Combretastatin A4 Phosphate Disodium (also called CA4P, Fosbretabulin; CA 4DP; CA-4P; Zybrestat) is the water-soluble prodrug that has to be activated to the active form, Combretastatin A4 (CA4), which is a highly potent MTA (microtubule-targeting agent) or tubulin inhibitor that acts as a potent anticancer agent that binds β-tubulin with a Kd of 0.4 μM in a cell-free assay. It was originally isolated from African tree Combretum caffrum. Combretastatin A4 inhibits the polymerization of tubulin with an IC50 of 2.4 μM, and also disrupts tumor vasculature. Under in vivo conditions, the prodrug fosbretabulin is dephosphorylated and activated to its active form, combretastatin A4, which binds to tubulin dimers and prevents microtubule polymerization, resulting in mitotic arrest and apoptosis in endothelial cells.

Physicochemical Properties

Molecular Formula	C18H19O8P.2NA
Molecular Weight	440.29
Exact Mass	440.061
CAS #	168555-66-6
Related CAS #	168555-66-6 (disodium);222030-63-9 (free acid);404886-32-4 ( tromethamine);
PubChem CID	6918309
Appearance	White to off-white solid powder
Boiling Point	611.8ºC at 760 mmHg
Melting Point	238-242ºC
Vapour Pressure	7.99E-16mmHg at 25°C
LogP	4.239
Hydrogen Bond Donor Count	0
Hydrogen Bond Acceptor Count	8
Rotatable Bond Count	7
Heavy Atom Count	29
Complexity	496
Defined Atom Stereocenter Count	0
SMILES	COC1=C(C=C(C=C1)/C=C\C2=CC(=C(C(=C2)OC)OC)OC)OP(=O)([O-])[O-].[Na+].[Na+]
InChi Key	VXNQMUVMEIGUJW-XNOMRPDFSA-L
InChi Code	InChI=1S/C18H21O8P.2Na/c1-22-14-8-7-12(9-15(14)26-27(19,20)21)5-6-13-10-16(23-2)18(25-4)17(11-13)24-3;;/h5-11H,1-4H3,(H2,19,20,21);;/q;2*+1/p-2/b6-5-;;
Chemical Name	disodium;[2-methoxy-5-[(Z)-2-(3,4,5-trimethoxyphenyl)ethenyl]phenyl] phosphate
Synonyms	CA 4DP; CA 4P; Combretastatin A4 disodium phosphate; Combretastatin A4 phosphate disodium; CA4P; CA4DP; Combretastatin A4 phosphate; Fosbretabulin disodium; Zybrestat
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 Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.
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	FosbretabuLin disodium suppresses the proliferation of leukemia P-388, pancreatic BXPC-3, neuroblast SK-N-SH, thyroid SW1736, lung-NSC NCI-H460, prostate DU-145, and pharyngeal FADU with EC50 of 0.0029, 0.23, and 0.00025, respectively., 0.00061, 0.00035, 0.00072, and 0.00045 μg/mL[2].
ln Vivo	In rats, fosbretabuLin disodium (100 mg/kg; ip) decreases tumor blood flow and raises mean arterial blood pressure (MABP) one and six hours after injection [3].
Animal Protocol	Animal/Disease Models: Male BD9 rats (7-9 weeks) bearing the sc implanted P22 tumor[3] Doses: 100 mg/kg Route of Administration: A single ip injections Experimental Results: Dramatically raised the MABP by about 30%, and decreased the heart rate at 1 h after administration. decreased the blood flow in the tumor.
References	[1]. Combretastatin A-4 inhibits cell growth and metastasis in bladder cancer cells and retards tumour growth in a murine orthotopic bladder tumour model. Br J Pharmacol. 2010 Aug;160(8):2008-27. [2]. Antineoplastic agents. 445. Synthesis and evaluation of structural modifications of (Z)- and (E)-combretastatin A-41. J Med Chem. 2005 Jun 16;48(12):4087-99. [3]. Combretastatin A-4 phosphate as a tumor vascular-targeting agent: early effects in tumors and normal tissues. Cancer Res. 1999 Apr 1;59(7):1626-34.
Additional Infomation	Fosbretabulin Disodium is the disodium salt of a water-soluble phosphate derivative of a natural stilbenoid phenol derived from the African bush willow (Combretum caffrum) with potential vascular disrupting and antineoplastic activities. Upon administration, the prodrug fosbretabulin is dephosphorylated to its active metabolite, the microtubule-depolymerizing agent combretastatin A4, which binds to tubulin dimers and prevents microtubule polymerization, resulting in mitotic arrest and apoptosis in endothelial cells. In addition, this agent disrupts the engagement of the endothelial cell-specific junctional molecule vascular endothelial-cadherin (VE-cadherin) and so the activity of the VE-cadherin/beta-catenin/Akt signaling pathway, which may result in the inhibition of endothelial cell migration and capillary tube formation. As a result of fosbretabulin's dual mechanism of action, the tumor vasculature collapses, resulting in reduced tumor blood flow and ischemic necrosis of tumor tissue.

Solubility Data

Solubility (In Vitro)	DMSO:<1 mg/mL Water:28 mg/mL (63.59 mM) Ethanol:<1 mg/mL
Solubility (In Vivo)	Solubility in Formulation 1: 14.29 mg/mL (32.46 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication (<60°C). Solubility in Formulation 2: Saline with a few drops of 5% Na2CO3: 30 mg/mL  (Please use freshly prepared in vivo formulations for optimal results.)

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	2.2712 mL	11.3562 mL	22.7123 mL
	5 mM	0.4542 mL	2.2712 mL	4.5425 mL
	10 mM	0.2271 mL	1.1356 mL	2.2712 mL

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.