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DMXAA (Vadimezan)

Catalog No.
A8233
肿瘤血管破坏剂,细胞凋亡诱导剂。
组合的产品项目
规格价格库存 数量
10mM (in 1mL DMSO)
¥ 1,000.00
现货
5mg
¥ 850.00
现货
25mg
¥ 2,600.00
现货
100mg
¥ 6,800.00
现货

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Background

DMXAA (Vadimezan, AS-1404) is a selective inhibitor of DT-diaphorase with Ki50 and IC50 value of 20 μM and 62.5 μM, respectively [1, 2].

DT-diaphorase (DTD) is an obligate two-electron reductase and it has been reported that the expression of DTD is elevated in a variety of cancers [2].

DMXAA (Vadimezan) a potent DT-diaphorase inhibitor and is also reported as a multi-inhibitor for several kinases. When tested with sections of colon 38 tumors isolated from C57Bl/6 mice at different time, DMXAA (Vadimezan) (25 mg/kg) showed a high induction on endothelium cell apoptosis after 30 min treatment and showed intensely apoptotic vessels and large areas of necrosis of the tumor after 3 h treatment [2]. In NSCLC cell line A549 cells, DMXAA (Vadimezan) treatment arrested cell in G1 phase and induced cell apoptosis and autophagy by increasing cytosolic level of cytochrome and activation of caspase3 in a dose dependent manner from 0.1 μM to 10 μM [3].

In C57Bl/6 mice model with luciferase-expressing murine GL261 glioma cells subcutaneous xenograft, administration of DMXAA (Vadimezan) (25 mg/kg) resulted in widespread necrosis at 24 h, a 9-day growth delay and complete regressions in 50 % mice. Furthermore, co-administration of lenalidomide (100 mg/kg) significantly increased the growth delay to 20 days and the percentage of cures to 83 % [4].

It is reported that DMXAA (Vadimezan) is a multi-inhibitor to several kinases, with most potent effects being on members of the VEGFR (vascular endothelial growth factor receptor) tyrosine kinase family. In zebrafish embryos and HUVECs (human umbilical vein endothelial cells), DMXAA (Vadimezan) blocked the angiogenesis and VEGFR2 signalling [5].

References:
[1].  Phillips, R.M., Inhibition of DT-diaphorase (NAD(P)H:quinone oxidoreductase, EC 1.6.99.2) by 5,6-dimethylxanthenone-4-acetic acid (DMXAA) and flavone-8-acetic acid (FAA): implications for bioreductive drug development. Biochem Pharmacol, 1999. 58(2): p. 303-10.
[2].  Ching, L.M., et al., Induction of endothelial cell apoptosis by the antivascular agent 5,6-Dimethylxanthenone-4-acetic acid. Br J Cancer, 2002. 86(12): p. 1937-42.
[3].  Pan, S.T., et al., Proteomic response to 5,6-dimethylxanthenone 4-acetic acid (DMXAA, vadimezan) in human non-small cell lung cancer A549 cells determined by the stable-isotope labeling by amino acids in cell culture (SILAC) approach. Drug Des Devel Ther, 2015. 9: p. 937-68.
[4].  Yung, R., et al., Efficacy against subcutaneous or intracranial murine GL261 gliomas in relation to the concentration of the vascular-disrupting agent, 5,6-dimethylxanthenone-4-acetic acid (DMXAA), in the brain and plasma. Cancer Chemother Pharmacol, 2014. 73(3): p. 639-49.
[5].   Buchanan, C.M., et al., DMXAA (Vadimezan, ASA404) is a multi-kinase inhibitor targeting VEGFR2 in particular. Clin Sci (Lond), 2012. 122(10): p. 449-57.

文献引用

1. Pryke KM, Abraham J, et al. "A Novel Agonist of the TRIF Pathway Induces a Cellular State Refractory to Replication of Zika, Chikungunya, and Dengue Viruses." MBio. 2017 May 2;8(3). pii: e00452-17. PMID:28465426
2. Sali, Tina M., et al. "Characterization of a Novel Human-Specific STING Agonist that Elicits Antiviral Activity Against Emerging Alphaviruses." PLoS pathogens 11.12 (2015). PMID:26646986

Chemical Properties

Physical AppearanceA solid
StorageStore at -20°C
M.Wt282.29
Cas No.117570-53-3
FormulaC17H14O4
SynonymsAS-1404, 5,6-MeXAA, NSC-640488, Vadimezan
Solubility≥14.1mg/mL in DMSO, insoluble in EtOH,insoluble in H2O
Chemical Name2-(5,6-dimethyl-9-oxoxanthen-4-yl)acetic acid
SDFDownload SDF
Canonical SMILESCC1=C(C2=C(C=C1)C(=O)C3=C(O2)C(=CC=C3)CC(=O)O)C
运输条件试用装:蓝冰运输。 其他可选规格:常温运输或根据您的要求用蓝冰运输。
一般建议为了使其更好的溶解,请用37℃加热试管并在超声波水浴中震动片刻。不同厂家不同批次产品溶解度各有差异,仅做参考。若实验所需浓度过大至产品溶解极限,请添加助溶剂助溶或自行调整浓度。

试验操作

细胞实验: [1]

细胞系

HECPP细胞

制备方法

该化合物在DMSO中的溶解度大于10 mM,若配制更高浓度的溶液,一般步骤如下:请将试管置于37℃加热10分钟和/或将其置于超声波浴中震荡一段时间。原液于-20℃可放置数月。

反应条件

IC50:500 μg/mL,24 hours

实验结果

在HECPP细胞中,DMXAA不诱导TNF或干扰素的mRNA。400 μg/mL的DMXAA孵育2小时后,IP-10的mRNA上调。400 μg/mL的DMXAA孵育6小时后观察到凋亡细胞,凋亡数量随着时间延长而增加。高于100 μg/mL浓度下,24小时的凋亡细胞数量随着DMXAA的剂量增加成线性增加。500 μg/mL 的DMXAA孵育24小时后诱导50%的凋亡。

动物实验: [2]

动物模型

注射344SQ-ELuc细胞的雄性129/Sv小鼠

给药剂量

腹腔注射,25 mg/kg

实验结果

一旦肿瘤建立(皮下肿瘤,第7天或第14天)后,腹腔给药5 mg/kg的DMXAA。在6和24小时进行BLI。344SQ-ELuc NSCLC皮下肿瘤对DMXAA快速响应,药物注射后生物发光(BLI)信号的标记减少约2-logs。在DMXAA处理后BLI的下降不是由于直接的肿瘤细胞毒性作用,因为DMXAA对344SQ-ELuc细胞活力没有不利影响。

注意事项

请于室内测试所有化合物的溶解度。虽然化合物的实际溶解度可能与其理论值略有不同,但仍处于实验系统误差的允许范围内。

References:

[1] Ching L M, Cao Z, Kieda C, et al. Induction of endothelial cell apoptosis by the antivascular agent 5, 6-dimethylxanthenone-4-acetic acid. British journal of cancer, 2002, 86(12): 1937-1942.

[2] Downey C M, Aghaei M, Schwendener R A, et al. DMXAA Causes Tumor Site-Specific Vascular Disruption in Murine Non-Small Cell Lung Cancer, and like the Endogenous Non-Canonical Cyclic Dinucleotide STING Agonist, 2′ 3′-cGAMP, Induces M2 Macrophage Repolarization. PloS one, 2014, 9(6): e99988.

生物活性

描述 DMXAA(Vadimezan)是一种血管破坏剂(VDA)和DT-黄递酶的竞争性抑制剂,Ki值和IC50值分别为20 μM和62.5 μM。
靶点 DT-diaphorase DT-diaphorase        
IC50 62.5 μM 20 μM (Ki)        

质量控制

化学结构

DMXAA (Vadimezan)

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DMXAA (Vadimezan)

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DMXAA (Vadimezan)

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DMXAA (Vadimezan)

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DMXAA (Vadimezan)

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DMXAA (Vadimezan)

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DMXAA (Vadimezan)