 Chemical Structure.png)
Combretastatin A4 (CA-4; CRC-87-09; Combretastatin A-4) is a highly potent tubulin/microtubule inhibitor or microtubule polymerization destablizer with potential antitumor activity. It belongs to the so called microtubule-targeting agent (MTA) or microtubule disrupting agent and acts by binding to β-tubulin with a Kd of 0.4 μM. It has been in clinical trials for treating various cancers.
Physicochemical Properties
| Molecular Formula | C18H20O5 | |
| Molecular Weight | 316.35 | |
| Exact Mass | 316.131 | |
| CAS # | 117048-59-6 | |
| Related CAS # |
|
|
| PubChem CID | 5351344 | |
| Appearance | White to light yellow solid powder | |
| Density | 1.2±0.1 g/cm3 | |
| Boiling Point | 490.3±45.0 °C at 760 mmHg | |
| Melting Point | 84.5-85.5ºC | |
| Flash Point | 250.3±28.7 °C | |
| Vapour Pressure | 0.0±1.3 mmHg at 25°C | |
| Index of Refraction | 1.607 | |
| LogP | 3.57 | |
| Hydrogen Bond Donor Count | 1 | |
| Hydrogen Bond Acceptor Count | 5 | |
| Rotatable Bond Count | 6 | |
| Heavy Atom Count | 23 | |
| Complexity | 358 | |
| Defined Atom Stereocenter Count | 0 | |
| SMILES | COC1=C(C=C(C=C1)/C=C\C2=CC(=C(C(=C2)OC)OC)OC)O |
|
| InChi Key | HVXBOLULGPECHP-WAYWQWQTSA-N | |
| InChi Code | InChI=1S/C18H20O5/c1-20-15-8-7-12(9-14(15)19)5-6-13-10-16(21-2)18(23-4)17(11-13)22-3/h5-11,19H,1-4H3/b6-5- | |
| Chemical Name | 2-methoxy-5-[(Z)-2-(3,4,5-trimethoxyphenyl)ethenyl]phenol | |
| Synonyms |
|
|
| HS Tariff Code | 2934.99.9001 | |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
|
| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| ln Vitro | Forward scatter is greatly reduced and the proportion of Annexin-V bound cells is significantly increased when combretastatin A4 phosphate (≥ 50 μM) is used. The amount of hemolysis is not considerably increased by combretastatin A4 phosphate. Combretastatin A4 phosphate at concentrations of several hundred μM markedly increased Fluo3 fluorescence. When extracellular Ca2+ is removed, the effect of Combretastatin A4 phosphate (100 μM) on Annexin-V binding is greatly reduced but not completely eliminated. ROS and ceramide are not significantly increased by combretastatin A4 phosphate (≥ 50 μM), but it does dramatically lower GSH abundance and ATP levels [2]. Strong synergistic cytotoxicity was demonstrated by polymer capsules co-encapsulating doxorubicin-combretastatin-A4 phosphate (1:10) against human nasopharyngeal epithelial carcinoma (KB) cells [3]. The expression of these important molecules and the quantity of VM in 3-D cells are unaffected by pretreatment with combretastatin A4 phosphate [4]. | ||
| ln Vivo | Thirty minutes after the treatment, rats given 120 mg/10 mL/kg of Combretastatin A4 disodium phosphate had more DBP and MBP. Rats treated with Combretastatin A4 disodium phosphate 120 mg/10 mL/kg showed the following toxicokinetic characteristics for both Combretastatin A4 and its phosphate: Cmax, T1/2, and AUC0-inf values of Combretastatin A4 were 156± 13 μM, 5.87±1.69 h, and 89.4±10.1 h·μM[1]. W256 tumors showed a substantial intratumoral hypoxia following combretastatin A4 phosphate therapy, which was associated by an increase in VM development. Tumor growth was delayed with cercopetastatin A4 phosphate for a mere two days, however the growth of the tumor quickly resumed. Positive correlations were seen between the VM density and the tumor weight and volume on day 8. Through the HIF-1α/EphA2/PI3K/matrix metalloproteinase (MMP) signaling pathway, cercetastatin A4 phosphate stimulates hypoxia and VM formation in W256 tumors, which impairs tumor renewal [4]. | ||
| Animal Protocol |
|
||
| ADME/Pharmacokinetics |
Metabolism / Metabolites Combretastatin A4 has known human metabolites that include (2S,3S,4S,5R)-3,4,5-trihydroxy-6-[2-methoxy-5-[(Z)-2-(3,4,5-trimethoxyphenyl)ethenyl]phenoxy]oxane-2-carboxylic acid. |
||
| References |
[1]. Combretastatin A4 disodium phosphate-induced myocardial injury. J Toxicol Pathol. 2016 Jul;29(3):163-71. [2]. Stimulation of Eryptosis by Combretastatin A4 Phosphate Disodium (CA4P). Cell Physiol Biochem. 2016;38(3):969-8. [3]. 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]. 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. |
||
| Additional Infomation |
Combretastatin A4 is a stilbenoid. Combretastatin A4 has been reported in Combretum caffrum with data available. Combretastatin A-4 is an inhibitor of microtubule polymerization derived from the South African willow bush which causes mitotic arrest and selectively targets and reduces or destroys existing blood vessels, causing decreased tumor blood supply. See also: Fosbretabulin (annotation moved to). |
Solubility Data
| Solubility (In Vitro) |
|
|||
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 3 mg/mL (9.48 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 30.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 3 mg/mL (9.48 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 30.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. Solubility in Formulation 3: 5% DMSO +50% PEG 300 +ddH2O: 30mg/mL (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.1611 mL | 15.8053 mL | 31.6106 mL | |
| 5 mM | 0.6322 mL | 3.1611 mL | 6.3221 mL | |
| 10 mM | 0.3161 mL | 1.5805 mL | 3.1611 mL |