the study herein designed and synthesized eight glycoconjugates of natural product harmine (14a-14h)by introducing a cyclohexylmethyloxyl group at its C⁷ position and coupling a methyl-2-amino-β-D-glucopyranoside to the N⁹ position through different lengths of alkyl chains.In vitro anti-tumor activity screening and structure-activity relationship studies showed that the antitumor activity of the conjugates increased with the lengthening of the alkyl chain in the linker.Compound 14h exhibited significantly better proliferative inhibitory activity against MDA-MB-231 breast cancer cells than harmine.As compared to harmine, the introduction of the carbohydrate moiety improved the water solubility of compound 14h and enhanced its tumor cell selectivity through the Warburg effect.Mechanism of action studies revealed that compound 14h induced apoptosis and G0/G1 cell cycle arrest in MDA-MB-231 cells, and inhibited tumor cell migration by interfering with epithelial-mesenchymal transition process.This study provides a new approach for the development of antitumor drugs based on harmine.
- harmine,
- 2-amino-2-deoxy-D-glucose,
- glycoconjugate drugs,
- antitumor activity

FullText(HTML)

References (26)

References

[1]	Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020[J]. CA Cancer J Clin, 2020, 70(1): 7-30.
[2]	Yang GX, Xiong J, Hu JF. 2017’s advanced natural products chemistry researches in China(1)[J]. J China Pharm Univ (中国药科大学学报), 2018, 49(5): 511-520.
[3]	Alam MM, Malebari AM, Syed N, et al. Design, synthesis and molecular docking studies of thymol based 1, 2, 3-triazole hybrids as thymidylate synthase inhibitors and apoptosis inducers against breast cancer cells[J]. Bioorg Med Chem, 2021, 38: 116136.
[4]	Wang HB, He Y, Jian ML, et al. Breaking the bottleneck in anticancer drug development: efficient utilization of synthetic biology[J]. Molecules, 2022, 27(21): 7480.
[5]	Kumar K, Wang P, Wilson J, et al. Synthesis and biological validation of a harmine-based, central nervous system (CNS)-avoidant, selective, human β-cell regenerative dual-specificity tyrosine phosphorylation-regulated kinase A (DYRK1A) inhibitor[J]. J Med Chem, 2020, 63(6): 2986-3003.
[6]	Zhu YG, Lv YX, Guo CY, et al. Harmine inhibits the proliferation and migration of glioblastoma cells via the FAK/AKT pathway[J]. Life Sci, 2021, 270: 119112.
[7]	Zhang L, Li DC, Yu SL. Pharmacological effects of harmine and its derivatives: a review[J]. Arch Pharm Res, 2020, 43(12): 1259-1275.
[8]	Lakshmi Manasa K, Thatikonda S, Sigalapalli DK, et al. Design and synthesis of β-carboline linked aryl sulfonyl piperazine derivatives: DNA topoisomerase II inhibition with DNA binding and apoptosis inducing ability[J]. Bioorg Chem, 2020, 101: 103983.
[9]	Marconi GD, Fonticoli L, Rajan TS, et al. Epithelial-mesenchymal transition (EMT): the type-2 EMT in wound healing, tissue regeneration and organ fibrosis[J]. Cells, 2021, 10(7): 1587.
[10]	Zhao TM, Yang Y, Yang J, et al. Harmine-inspired design and synthesis of benzo[d]imidazo[2, 1-b]thiazole derivatives bearing 1, 3, 4-oxadiazole moiety as potential tumor suppressors[J]. Bioorg Med Chem, 2021, 46: 116367.
[11]	He JR, Chen SS, Yu T, et al. Harmine suppresses breast cancer cell migration and invasion by regulating TAZ-mediated epithelial-mesenchymal transition[J]. Am J Cancer Res, 2022, 12(6): 2612-2626.
[12]	Nafie E, Lolarga J, Lam B, et al. Harmine inhibits breast cancer cell migration and invasion by inducing the degradation of Twist1[J]. PLoS One, 2021, 16(2): e0247652.
[13]	Lu DH, Qu LL, Wang C, et al. Harmine-based dual inhibitors targeting histone deacetylase (HDAC) and DNA as a promising strategy for cancer therapy[J]. Bioorg Chem, 2022, 120: 105604.
[14]	Du HT, Tian S, Chen JC, et al. Synthesis and biological evaluation of N⁹-substituted harmine derivatives as potential anticancer agents[J]. Bioorg Med Chem Lett, 2016, 26(16): 4015-4019.
[15]	Tang L. Design, synthesis and antitumor activity in vitro of derivatives of harmine N9-cinnamic acid(去氢骆驼蓬碱N⁹位-肉桂酸衍生物的设计、合成与体外抗肿瘤活性研究)[D]. Lanzhou: Lanzhou University, 2020.
[16]	Filali I, Bouajila J, Znati M, et al. Synthesis of new isoxazoline derivatives from harmine and evaluation of their anti-Alzheimer, anti-cancer and anti-inflammatory activities[J]. J Enzyme Inhib Med Chem, 2015, 30(3): 371-376.
[17]	Frédérick R, Bruyère C, Vancraeynest C, et al. Novel trisubstituted harmine derivatives with original in vitro anticancer activity[J]. J Med Chem, 2012, 55(14): 6489-6501.
[18]	Fu JJ, Yang JX, Seeberger PH, et al. Glycoconjugates for glucose transporter-mediated cancer-specific targeting and treatment[J]. Carbohydr Res, 2020, 498: 108195.
[19]	Zhang XR, Ruan Q, Jiang YH, et al. Evaluation of ^99mTc-CN5DG as a broad-spectrum SPECT probe for tumor imaging[J]. Transl Oncol, 2021, 14(1): 100966.
[20]	Wang HF, Yang XD, Zhao CL, et al. Glucose-conjugated platinum(IV) complexes as tumor-targeting agents: design, synthesis and biological evaluation[J]. Bioorg Med Chem, 2019, 27(8): 1639-1645.
[21]	Chen F, Huang GL. Application of glycosylation in targeted drug delivery[J]. Eur J Med Chem, 2019, 182: 111612.
[22]	Cao J, Cui SS, Li SW, et al. Targeted cancer therapy with a 2-deoxyglucose-based adriamycin complex[J]. Cancer Res, 2013, 73(4): 1362-1373.
[23]	Punganuru SR, Mostofa AGM, Madala HR, et al. Potent anti-proliferative actions of a non-diuretic glucosamine derivative of ethacrynic acid[J]. Bioorg Med Chem Lett, 2016, 26(12): 2829-2833.
[24]	Wang SQ, Chen YT, Xia C, et al. Synthesis and evaluation of glycosylated quercetin to enhance neuroprotective effects on cerebral ischemia-reperfusion[J]. Bioorg Med Chem, 2022, 73: 117008.
[25]	He QL, Minn I, Wang QL, et al. Targeted delivery and sustained antitumor activity of triptolide through glucose conjugation[J]. Angew Chem Int Ed, 2016, 55(39): 12035-12039.
[26]	Henderson AS, Medina S, Bower JF, et al. Nucleophilic aromatic substitution (SNAr) as an approach to challenging carbohydrate-aryl ethers[J]. Org Lett, 2015, 17(19): 4846-4849.

[1]	NING Manru, XU Kehui, HANG Taijun, SONG Min. Separation and identification of folic acid and its related substances by liquid chromatography-mass spectrometry[J]. Journal of China Pharmaceutical University, 2025, 56(1): 56-64. DOI: 10.11665/j.issn.1000-5048.2024052201
[2]	TANG Xiaohang, SONG Huilin, YAO Liying, QIN Guowen, WANG Xingchen, LIU Wenyuan, JI Shunli. Determination of non-steroidal anti-inflammatory drugs in the environmental water samples by a polyvinylimide-modified magnetic nanoparticles-based solid phase extraction coupled with high-performance liquid chromatography[J]. Journal of China Pharmaceutical University, 2024, 55(4): 485-492. DOI: 10.11665/j.issn.1000-5048.2023081802
[3]	ZHANG Qian, HUANG Minwen, FANG Wang, ZHANG Mei, HANG Taijun, YUAN Yaozuo. Determination of the content and related substances of neomycin sulfate by HPLC combined with pulsed amperometric detection[J]. Journal of China Pharmaceutical University, 2019, 50(2): 193-199. DOI: 10.11665/j.issn.1000-5048.20190210
[4]	XU Dejin, YUAN Wenbo, LYU Juan. Determination of vancomycin in human serum by in situ formed ionic liquids microextraction-ultra performance liquid chromatography(ISFILM-UPLC)methods[J]. Journal of China Pharmaceutical University, 2017, 48(2): 196-200. DOI: 10.11665/j.issn.1000-5048.20170210
[5]	YUAN Wenbo, DING Yongjuan, XU Jingjing. Determination of 5-fluorouracil in serum by direct protein precipitation-ultra performance liquid chromatography[J]. Journal of China Pharmaceutical University, 2015, 46(1): 81-84. DOI: 10.11665/j.issn.1000-5048.20150111
[6]	LIU Yongli, ZHAO Zhenxia, LI Dongmei, FENG Li. Simultaneous determination of seven components in Huoxiang Zhengqi liquid by ultra-performance liquid chromatography[J]. Journal of China Pharmaceutical University, 2013, 44(3): 249-252. DOI: 10.11665/j.issn.1000-5048.20130312
[7]	Study on Main Related Substance and Photodecomposed Product in Chloroprocaine Hydrochloride Injection[J]. Journal of China Pharmaceutical University, 2002, (1): 37-39.
[8]	HPLC Determination of Nicardipine in Human Plasma and Its Pharmacokinetic Parameters[J]. Journal of China Pharmaceutical University, 1998, (3): 47-50.
[9]	High Performance Liquid Chromatographic Simultaneous Determination of Trimethoprim, Spulphamethoxazole and Acetylsulphamethoxazole in Biological Fluids[J]. Journal of China Pharmaceutical University, 1993, (6): 348-350.
[10]	Quantitative Determination of Bendazac Lysine By RP-HPLC[J]. Journal of China Pharmaceutical University, 1992, (5): 307-309.

Cited By

Get Citation

PDF

XML

Article views (177) PDF downloads (252)

Turn off MathJax

Article Contents

Abstract

References

Synthesis and antitumor activity evaluation of glycoconjugates derived from natural product harmine

Abstract

References

Related Articles

Catalog

Synthesis and antitumor activity evaluation of glycoconjugates derived from natural product harmine

Abstract

References

Related Articles

Catalog

Export File

Citation

Format

Content