Combretastatin
Encyclopedia
The combretastatins are a class of natural stilbenoid natural phenol
s. A variety of different natural combretastatin molecules are present in the bark of Combretum caffrum
, commonly known as South African Bush Willow. Despite having a similar name combretastatin is unrelated to statins, a family of cholesterol lowering drugs.
Molecules that fall into the combretastatin family generally share 3 common structural features: a trimethoxy "A"-ring, a "B"-ring containing substitutents often at C3' and C4', and an ethene bridge between the two rings which provides necessary structural rigidity. Molecules with C3' amino and hydroxyl
substituents are very active, and molecules with C4' hydroxyl or methoxy
substituents are also cytotoxic. Of the natural products presently known combretastatin A-4
is the most potent in regards to both tubulin
binding ability and cytotoxicity
. Combretastatin A-1
is also a potent cytotoxic agent.
disruption in tumor
s. Combretastatin binds to the β-subunit of tubulin
at what is called the colchicine site, referring to the previously discovered vascular disrupting agent colchicine
. Inhibition of tubulin polymerization
prevents cancer
cells from producing microtubules. Microtubules are essential to cytoskeleton
production, intercellular movement, cell movement, and formation of the mitotic spindle
used in chromosome segregation and cellular division. The anti-cancer activity from this action results from a change in shape in vasculature endothelial cells. Endothelial cells treated with combretastatin rapidly balloon in shape causing a variety of effects which result in necrosis
of the tumor core. The tumor edge is supported by normal vasculature and remains, for the most part, unaffected. As a result it is likely that any therapeutic use will involve a combination of drugs or treatment options.
, the most potent naturally occurring combretastatin known, its phosphate prodrug
(CA-4-P
), and other analogs
of CA-4 such as ombrabulin
are currently being investigated in a number of clinical trials. In July 2007 the pharmaceutical company OXiGENE initiated a 180-patient phase III clinical trial of CA-4-P in combination with carboplatin
for the treatment of anaplastic thyroid cancer
. There is currently no fully FDA approved treatment for this form of cancer.
Natural phenol
Natural phenols, bioavailable phenols, plant phenolics, low molecular weight phenols or phenoloids are a class of natural products. They are small molecules containing one or more phenolic group. These molecules are smaller in size than polyphenols, containing less than 12 phenolic groups...
s. A variety of different natural combretastatin molecules are present in the bark of Combretum caffrum
Combretum caffrum
Combretum caffrum is the Eastern Cape South African Bushwillow tree.-Biochemistry:In C. caffrum, combretastatins A-1, A-4 and B-1 can be found....
, commonly known as South African Bush Willow. Despite having a similar name combretastatin is unrelated to statins, a family of cholesterol lowering drugs.
Natural combretastatins
Hydroxyl
A hydroxyl is a chemical group containing an oxygen atom covalently bonded with a hydrogen atom. In inorganic chemistry, the hydroxyl group is known as the hydroxide ion, and scientists and reference works generally use these different terms though they refer to the same chemical structure in...
substituents are very active, and molecules with C4' hydroxyl or methoxy
Methoxy
In chemistry , methoxy refers to the functional group consisting of a methyl group bound to oxygen. This alkoxy group has the formula O–CH3.The word is used in organic nomenclature usually to describe an ether...
substituents are also cytotoxic. Of the natural products presently known combretastatin A-4
Combretastatin A-4
Combretastatin A-4 is a combretastatin, a type of stilbenoid. It can be isolated from Combretum caffrum, the Eastern Cape South African Bushwillow tree.-Derivatives:...
is the most potent in regards to both tubulin
Tubulin
Tubulin is one of several members of a small family of globular proteins. The most common members of the tubulin family are α-tubulin and β-tubulin, the proteins that make up microtubules. Each has a molecular weight of approximately 55 kiloDaltons. Microtubules are assembled from dimers of α- and...
binding ability and cytotoxicity
Cytotoxicity
Cytotoxicity is the quality of being toxic to cells. Examples of toxic agents are a chemical substance, an immune cell or some types of venom .-Cell physiology:...
. Combretastatin A-1
Combretastatin A-1
Combretastatin A-1 is a combretastatin, a chemical compound belonging to stilbenoid class. It can be found in Combretum caffrum, the Eastern Cape South African Bushwillow tree....
is also a potent cytotoxic agent.
Biological function
Members of the combretastatin family possess varying ability to cause vascularBlood vessel
The blood vessels are the part of the circulatory system that transports blood throughout the body. There are three major types of blood vessels: the arteries, which carry the blood away from the heart; the capillaries, which enable the actual exchange of water and chemicals between the blood and...
disruption in tumor
Tumor
A tumor or tumour is commonly used as a synonym for a neoplasm that appears enlarged in size. Tumor is not synonymous with cancer...
s. Combretastatin binds to the β-subunit of tubulin
Tubulin
Tubulin is one of several members of a small family of globular proteins. The most common members of the tubulin family are α-tubulin and β-tubulin, the proteins that make up microtubules. Each has a molecular weight of approximately 55 kiloDaltons. Microtubules are assembled from dimers of α- and...
at what is called the colchicine site, referring to the previously discovered vascular disrupting agent colchicine
Colchicine
Colchicine is a medication used for gout. It is a toxic natural product and secondary metabolite, originally extracted from plants of the genus Colchicum...
. Inhibition of tubulin polymerization
Polymerization
In polymer chemistry, polymerization is a process of reacting monomer molecules together in a chemical reaction to form three-dimensional networks or polymer chains...
prevents cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
cells from producing microtubules. Microtubules are essential to cytoskeleton
Cytoskeleton
The cytoskeleton is a cellular "scaffolding" or "skeleton" contained within a cell's cytoplasm and is made out of protein. The cytoskeleton is present in all cells; it was once thought to be unique to eukaryotes, but recent research has identified the prokaryotic cytoskeleton...
production, intercellular movement, cell movement, and formation of the mitotic spindle
Mitotic spindle
In cell biology, the spindle fibers are the structure that separates the chromosomes into the daughter cells during cell division. It is part of the cytoskeleton in eukaryotic cells...
used in chromosome segregation and cellular division. The anti-cancer activity from this action results from a change in shape in vasculature endothelial cells. Endothelial cells treated with combretastatin rapidly balloon in shape causing a variety of effects which result in necrosis
Necrosis
Necrosis is the premature death of cells in living tissue. Necrosis is caused by factors external to the cell or tissue, such as infection, toxins, or trauma. This is in contrast to apoptosis, which is a naturally occurring cause of cellular death...
of the tumor core. The tumor edge is supported by normal vasculature and remains, for the most part, unaffected. As a result it is likely that any therapeutic use will involve a combination of drugs or treatment options.
Synthesis
A variety of possible routes to the combretastatin skeleton are possible. One reasonably easy synthesis is as follows:- 1-Bromomethyl-3,4,5-trimethoxybenzene undergoes an SN2 reaction with triphenylphosphineTriphenylphosphineTriphenylphosphine is a common organophosphorus compound with the formula P3 - often abbreviated to PPh3 or Ph3P. It is widely used in the synthesis of organic and organometallic compounds. PPh3 exists as relatively air stable, colorless crystals at room temperature...
, which yields a phosphoniumPhosphoniumThe phosphonium cation describes positively charged polyatomic cations with the chemical formula . Salts of the parent PH4+ are rarely encountered, but this ion is an intermediate in the preparation of the industrially useful tetrakisphosphonium chloride:Organic phosphonium salts are common...
salt. - This compound, through an ylideYlideAn ylide or ylid is a neutral dipolar molecule containing a formally negatively charged atom directly attached to a hetero atom with a formal positive charge , and in which both atoms have full octets of electrons. Ylides are thus 1,2-dipolar compounds...
intermediate, is coupled to a benzaldehydeBenzaldehydeBenzaldehyde is an organic compound consisting of a benzene ring with a formyl substituent. It is the simplest aromatic aldehyde and one of the most industrially useful. This colorless liquid has a characteristic pleasant almond-like odor...
-derived B-ring possessing the desired substitutents using a Wittig olefination. - The Wittig reaction produces varying amounts of E and Z isomers depending mainly on solvent polarityChemical polarityIn chemistry, polarity refers to a separation of electric charge leading to a molecule or its chemical groups having an electric dipole or multipole moment. Polar molecules interact through dipole–dipole intermolecular forces and hydrogen bonds. Molecular polarity is dependent on the difference in...
, temperature, metal cation coordination effectsComplex (chemistry)In chemistry, a coordination complex or metal complex, is an atom or ion , bonded to a surrounding array of molecules or anions, that are in turn known as ligands or complexing agents...
, and the electronic effect of substituents on either the triphenylphosphine salt or the benzaldehyde. Generally cis-combretastatin possesses significantly improved ability to inhibit tubulin polymerization as well as cytotoxicityCytotoxicityCytotoxicity is the quality of being toxic to cells. Examples of toxic agents are a chemical substance, an immune cell or some types of venom .-Cell physiology:...
.
Clinical studies
Combretastatin A-4Combretastatin A-4
Combretastatin A-4 is a combretastatin, a type of stilbenoid. It can be isolated from Combretum caffrum, the Eastern Cape South African Bushwillow tree.-Derivatives:...
, the most potent naturally occurring combretastatin known, its phosphate prodrug
Prodrug
A prodrug is a pharmacological substance administered in an inactive form. Once administered, the prodrug is metabolised in vivo into an active metabolite, a process termed bioactivation. The rationale behind the use of a prodrug is generally for absorption, distribution, metabolism, and...
(CA-4-P
Combretastatin A-4 phosphate
Combretastatin A-4 phosphate is a microtubule destabilizing drug, a type of vascular-targeting agent, a drug designed to damage the vasculature of cancer tumors causing central necrosis. It is a derivative of combretastatin.Combretastatin A-4 phosphate is a prodrug. In vivo, it is...
), and other analogs
Analog (chemistry)
In chemistry, a structural analog , also known as chemical analog or simply analog, is a compound having a structure similar to that of another one, but differing from it in respect of a certain component. It can differ in one or more atoms, functional groups, or substructures, which are replaced...
of CA-4 such as ombrabulin
Ombrabulin
Ombrabulin is an experimental drug candidate discovered by Ajinomoto and under development by Sanofi-Aventis. It is currently in Phase III clinical trials for the treatment of advanced-stage soft-tissue sarcoma....
are currently being investigated in a number of clinical trials. In July 2007 the pharmaceutical company OXiGENE initiated a 180-patient phase III clinical trial of CA-4-P in combination with carboplatin
Carboplatin
Carboplatin, or cis-Diammineplatinum is a chemotherapy drug used against some forms of cancer...
for the treatment of anaplastic thyroid cancer
Anaplastic thyroid cancer
Anaplastic thyroid cancer is a form of thyroid cancer which has a very poor prognosis due to its aggressive behavior and resistance to cancer treatments.-Presentation:...
. There is currently no fully FDA approved treatment for this form of cancer.