DMXAA (Vadimezan)

Names

[ Name ]:
DMXAA (Vadimezan)

[Synonym ]:
5,6-Dimethyl-9-oxo-9H-xanthene-4-acetic acid
5,6-dimethylxanthenoneacetic acid
(5,6-Dimethyl-9-oxo-9H-xanthen-4-yl)acetic acid
Vadimezan
2-(5,6-Dimethyl-9-oxo-9H-xanthen-4-yl)acetic acid
9H-Xanthene-4-acetic acid, 5,6-dimethyl-9-oxo-
T C666 BO IVJ D1 E1 N1VQ
ASA-404
DMXAA
5,6-Dimethylxanthenone-4-acetic acid

Biological Activity

[Description]:

Vadimezan (ASA-404; DMXAA), the vascular disrupting agent, is a murine agonist of the stimulator of interferon genes (STING) and also a potent inducer of type I IFNs and other cytokines.

[Related Catalog]:

Signaling Pathways >> Immunology/Inflammation >> Interleukin Related

Signaling Pathways >> Immunology/Inflammation >> STING

Research Areas >> Cancer

[Target]

STING[1], type I IFNs[2]

[In Vitro]

Vadimezan (DMXAA), the vascular disrupting agent, is a murine agonist of the stimulator of interferon genes (STING) and also a potent inducer of type I IFNs and other cytokines. Vadimezan (DMXAA) has no detrimental effect on 344SQ-ELuc cell viability. It is found that Vadimezan-mediated up regulation of the NF-κB pathway as shown by increased p65 phosphorylation in M2 macrophages[1]. Results demonstrate that Vadimezan (DMXAA)-treated cells are protected from VSV-induced cytotoxicity at all MOIs in contrast to medium-pretreated macrophages. Vadimezan (DMXAA) effectively inhibits growth of both strains of influenza, demonstrating the potential of Vadimezan for treatment of drug-resistant strains of human influenza[2].

[In Vivo]

344SQ-ELuc NSCLC subcutaneous tumors respond dramatically to Vadimezan (DMXAA), with a marked decrease in bioluminescence (BLI) signals post-drug injection. Vadimezan (DMXAA) treatment of 344SQ-ELuc metastases yields no decrease in photon emission rates, with the tumors remaining histologically similar to controls after this treatment. As with the large subcutaneous tumors, Vadimezan (DMXAA) administration to mice with small subcutaneous tumors still leads to ~2-log decreases in photon emission at both 6 and 24 hours[1]. In vivo, Vadimezan (DMXAA) is a more potent inducer of IFN-β mRNA and a relatively poor inducer of TNF-α mRNA. Vadimezan (DMXAA) administration leads to significantly less weight loss in influenza-infected mice[2].

[Kinase Assay]

M2-polarized macrophages are treated with 20 µg/mL Vadimezan (ASA-404) or DMSO vehicle for 30 min. Cells are then lysed and protein denatured in SDS buffer and samples sent for RPPA analysis. Differential abundance of various proteins and/or their phosphorylation status in response to Vadimezan (ASA-404) is assessed[1].

[Cell Assay]

RAW 264.7 macrophages are cultured and plated at 1×105 cells/well in a 96-well plate. After overnight incubation at 37°C, cells are treated with medium containing vehicle or Vadimezan (DMXAA) (100 μg/mL). After 6 h, the culture medium is replaced with serum-free DMEM containing VSV at the indicated MOI for 1 h. Cells are then maintained in complete DMEM with 10% FBS. Twenty-four hours later, cells are washed with PBS, fixed with 10% buffered formalin, and rinsed thoroughly with distilled water. Adherent cells are stained with crystal violet[2].

[Animal admin]

Male 129/Sv mice (6 to 12 week old) are used in this study. To generate subcutaneous tumors, 5×105 344SQ-ELuc cells in 100 µL PBS are injected in both posterior flanks of mice. Tumor growth is monitored every 2 to 4 days via BLI. Once tumors are established (day 10 for systemic metastases; day 7 or day 14 for subcutaneous tumors), mice are given 25 mg/kg of Vadimezan (DMXAA), or DMSO vehicle by i.p. injection. BLI is carried out at 6 and 24 hours [1].

[References]

[1]. Downey CM, 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 Jun 18;9(6):e99988.

[2]. Shirey KA, et al. The anti-tumor agent, 5,6-dimethylxanthenone-4-acetic acid (DMXAA), induces IFN-beta-mediated antiviral activity in vitro and in vivo. J Leukoc Biol. 2011 Mar;89(3):351-7.

[Related Small Molecules]

Chemical & Physical Properties

[ Density]:
1.3±0.1 g/cm3

[ Boiling Point ]:
520.9±50.0 °C at 760 mmHg

[ Melting Point ]:
264 °C

[ Molecular Formula ]:
C₁₇H₁₄O₄

[ Molecular Weight ]:
282.291

[ Flash Point ]:
197.1±23.6 °C

[ Exact Mass ]:
282.089203

[ PSA ]:
67.51000

[ LogP ]:
3.60

[ Appearance of Characters ]:
solid | light brown

[ Vapour Pressure ]:
0.0±1.4 mmHg at 25°C

[ Index of Refraction ]:
1.633

[ Storage condition ]:
2-8°C

[ Water Solubility ]:
DMSO: 17 mg/mL, soluble

MSDS

Click to get detail MSDS

Safety Information

[ Symbol ]:

GHS07, GHS09

[ Signal Word ]:
Warning

[ Hazard Statements ]:
H302-H400

[ Precautionary Statements ]:
P273

[ Personal Protective Equipment ]:
dust mask type N95 (US);Eyeshields;Faceshields;Gloves

[ Hazard Codes ]:
Xn: Harmful;N: Dangerous for the environment;

[ Risk Phrases ]:
R22;R50/53

[ Safety Phrases ]:
60-61

[ RIDADR ]:
UN 3077

[ WGK Germany ]:
3

[ RTECS ]:
ZD5536200

[ HS Code ]:
2932999099

Synthetic Route

Click to get detail synthetic route

Precursor & DownStream

Precursor

DownStream

Customs

[ HS Code ]: 2932999099

[ Summary ]:
2932999099. other heterocyclic compounds with oxygen hetero-atom(s) only. VAT:17.0%. Tax rebate rate:13.0%. . MFN tariff:6.5%. General tariff:20.0%

Articles

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. 9 , 937-68, (2015)

5,6-Dimethylxanthenone 4-acetic acid (DMXAA), also known as ASA404 and vadimezan, is a potent tumor blood vessel-disrupting agent and cytokine inducer used alone or in combination with other cytotoxic...

Casein kinase II controls TBK1/IRF3 activation in IFN response against viral infection.

J. Immunol. 194 , 4477-88, (2015)

By sensing viral nucleic acids, host innate receptors elicit signaling pathways converging on TBK1-IFN regulatory factor (IRF)3 axis in mediating IFN-αβ induction and defense mechanisms. In contrast, ...

TLR9 and STING agonists synergistically induce innate and adaptive type-II IFN.

Eur. J. Immunol. 45(4) , 1159-69, (2015)

Agonists for TLR9 and Stimulator of IFN Gene (STING) act as vaccine adjuvants that induce type-1 immune responses. However, currently available CpG oligodeoxynucleotide (ODN) (K-type) induces IFNs onl...