NO供体型大黄酸衍生物的合成及抗肿瘤活性

柏志伟; 尚飞扬; 戴卫国; 何黎琴

doi:10.11665/j.issn.1000-5048.20210105

NO供体型大黄酸衍生物的合成及抗肿瘤活性

安徽中医药大学药学院,合肥 230031

基金项目: 安徽省自然科学基金资助项目（No.KJ2017A292）

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出版历程
- 收稿日期: 2020-09-07
- 修回日期: 2020-12-28
- 刊出日期: 2021-02-24

Synthesis and antitumor activities of NO-donating rhein derivatives

College of Pharmacy, Anhui University of Chinese Medicine, Hefei 230031, China

Funds: This study was supported by the Natural Science Foundation of Anhui Province(No.KJ2017A292)

摘要

摘要: 以大黄酸为原料，利用其羧基通过不同的连接臂与呋咱氮氧化合物偶联，得到7个NO供体型大黄酸衍生物，其结构经红外光谱、核磁共振氢谱和质谱确证。采用MTT法测试了目标化合物对人肝癌细胞HepG2、Bel-7402，人结肠癌细胞HCT116，人骨肉瘤细胞U2OS，耐药细胞Bel-7402/5-FU及正常肝细胞LO2的体外抗细胞增殖活性。结果显示，所有目标化合物对受试的肿瘤细胞和耐药细胞均具有较强的增殖抑制活性，其中化合物4g对人肝癌细胞HepG2、Bel-7402，人骨肉瘤细胞U2OS及耐药细胞Bel-7402/5-FU具有强的增殖抑制活性，而且对正常细胞影响很小，表现出较好的选择性。采用Griess法测定了目标化合物4g在肿瘤细胞HepG2中对NO释放的影响。结果表明，化合物4g在细胞中能释放高浓度的NO，其抗肿瘤作用可能与NO的释放相关。NO清除剂验证实验表明，化合物4g的抗肿瘤活性部分来自于NO的释放。
- 大黄酸 /
- 衍生物 /
- 呋咱氮氧化合物 /
- 合成 /
- 抗肿瘤活性
Abstract: Seven target compounds coupled by rhein and furoxan were synthesized and their chemical structures were confirmed by ¹H NMR, IR, and MS. All target compounds were evaluated for anti-proliferative activity against human hepatoma cells HepG2 and Bel-7402, human colon cancer cells HCT116, human osteosarcoma cells U2OS, drug-resistant cells Bel-7402/5-FU and normal hepatocytes cells LO2 in vitro by thiazolyl blue(MTT) colorimetry. The results indicated that all target compounds had more potent anti-proliferative activity than their parent compound rhein. Additionally, compound 4g had stronger proliferation inhibitory activity on HepG2, Bel-7402, U2OS and Bel-7402/5-FU,with little effect on the proliferation of normal cells, exhibiting selective inhibitory activity. Griess assay was used to measure the release of nitric oxide in vitro. Results showed that compound 4g could increase the releases NO in HepG2 cells, which may be associated with its antitumor effects. Furthermore, the antitumor activity of compound 4g was attenuated by NO scavenger (hemoglobin), which indicates that the antitumor activity of compound 4g may be partly related to the release of NO.
- rhein /
- derivatives /
- furoxan /
- synthesis /
- anti-tumor activity

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参考文献(23)

[1]	. Osteoarthr Cartilage， 1996，4（4）：251-261.
[2]	Shi P， Huang ZW， Chen GC. Rhein induces apoptosis and cell cycle arrest in human hepatocellular carcinoma BEL-7402 cells［J］. Am J Chin Med， 2008， 36（4）： 805-813.
[3]	Fernand VE， Losso JN， Truax RE， et al. Rhein inhibits angiogenesis and the viability of hormone-dependent and -independent cancer cells under normoxic or hypoxic conditions in vitro［J］. Chem Biol Interact， 2011， 192（3）： 220-232.
[4]	Du Q， Bian XL， Xu XL， et al. Role of mitochondrial permeability transition in human hepatocellular carcinoma HepG2 cell death induced by rhein［J］. Fitoterapia， 2013， 91： 68-73.
[5]	Huang YH， Zhen YS. Rhein induces apoptosis in cancer cells and shows synergy with mitomycin［J］. Acta Pharm Sin（药学学报）， 2001，36（5）：334-338.
[6]	Viayna E， Sola I， Bartolini M， et al. Synthesis and multitarget biological profiling of a novel family of rhein derivatives as disease-modifying anti-Alzheimer agents［J］. J Med Chem， 2014， 57（6）： 2549-2567.
[7]	van Gorkom BA， Timmer-Bosscha H， de Jong S， et al. Cytotoxicity of Rhein， the active metabolite of sennoside laxatives， is reduced by multidrug resistance-associated protein 1［J］. Br J Cancer， 2002， 86（9）： 1494-1500.
[8]	Chang CY， Chan HL， Lin HY， et al. Rhein induces apoptosis in human breast cancer cells［J］. Evid Based Complement Alternat Med， 2012， 2012： 952504.
[9]	Miccadei S， Pulselli R， Floridi A. Effect of lonidamine and Rhein on the phosphorylation potential generated by respiring rat liver mitochondria［J］. Anticancer Res， 1993， 13（5A）： 1507-1510.
[10]	Yao GY， Ye MY， Huang RZ， et al. Synthesis and antitumor activities of novel Rhein α-aminophosphonates conjugates［J］. Bioorg Med Chem Lett， 2014， 24（2）： 501-507.
[11]	Huang JK， Zhang Z， Huang P， et al. Design， synthesis and biological evaluation of rhein derivatives as anticancer agents［J］. Med Chem Comm， 2016，7：1812-1818.
[12]	Lin YJ， Huang YH， Zhen YZ， et al. Rhein lysinate induces apoptosis in breast cancer SK-Br-3 cells by inhibiting HER-2 signal pathway［J］. Acta Pharm Sin（药学学报）， 2008，43（11）：1099-1105.
[13]	Wan ZM， Chen H， Xie WL， et al. Effect of rhein derivative RH-01 on the growth of osteosarcoma［J］. Acta Acad Med CPAF（武警医学院学报）， 2008，17（6）：469-472.
[14]	Zhang WW， Huang JK， He LQ， et al. Design， synthesis and antitumor activity of rhein derivatives［J］. Chem World（化学世界）， 2017，58（6）：346-352.
[15]	Wang XL， Li Y， Zhao Q， et al. Design， synthesis and evaluation of nitric oxide releasing derivatives of 3-n-butylphthalide as antiplatelet and antithrombotic agents［J］. Org Biomol Chem， 2011， 9（16）： 5670-5681.
[16]	Stewart GD， Nanda J， Brown DJ， et al. NO-sulindac inhibits the hypoxia response of PC-3 prostate cancer cells via the Akt signalling pathway［J］. Int J Cancer， 2009， 124（1）： 223-232.
[17]	Gu XK， Tang XB， Huang ZJ， et al. Synthesis and antitumor activity of NO-releasing alkoxylbiphenyl derivatives［J］. J China Pharm Univ（中国药科大学学报）， 2014， 45（6）： 657-661.
[18]	Wu YX， Huang JK， Gao LL， et al. Design， synthesis and evaluation of nitric oxide-releasing derivatives of N-（n-butyl） matrinic acid and N-（n-Butyl） matrinol as anti-hepatocellular carcinoma agents［J］. Heterocycles， 2015，91（2）：301-312.
[19]	He LQ， Yang Q， Wu YX， et al. Novel hybrids of （phenylsulfonyl） furoxan and N-benzyl matrinol as anti-hepatocellular carcinoma agents［J］. Acta Pharm Sin.（药学学报）， 2015，50（5）：574 -578.
[20]	He LQ， Liu J， Yin DK， et al. Synthesis and biological evaluation of nitric oxide-releasing matrine derivatives as anticancer agents［J］. Chin Chem Lett， 2010， 21（4）： 381-384.
[21]	An R， Hou Z， Li JT， et al. Design， synthesis and biological evaluation of novel 4-substituted coumarin derivatives as antitumor agents［J］. Molecules， 2018， 23（9）： E2281.
[22]	Huang JK， He LQ， Zhang WW. Design， synthesis and evaluation of rhein-nitrate derivatives as anticancer agents［J］. Chem World（化学世界），2018， 59（11）： 717-721.
[23]	Han C， Wu LT， Zhou CY， et al. Design， synthesis and anti-NSCLC activity of NO donating amLinopyrimidines［J］. Chin J Med Chem（中国药物化学杂志）， 2016，26（3）：175-181.

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NO供体型大黄酸衍生物的合成及抗肿瘤活性

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出版历程

Synthesis and antitumor activities of NO-donating rhein derivatives

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出版历程

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