Capnellene
Encyclopedia
Capnellene is a naturally occurring hydrocarbon
derived from Capnella imbricata, a species of soft coral found in Indonesia
. Since the 1970s, capnellene has been targeted for synthesis by numerous investigators due to its stereochemistry
, functionality, and the interesting geometry of the carbon skeleton. Many alcohol
derivatives of capnellene have demonstrated potential as a chemotherapeutic
agent with antibacterial, anti-inflammatory
and anti-tumor properties.
Capnellene is also a sesquiterpene
, a class of terpene
s that are natural semiochemical
s. However, it is a non-isoprenoid sesquiterpene, meaning that unlike most sesquiterpenes its structure is not based on a repeated isoprene
unit. Capnellene is the presumed biosynthetic precursor to the capnellanols, a group of alcohols based on the capnellene skeleton that are also produced by Capnella imbricata, however the biosynthesis
of these compounds has not yet been elucidated.
properties, based on an earlier discovery of antimicrobial activity in gorgonian soft corals and a later study of antimicrobial terpenoid
compounds in alcyonarian
s. It was also postulated that capnellenes also protect the soft coral by preventing larval settlement.
Capnella imbricata is a rich source of many non-isoprenoid sesquiterpenes, which all share the cis,anti,cis-tricyclo[6.3.0.02,6]undecane ring system. Consequently, the first known isolation of a capnellane derivative was not capnellene but a capnellanol. As part of an ongoing search for terpenoids from marine sources, Kaisin et al. (1974) characterized the most abundant terpenoid, Δ9(12)-capnellene-3β,8β,10α-triol, from colonies of Capnella imbricata. The structure and absolute configuration
of the triol were determined by nuclear magnetic resonance (NMR) spectroscopy
and later confirmed by x-ray crystallography
.
Kaisin et al. (1974) coined the name “capnellane” for the hydrocarbon skeleton on which the molecule was based. However, Shiekh et al. (1976) also claim to have originated the name. The first isolation of the hydrocarbon form, Δ9(12)-capnellene, was achieved in 1978. Since then, numerous groups have isolated both Δ9(12)-capnellene and its alcohol derivatives.
) known as Kenya Tree Coral. Capnella is a widely distributed genus of soft coral, found primarily in the tropical reefs of Indonesia. These corals produce a variety of sterols, sesquiterpenes and diterpenes. Specifically, the capnellanol derivatives found in Capnella serve as a defense system by inhibiting the growth of microorganisms and the settlement of larvae on the coral’s surface. However, the details of this defense mechanism have not been extensively explored. Although the natural synthesis of capnellene and its derivatives is not yet understood, the sesquiterpene hydrocarbon precapnelladiene has been isolated from the same coral and research suggests that may be a biogenetic precursor
.
s. The second pentane ring was formed by condensation
of the aldehyde
by vinylmagnesium bromide, followed by Nazarov cyclization of the dienone. A regiospecific [3+2] cyclopentannulation, using ozonolysis
and an intramolecular aldol condensation
, formed the third ring and a simple dehydration reaction yielded the target capnellene.
Since the first synthesis, many investigators have successfully assembled capnellene and its derivatives. Approaches to this synthesis are diverse, and include central steps such as annululation, olefin metathesis
, radical cyclization
, and trapping reactions. The most heavily cited synthesis in the literature involves two key intermediates formed by a Stille reaction
, the palladium
-catalyzed coupling
of vinyl
triflate
with vinyl stannane
. The readily prepared trimethylcyclopentanone can be converted into vinyl triflate, which is coupled with vinylstannane in the first palladium-catalyzed step to yield the desired divinyl ketone. The second 5-membered ring is formed via Nazarov cyclization, and the product is prepared for a second palladium-catalyzed coupling. This step yields another divinyl ketone, which can be cyclized to an enone
, hydrated
, and converted to an alkene via olefination to yield capnellene.
in vitro
against cervical epitheloid carcinoma (Hela
), oral epidermoid (KB), medulloblastoma
(Daoy) and colon adenocarcinoma
(WiDr) human tumor cell lines. The diol was also effective against human leukemia
, renal leiomyoblastoma, colon and breast cancer
cell lines. In the same study, capnellene-8β-ol demonstrated selective toxicity for the renal leiomyoblastoma and ovarian cancer
cell lines, while 3β-acetoxycapnellene-8β,10α,14β-triol was active against leukemia cell lines. The antitumor properties of capnellene derivatives have yet to be explored in vivo
.
. Neuropathic pain is characterized by damage to peripheral or central nerves that results in pathological nociceptive transmission, the neuronal process that responds noxious stimuli. Two capnellene derivatives Δ9,12-capnellene-8β,10α-diol and 8α-acetoxy-Δ9,12-capnellene-10α-ol demonstrate potential as analgesics capable of attenuating neuropathic pain. These compounds have been shown in vivo to reduce two proteins that mediate inflammation, cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase
(iNOS). In vivo, Δ9,12-capnellene-8β,10α-diol inhibited hyperalgesia
behavior in the mouse model for neuropathic pain in a dose-dependent manner. Additionally, treatment with Δ9,12-capnellene-8β,10α-diol inhibited the up-regulation of immunoreactivity in the mouse model, specifically targeting the production of COX-2. Unlike many non-steroidal anti-inflammatory drugs(NSAIDs), Δ9,12-capnellene-8β,10α-diol is advantageous in its selectivity for the COX isoenzyme COX-2, avoiding many of the gastrointestinal side effects associated with the inhibition of COX-1. This fact would allow for the administration of Δ9,12-capnellene-8β,10α-diol in higher doses, potentially offering significant relief from neuropathic pain.
Hydrocarbon
In organic chemistry, a hydrocarbon is an organic compound consisting entirely of hydrogen and carbon. Hydrocarbons from which one hydrogen atom has been removed are functional groups, called hydrocarbyls....
derived from Capnella imbricata, a species of soft coral found in Indonesia
Indonesia
Indonesia , officially the Republic of Indonesia , is a country in Southeast Asia and Oceania. Indonesia is an archipelago comprising approximately 13,000 islands. It has 33 provinces with over 238 million people, and is the world's fourth most populous country. Indonesia is a republic, with an...
. Since the 1970s, capnellene has been targeted for synthesis by numerous investigators due to its stereochemistry
Stereochemistry
Stereochemistry, a subdiscipline of chemistry, involves the study of the relative spatial arrangement of atoms within molecules. An important branch of stereochemistry is the study of chiral molecules....
, functionality, and the interesting geometry of the carbon skeleton. Many alcohol
Alcohol
In chemistry, an alcohol is an organic compound in which the hydroxy functional group is bound to a carbon atom. In particular, this carbon center should be saturated, having single bonds to three other atoms....
derivatives of capnellene have demonstrated potential as a chemotherapeutic
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
agent with antibacterial, anti-inflammatory
Anti-inflammatory
Anti-inflammatory refers to the property of a substance or treatment that reduces inflammation. Anti-inflammatory drugs make up about half of analgesics, remedying pain by reducing inflammation as opposed to opioids, which affect the central nervous system....
and anti-tumor properties.
Structure
Δ9(12)-capnellene, also referred to simply as capnellene in the literature, is a monounsaturated hydrocarbon of the molecular formula C15H24. It features a tricyclic skeleton, a geminal dimethyl group, a tertiary methyl group, and an exocyclic methylene group.Capnellene is also a sesquiterpene
Sesquiterpene
Sesquiterpenes are a class of terpenes that consist of three isoprene units and have the molecular formula C15H24. Like monoterpenes, sesquiterpenes may be acyclic or contain rings, including many unique combinations...
, a class of terpene
Terpene
Terpenes are a large and diverse class of organic compounds, produced by a variety of plants, particularly conifers, though also by some insects such as termites or swallowtail butterflies, which emit terpenes from their osmeterium. They are often strong smelling and thus may have had a protective...
s that are natural semiochemical
Semiochemical
A semiochemical is a generic term used for a chemical substance or mixture that carries a message. These chemicals acts as messengers within or between species...
s. However, it is a non-isoprenoid sesquiterpene, meaning that unlike most sesquiterpenes its structure is not based on a repeated isoprene
Isoprene
Isoprene , or 2-methyl-1,3-butadiene, is a common organic compound with the formula CH2=CCH=CH2. Under standard conditions it is a colorless liquid...
unit. Capnellene is the presumed biosynthetic precursor to the capnellanols, a group of alcohols based on the capnellene skeleton that are also produced by Capnella imbricata, however the biosynthesis
Biosynthesis
Biosynthesis is an enzyme-catalyzed process in cells of living organisms by which substrates are converted to more complex products. The biosynthesis process often consists of several enzymatic steps in which the product of one step is used as substrate in the following step...
of these compounds has not yet been elucidated.
History
The capnellane group became a focal point for synthesis in the 1970s and 80’s. Scientists believed that these compounds had antimicrobialAntimicrobial
An anti-microbial is a substance that kills or inhibits the growth of microorganisms such as bacteria, fungi, or protozoans. Antimicrobial drugs either kill microbes or prevent the growth of microbes...
properties, based on an earlier discovery of antimicrobial activity in gorgonian soft corals and a later study of antimicrobial terpenoid
Terpenoid
The terpenoids , sometimes called isoprenoids, are a large and diverse class of naturally occurring organic chemicals similar to terpenes, derived from five-carbon isoprene units assembled and modified in thousands of ways. Most are multicyclic structures that differ from one another not only in...
compounds in alcyonarian
Alcyonarian
The Alcyonarian corals are organisms resembling the octocorals . This individual polyps formed colonies and bore sclerites. The Burgess shale organism Margaretia dorus resembles an Alcyonarian, according to C.D. Walcott , and was reclassified as green algae closely resembling modern Caulerpa by...
s. It was also postulated that capnellenes also protect the soft coral by preventing larval settlement.
Capnella imbricata is a rich source of many non-isoprenoid sesquiterpenes, which all share the cis,anti,cis-tricyclo[6.3.0.02,6]undecane ring system. Consequently, the first known isolation of a capnellane derivative was not capnellene but a capnellanol. As part of an ongoing search for terpenoids from marine sources, Kaisin et al. (1974) characterized the most abundant terpenoid, Δ9(12)-capnellene-3β,8β,10α-triol, from colonies of Capnella imbricata. The structure and absolute configuration
Absolute configuration
An absolute configuration in stereochemistry is the spatial arrangement of the atoms of a chiral molecular entity and its stereochemical description e.g. R or S....
of the triol were determined by nuclear magnetic resonance (NMR) spectroscopy
NMR spectroscopy
Nuclear magnetic resonance spectroscopy, most commonly known as NMR spectroscopy, is a research technique that exploits the magnetic properties of certain atomic nuclei to determine physical and chemical properties of atoms or the molecules in which they are contained...
and later confirmed by x-ray crystallography
X-ray crystallography
X-ray crystallography is a method of determining the arrangement of atoms within a crystal, in which a beam of X-rays strikes a crystal and causes the beam of light to spread into many specific directions. From the angles and intensities of these diffracted beams, a crystallographer can produce a...
.
Kaisin et al. (1974) coined the name “capnellane” for the hydrocarbon skeleton on which the molecule was based. However, Shiekh et al. (1976) also claim to have originated the name. The first isolation of the hydrocarbon form, Δ9(12)-capnellene, was achieved in 1978. Since then, numerous groups have isolated both Δ9(12)-capnellene and its alcohol derivatives.
Natural Isolation
Naturally occurring alcohol derivatives of capnellene have been isolated using simple acetone extraction from Capnella imbricata, a species of soft coral (order AlcyonaceaAlcyonacea
The Alcyonacea, or the soft corals are an order of corals which do not produce calcium carbonate skeletons. Soft corals contain minute, spiny skeletal elements called sclerites. Aside from their scientific utility in species identification, sclerites give these corals some degree of support and...
) known as Kenya Tree Coral. Capnella is a widely distributed genus of soft coral, found primarily in the tropical reefs of Indonesia. These corals produce a variety of sterols, sesquiterpenes and diterpenes. Specifically, the capnellanol derivatives found in Capnella serve as a defense system by inhibiting the growth of microorganisms and the settlement of larvae on the coral’s surface. However, the details of this defense mechanism have not been extensively explored. Although the natural synthesis of capnellene and its derivatives is not yet understood, the sesquiterpene hydrocarbon precapnelladiene has been isolated from the same coral and research suggests that may be a biogenetic precursor
Precursor (chemistry)
In chemistry, a precursor is a compound that participates in the chemical reaction that produces another compound. In biochemistry, the term "precursor" is used more specifically to refer to a chemical compound preceding another in a metabolic pathway....
.
Synthesis
Capnellene has been a popular target for synthesis due to its molecular architecture, its role in the defense mechanism of soft corals, and the challenge posed by the high degree of functionalization, stereochemical sophistication, and the complexity of the undecane skeleton. In 1981, the first stereocontrolled synthesis of (±)-Δ9(12)-capnellene was performed in nine steps, with an overall yield of 60%. Their starting reagent was a dimethylated cyclopentenyl carboxaldehyde and the overall synthesis took the form of a series of pentane ring annulationAnnulation
Annulation in organic chemistry is a chemical reaction in which a new ring is constructed on another molecule ....
s. The second pentane ring was formed by condensation
Condensation reaction
A condensation reaction is a chemical reaction in which two molecules or moieties combine to form one single molecule, together with the loss of a small molecule. When this small molecule is water, it is known as a dehydration reaction; other possible small molecules lost are hydrogen chloride,...
of the aldehyde
Aldehyde
An aldehyde is an organic compound containing a formyl group. This functional group, with the structure R-CHO, consists of a carbonyl center bonded to hydrogen and an R group....
by vinylmagnesium bromide, followed by Nazarov cyclization of the dienone. A regiospecific [3+2] cyclopentannulation, using ozonolysis
Ozonolysis
Ozonolysis is the cleavage of an alkene or alkyne with ozone to form organic compounds in which the multiple carbon–carbon bond has been replaced by a double bond to oxygen...
and an intramolecular aldol condensation
Aldol condensation
An aldol condensation is an organic reaction in which an enol or an enolate ion reacts with a carbonyl compound to form a β-hydroxyaldehyde or β-hydroxyketone, followed by a dehydration to give a conjugated enone....
, formed the third ring and a simple dehydration reaction yielded the target capnellene.
Since the first synthesis, many investigators have successfully assembled capnellene and its derivatives. Approaches to this synthesis are diverse, and include central steps such as annululation, olefin metathesis
Olefin metathesis
Olefin metathesis or transalkylidenation is an organic reaction that entails redistribution of alkylene fragments by the scission of carbon - carbon double bonds in olefins . Its advantages include the creation of fewer sideproducts and hazardous wastes. Yves Chauvin, Robert H. Grubbs, and Richard R...
, radical cyclization
Radical cyclization
Radical cyclization reactions are organic chemical transformations that yield cyclic products via radical intermediates. They usually proceed in three basic steps: selective radical generation, radical cyclization, and conversion of the cyclized radical to product.-Introduction:Radical cyclization...
, and trapping reactions. The most heavily cited synthesis in the literature involves two key intermediates formed by a Stille reaction
Stille reaction
The Stille reaction is a chemical reaction coupling an organotin compound with an sp2-hybridized organic halide catalyzed by palladium. The reaction is widely used in organic synthesis....
, the palladium
Palladium
Palladium is a chemical element with the chemical symbol Pd and an atomic number of 46. It is a rare and lustrous silvery-white metal discovered in 1803 by William Hyde Wollaston. He named it after the asteroid Pallas, which was itself named after the epithet of the Greek goddess Athena, acquired...
-catalyzed coupling
Coupling reaction
A coupling reaction in organic chemistry is a catch-all term for a variety of reactions where two hydrocarbon fragments are coupled with the aid of a metal catalyst...
of vinyl
Vinyl
A vinyl compound is any organic compound that contains a vinyl group ,which are derivatives of ethene, CH2=CH2, with one hydrogen atom replaced with some other group...
triflate
Triflate
Trifluoromethanesulfonate, also known by the trivial name triflate, is a functional group with the formula CF3SO3-. The triflate group is often represented by -OTf, as opposed to -Tf...
with vinyl stannane
Stannane
Stannane is the hydride of tin. Stannane can be prepared by the reaction of SnCl4 and LiAlH4. Stannane decomposes slowly at room temperature to give metallic tin and hydrogen and ignites on contact with air....
. The readily prepared trimethylcyclopentanone can be converted into vinyl triflate, which is coupled with vinylstannane in the first palladium-catalyzed step to yield the desired divinyl ketone. The second 5-membered ring is formed via Nazarov cyclization, and the product is prepared for a second palladium-catalyzed coupling. This step yields another divinyl ketone, which can be cyclized to an enone
Enone
An enone is an unsaturated chemical compound or functional group consisting of a conjugated system of an alkene and a ketone. The simplest enone is methyl vinyl ketone or CH2=CHCOCH3....
, hydrated
Hydration reaction
In organic chemistry, a hydration reaction is a chemical reaction in which a hydroxyl group and a hydrogen cation are added to the two carbon atoms bonded together in the carbon-carbon double bond which makes up an alkene functional group. The reaction usually runs in a strong acidic, aqueous...
, and converted to an alkene via olefination to yield capnellene.
Applications
Since the 1960s, marine organisms with robust chemical defense systems have been targeted for “molecular mining,” a method of drug discovery that probes organisms of interest for useful compounds. Chemical agents involved in the defense systems of these organisms often exhibit antibacterial, anti-inflammatory, and chemotherapeutic properties. Capnellene derivatives and their terrestrial counterparts, hirsutanes, demonstrate antibacterial and antitumor properties with pharmacological potential.Antitumor Properties
Capnellene-8β,10α-diol and its acylated derivatives exhibit significant cytotoxicityCytotoxicity
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:...
in vitro
In vitro
In vitro refers to studies in experimental biology that are conducted using components of an organism that have been isolated from their usual biological context in order to permit a more detailed or more convenient analysis than can be done with whole organisms. Colloquially, these experiments...
against cervical epitheloid carcinoma (Hela
Hela
Hela can stand for:* Hela, an ancient name for Sri Lanka* Hela , a name for the Sinhala people of Sri Lanka* Hela a Hindu caste found in North India* HeLa cells derived from Henrietta Lacks...
), oral epidermoid (KB), medulloblastoma
Medulloblastoma
Medulloblastoma is a highly malignant primary brain tumor that originates in the cerebellum or posterior fossa.Previously, medulloblastomas were thought to represent a subset of primitive neuroectodermal tumor of the posterior fossa...
(Daoy) and colon adenocarcinoma
Adenocarcinoma
Adenocarcinoma is a cancer of an epithelium that originates in glandular tissue. Epithelial tissue includes, but is not limited to, the surface layer of skin, glands and a variety of other tissue that lines the cavities and organs of the body. Epithelium can be derived embryologically from...
(WiDr) human tumor cell lines. The diol was also effective against human leukemia
Leukemia
Leukemia or leukaemia is a type of cancer of the blood or bone marrow characterized by an abnormal increase of immature white blood cells called "blasts". Leukemia is a broad term covering a spectrum of diseases...
, renal leiomyoblastoma, colon and breast cancer
Breast cancer
Breast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...
cell lines. In the same study, capnellene-8β-ol demonstrated selective toxicity for the renal leiomyoblastoma and ovarian cancer
Ovarian cancer
Ovarian cancer is a cancerous growth arising from the ovary. Symptoms are frequently very subtle early on and may include: bloating, pelvic pain, difficulty eating and frequent urination, and are easily confused with other illnesses....
cell lines, while 3β-acetoxycapnellene-8β,10α,14β-triol was active against leukemia cell lines. The antitumor properties of capnellene derivatives have yet to be explored in vivo
In vivo
In vivo is experimentation using a whole, living organism as opposed to a partial or dead organism, or an in vitro controlled environment. Animal testing and clinical trials are two forms of in vivo research...
.
Anti-Inflammatory Properties
Capnellene derivatives have recently been identified as possible treatments for neuropathic painNeuropathic pain
Neuropathic pain results from lesions or diseases affecting the somatosensory system. It may be associated with abnormal sensations called dysesthesia, which occur spontaneously and allodynia that occurs in response to external stimuli. Neuropathic pain may have continuous and/or episodic ...
. Neuropathic pain is characterized by damage to peripheral or central nerves that results in pathological nociceptive transmission, the neuronal process that responds noxious stimuli. Two capnellene derivatives Δ9,12-capnellene-8β,10α-diol and 8α-acetoxy-Δ9,12-capnellene-10α-ol demonstrate potential as analgesics capable of attenuating neuropathic pain. These compounds have been shown in vivo to reduce two proteins that mediate inflammation, cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase
Nitric oxide synthase
Nitric oxide synthases are a family of enzymes that catalyze the production of nitric oxide from L-arginine. NO is an important cellular signaling molecule, having a vital role in many biological processes...
(iNOS). In vivo, Δ9,12-capnellene-8β,10α-diol inhibited hyperalgesia
Hyperalgesia
Hyperalgesia is an increased sensitivity to pain, which may be caused by damage to nociceptors or peripheral nerves. Temporary increased sensitivity to pain also occurs as part of sickness behavior, the evolved response to infection.-Types:...
behavior in the mouse model for neuropathic pain in a dose-dependent manner. Additionally, treatment with Δ9,12-capnellene-8β,10α-diol inhibited the up-regulation of immunoreactivity in the mouse model, specifically targeting the production of COX-2. Unlike many non-steroidal anti-inflammatory drugs(NSAIDs), Δ9,12-capnellene-8β,10α-diol is advantageous in its selectivity for the COX isoenzyme COX-2, avoiding many of the gastrointestinal side effects associated with the inhibition of COX-1. This fact would allow for the administration of Δ9,12-capnellene-8β,10α-diol in higher doses, potentially offering significant relief from neuropathic pain.