Combretastatin A4

Names

[ Name ]:
Combretastatin A4

[Synonym ]:
(Z)-2-Methoxy-5-[2-(3,4,5,-trimethoxyphenyl)ethenyl]phenol
(Z)-CombretastatinA4
Phenol, 2-methoxy-5-(2-(3,4,5-trimethoxyphenyl)ethenyl)-, (Z)-
(Z)-2-Methoxy-5-(3,4,5-trimethoxystyryl)phenol
3'-Hydroxy-3,4,4',5-tetramethoxy-cis-stilbene
CS A4
2-Methoxy-5-[(Z)-2-(3,4,5-trimethoxyphenyl)ethenyl]benzolol
2-methoxy-5-[(Z)-2-(3,4,5-trimethoxyphenyl)ethenyl]phenol
2-Methoxy-5-[(Z)-2-(3,4,5-trimethoxyphenyl)vinyl]phenol
Combretastatin A-4
3,4,5-Trimethoxy-3'-hydroxy-4'-methoxy-(Z)-stilbene
Phenol, 2-methoxy-5-[(Z)-2-(3,4,5-trimethoxyphenyl)ethenyl]-

Biological Activity

[Description]:

Combretastatin A4 is a microtubule-targeting agent that binds β-tubulin with Kd of 0.4 μM.

[Related Catalog]:

Signaling Pathways >> Cell Cycle/DNA Damage >> Microtubule/Tubulin

Signaling Pathways >> Cytoskeleton >> Microtubule/Tubulin

Natural Products >> Others

Research Areas >> Cancer

[Target]

Kd: 0.4 μM (β-tubulin)

[In Vitro]

Combretastatin A4 phosphate (≥ 50 µM) significantly increases the percentage of annexin-V-binding cells and significantly decreases forward scatter. Combretastatin A4 phosphate does not appreciably increase hemolysis. Hundred µM Combretastatin A4 phosphate significantly increases Fluo3-fluorescence. The effect of Combretastatin A4 phosphate (100 µM) on annexin-V-binding is significantly blunted, but not abolished, by removal of extracellular Ca2+. Combretastatin A4 phosphate (≥ 50 µM) significantly decreases GSH abundance and ATP levels but does not significantly increase ROS or ceramide[2]. Polymersomes co-encapsulating doxorubicin-combretastatin-A4 phosphate (1:10) shows strong synergistic cytotoxicity against human nasopharyngeal epidermal carcinoma (KB) cells[3]. Pretreatment with Combretastatin A4 phosphate does not influence the amount of VM in 3-D culture as well as the expression of these key molecules[4].

[In Vivo]

DBP and MBP at 30 minutes after administration are higher in rats treated with Combretastatin A4 disodium phosphate 120 mg/10 mL/kg. The toxicokinetic parameters of Combretastatin A4 phosphate and Combretastatin A4 in rats treated with Combretastatin A4 disodium phosphate 120 mg/10 mL/kg are indicated, and the values of Cmax, T1/2, and AUC0-inf for Combretastatin A4 are 156±13 μM, 5.87±1.69 h, and 89.4±10.1 h·μM, respectively[1]. In vivo, W256 tumors show marked intratumoral hypoxia after Combretastatin A4 phosphate treatment, accompanied by increased VM formation. Combretastatin A4 phosphate exhibits only a delay in tumor growth within 2 days but rapid tumor regrowth afterward. VM density is positively related to tumor volume and tumor weight at day 8. Combretastatin A4 phosphate causes hypoxia which induces VM formation in W256 tumors through HIF-1α/EphA2/PI3K/matrix metalloproteinase (MMP) signaling pathway, resulting in the consequent regrowth of the damaged tumor[4].

[Animal admin]

Rats: Rats are administered a single intravenous dose of Combretastatin A4 disodium phosphate at 120 mg/10 mL/kg by bolus infusion (n=3). Blood is taken via the jugular vein and collected in heparin-coated tubes at 10 minutes and 1, 3, 6, and 24 hours after administration. Plasma is separated by centrifugation immediately after sampling. After centrifugation, an aliquot of plasma is mixed with the equivalent volume of 1% formic acid and stored at −20°C. The thawed plasma samples are purified by solid-phase extraction, and the plasma concentrations of combretastatin A4 phosphate (free base of Combretastatin A4 disodium phosphate; Combretastatin A4 phosphate) and combretastatin A4 (the metabolite of Combretastatin A4 disodium phosphate; Combretastatin A4 ) are determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Toxicokinetic parameters [maximum concentration (Cmax), terminal half-life (T1/2), and area under the concentration-time curve from time zero to infinity (AUC0-inf)] are obtained by non-compartmental analysis using Phoenix WinNonlin 6.3.

[References]

[1]. Tochinai R, et al. Combretastatin A4 disodium phosphate-induced myocardial injury. J Toxicol Pathol. 2016 Jul;29(3):163-71.

[2]. Signoretto E, et al. Stimulation of Eryptosis by Combretastatin A4 Phosphate Disodium (CA4P). Cell Physiol Biochem. 2016;38(3):969-81

[3]. Zhu J, et al. Co-Encapsulation of Combretastatin-A4 Phosphate and Doxorubicin in Polymersomes for Synergistic Therapy of Nasopharyngeal Epidermal Carcinoma. J Biomed Nanotechnol. 2015 Jun;11(6):997-1006.

[4]. Yao N, et al. Combretastatin A4 phosphate treatment induces vasculogenic mimicry formation of W256 breast carcinoma tumor in vitro and in vivo. Tumour Biol. 2015 Nov;36(11):8499-510.

[Related Small Molecules]

Chemical & Physical Properties

[ Density]:
1.2±0.1 g/cm3

[ Boiling Point ]:
490.3±45.0 °C at 760 mmHg

[ Melting Point ]:
84.5-85.5ºC

[ Molecular Formula ]:
C₁₈H₂₀O₅

[ Molecular Weight ]:
316.348

[ Flash Point ]:
250.3±28.7 °C

[ Exact Mass ]:
316.131073

[ PSA ]:
57.15000

[ LogP ]:
3.57

[ Vapour Pressure ]:
0.0±1.3 mmHg at 25°C

[ Index of Refraction ]:
1.607

[ Storage condition ]:
Desiccate at -20°C

[ Water Solubility ]:
DMSO: >10mg/mL

MSDS

Click to get detail MSDS

Safety Information

[ Symbol ]:

GHS05, GHS06

[ Signal Word ]:
Danger

[ Hazard Statements ]:
H301 + H311 + H331-H318

[ Precautionary Statements ]:
P261-P280-P301 + P310-P305 + P351 + P338-P311

[ Personal Protective Equipment ]:
Eyeshields;Faceshields;Gloves;type P2 (EN 143) respirator cartridges

[ Hazard Codes ]:
T: Toxic;

[ Risk Phrases ]:
R23/24/25;R41

[ Safety Phrases ]:
26-36/37-39-45

[ RIDADR ]:
UN 2811

[ Packaging Group ]:
Ⅲ

[ Hazard Class ]:
6.0

Synthetic Route

Click to get detail synthetic route

Precursor & DownStream

Precursor

DownStream

Articles

Microfluidic Synthesis of Hybrid Nanoparticles with Controlled Lipid Layers: Understanding Flexibility-Regulated Cell-Nanoparticle Interaction.

ACS Nano 9 , 9912-21, (2015)

The functionalized lipid shell of hybrid nanoparticles plays an important role for improving their biocompatibility and in vivo stability. Yet few efforts have been made to critically examine the shel...

The vascular disrupting activity of OXi8006 in endothelial cells and its phosphate prodrug OXi8007 in breast tumor xenografts.

Cancer Lett. 369 , 229-41, (2015)

This study describes the vascular disrupting ability and the mechanism of action of the indole-based tubulin-binding compound, OXi8006, and its water-soluble phosphate prodrug OXi8007. Treatment of ra...

PD806: a novel oral vascular disrupting agent shows antitumor and antivascular effects in vitro and in vivo.

Anticancer Drugs 26(2) , 148-59, (2014)

The aim of this study was to investigate the antitumor and antivascular effects of PD806, a new oral prodrug of AVE8063 in vitro and in vivo. The cytotoxicity of PD806 was determined against H22, Walk...