天然产物去氢骆驼蓬碱糖基偶联物的合成及抗肿瘤活性评价

刘晓涵; 谭云鹰; 李强; 陈旭; 傅俊杰; 尹健

doi:10.11665/j.issn.1000-5048.2023041101

天然产物去氢骆驼蓬碱糖基偶联物的合成及抗肿瘤活性评价

1.
江南大学生物工程学院糖化学与生物技术教育部重点实验室，无锡 214122
2.
江南大学生命科学与健康工程学院，无锡 214122

基金项目: 江南大学糖化学与生物技术教育部重点实验室开放课题资助项目（No.KLCCB-KF202003）

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- 收稿日期: 2023-04-10
- 修回日期: 2023-12-11
- 刊出日期: 2023-12-24

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)

摘要

摘要: 基于本课题组前期工作基础，在天然产物去氢骆驼蓬碱（harmine）的C⁷位氧上引入环己基甲基，并在N⁹位上通过不同长度的烷基链偶联甲基2-氨基-β-D-葡萄糖苷，设计并合成了8个去氢骆驼蓬碱糖基偶联物（14a ~ 14h）。体外抗肿瘤活性筛选和构效关系研究发现，偶联物的抗肿瘤活性随连接臂中烷基链长度的延长而增加。化合物14h对MDA-MB-231乳腺癌细胞的增殖抑制活性显著优于去氢骆驼蓬碱。与去氢骆驼蓬碱相比，糖基的引入改善了化合物14h的水溶性，并通过Warburg效应提高了化合物14h的肿瘤细胞选择性。机制研究发现化合物14h可诱导MDA-MB-231细胞凋亡和G₀/G₁期细胞阻滞，并能通过干扰细胞上皮-间充质转化进程抑制肿瘤细胞迁移。本研究为基于去氢骆驼蓬碱的抗肿瘤药物的开发提供了新思路。
- 去氢骆驼蓬碱 /
- 2-氨基-2-脱氧-D-葡萄糖 /
- 糖基偶联药物 /
- 抗肿瘤活性
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

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参考文献(26)

[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.

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天然产物去氢骆驼蓬碱糖基偶联物的合成及抗肿瘤活性评价

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出版历程

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

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出版历程

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