Marine Pharmacognosy
Encyclopedia
For many years, traditional Western pharmacognosy
focused on the investigation and identification of medically important plants and animals in the terrestrial environment, although many marine organisms were used in Traditional Chinese Medicine
. With the development of the open-circuit self-contained underwater breathing apparatus or SCUBA
in the 1940s, some chemists turned to more pioneering work looking for new medicines in the marine environment. In the United States, the road has been long for the first FDA approval of a drug directly from the sea, but in 2004, the approval of ziconotide isolated from a marine cone snail has paved the way for other marine-derived compounds moving through clinical trials.
With 79% of the earth’s surface covered by water, research into the chemistry of marine organisms is relatively unexplored and represents a vast resource for new medicines to combat major diseases such as cancer
, AIDS
or malaria
. Research typically focuses on sessile organisms or slow moving animals because of their inherent need for chemical defenses. Standard research involves an extraction of the organism in a suitable solvent followed by either an assay of this crude extract for a particular disease target or a rationally guided isolation of new chemical compounds using standard chromatography
techniques.
organisms, are believed to have evolved chemical defenses to protect themselves. It is also believed that the compounds would have to be extremely potent due to the dilution effect of seawater. This has been described to be analogues to pheromones but with the purpose of repelling instead of attracting. As well, predators have evolved chemical weapons in order to paralyze or kill prey. Conus magus
is an example of a cone snail that has a poisoned harpoon-like projectile which it uses to paralyze prey like small fish. Some organisms, like the Viperfish
, are believed to attract small fish or prey by using it's photophore
.
Many different marine organisms have been explored for bioactive compounds. Some vertebrate animals include fish, sharks and snakes. Some examples of invertebrates are sponges, coelenterates, tunicates, echinoderms, corals, algae, molluscs and bryozoans. Some microorganisms include bacteria, fungi and cyanobacteria.
. Marine environments may contain over 80% of the world's plant and animal species. The diversity of coral reefs can be extraordinary with species diversity reaching 1000 species per meter squared. The greatest marine tropical biodiversity is reported to be in the Indo-Pacific Ocean.
. Sample collection from deep water can be completed via dredging however, this is a very invasive technique which destroys the local habitat, does not allow for repeated sampling from the same location and compromises sample integrity. Corers
can be used for sediment sample collection from deep locations quickly, easily and inexpensively. SCUBA diving
was introduced in the 1940s however, it was not widely used until it became popular in the 1970s. SCUBA diving is limited in the duration that divers can spend underwater when conducted from the surface. If prolonged dives were necessary, a underwater laboratory could be used. Aquarius
is the only underwater laboratory dedicated to marine science. For sample collection from depths that cannot be achieved by SCUBA diving, submersibles
may be used. Sample collection by submersibles can be extremely expensive with costs for a submersible, support ship, technicians and support staff ranging between $10,000 to $45,000 per day.
, chromatographic purification
, dereplication, structure elucidation and bioassay
testing. The steps do not have to follow that particular order and many steps may be completed simultaneously. In the first step, the sample may be triturated
and extracted
with a suitable solvent or macerated. Some solvents used are methanol
:chloroform
, ethanol
, acetonitrile
, or others. The purpose is to remove organic compounds that have a medium polarity which are considered more "drug-like"
. Ideally,polar compounds like salts
, peptides
, sugars
as well as very non-polar compounds like lipids
are left behind to simplify chromatography since they are not generally considered "drug-like". Drying of the sample could be completed before extraction by lyophilisation to remove any excess water and therefore limit the amount of highly polar compounds extracted.
The next step depends on the methodology of individual laboratories. Bioassay-guided fractionation is a common method to find biologically active compounds. This involves testing the crude extract or preliminary fractions from chromatography in an assay or multiple assays, determining what fractions or crude extracts show activity in the specific assays, and further fractionating the active fractions or extracts. This step is than repeated where the new fractions are tested and the active fractions are further fractionated. This continues until the fraction only contains one compound. Dereplication is ideally performed as early as possible to determine if the active compound has been previously reported in order to prevent "rediscovering" a compound. This can be performed using Liquid Chromatography- Mass Spectrometry
(LC-MS) data or Nuclear Magnetic Resonance
(NMR) data obtained in the biological assay-guided process and than comparing the information to that found in databases of previously reported compounds.
Structure elucidation is performed by using NMR data obtained of the compound and High Resolution Mass Spectrometry (HR-MS) Data. Tandem Mass Spectrometry
can also be useful, especially for large molecules like glycolipids
, proteins
, polysaccharides
or peptides
. Completed characterization for publication purposes may require Infrared (IR)
, Ultraviolet-visible (UV-vis)
, specific rotation
and melting point
data. Obtaining a crystal structure
via X-ray crystallography
can greatly accelerate and simplify structure elucidation however, obtaining crystals can be quite difficult.
There are many different bioassays available for testing. There are anticancer
, antimicrobial
, antiviral
, anti-inflammatory
, antiparasitic, anticholesterolemic
, and many other differ assays. For MTT assay
and cytosolic
Lactate dehydrogenase (LDH)
release are common cytotoxicity
or cell viability assays
.
|+ Clinical Pipeline of Marine Pharmacology, July 2011. From http://marinepharmacology.midwestern.edu/clinPipeline.htm>
Clinical Status Compound Name Trademark Marine Organismα Chemical Class Molecular Target Clinical Trialsβ Disease Area
FDA-Approved
Cytarabine (Ara-C)
Cytosar-U®
Sponge
Nucleoside
DNA Polymerase
>50/711
Cancer
Vidarabine (Ara-A)
Vira-A®
Sponge
Nucleoside
Viral DNA Polymerase
0
Antiviral
Ziconotide
Prialt®
Cone Snail
Peptide
N-Type Ca2+ Channel
2/5
Analgesic
Eribulin Mesylate (E7389)
Halaven®
Sponge
Macrolide
Microtubules
19/27
Cancer
Omega-3-Fatty Acid Ethyl Esters
Lovaza®
Fish
Omega-3 Fatty Acids
Triglyceride
-Synthesizing Enzymes
45/94
Hypertriglyceridemia
Trabectedin (ET-743)
EU Approved only
Yondelis®
Tunicate
Alkaloid
Minor Groove of DNA
17/34
Cancer
Phase III
Brentuximab Vedotin (SGN-35)
Adcetris®
Mollusk
Antibody-Drug Conjugate
(MM Auristatin E)
CD30
and Microtubules
9/19
Cancer
Plitidepsin
Aplidin®
Tunicate
Depsipeptide
Rac1
and JNK
Activation
1/7
Cancer
Phase II
DMXBA (GTS-21)
N/A
Worm
Alkaloid
Alpha-7 Nicotinic Acetylcholine Receptor
0/3
Congnition, Schizophrenia
Plinabulin (NPI 2358)
N/A
Fungus
Diketopiperazine
Microtubules and JNK Stress Protein
1/2
Cancer
Elisidepsin
Irvalec®
Mollusk
Depsipeptide
Plasma Membrane Fluidity
1/2
Cancer
PM00104
Zalypsis®
Nudibranch
Alkaloid
DNA-Binding
2/3
Cancer
Glembatumumab Vedotin (CDX-011)
N/A
Mollusk
Antibody Drug Conjugate (MM Auristatin E)
Glycoprotein NMB and Microtubules
1/3
Cancer
Phase I
Marizomib (Salinosporamide A)
N/A
Bacterium
Beta-Lactone-Gamma Lactam
20S Proteasome
4/4
Cancer
PM01183
N/A
Tunicate
Alkaloid
Minor Groove of DNA
N/A
Cancer
SGN-75
N/A
Mollusk
Antibody Drug Conjugate (MM Auristatin F)
CD70
and Microtubules
2/2
Cancer
ASG-5ME
N/A
Mollusk
Antibody Drug Conjugate (MM auristatin E)
ASG-5 and Microtubules
2/2
Cancer
Hemiasterlin (E7974)
N/A
Sponge
Tripeptide
Microtubules
0/3
Cancer
Bryostatin 1
N/A
Bryozoa
Polyketide
Protein Kinase C
0/38
Cancer, Alzheimers
Pseudopterosins
N/A
Soft Coral
Diterpene Glycoside
Eicosanoid Metabolism
N/A
Wound Healing
αIncludes natural products or natural product derivatives or analogues;
βNumber of active trials/number of total trials from http://www.clinicaltrials.gov/ as of July 2011
Pharmacognosy
Pharmacognosy is the study of medicines derived from natural sources. The American Society of Pharmacognosy defines pharmacognosy as "the study of the physical, chemical, biochemical and biological properties of drugs, drug substances or potential drugs or drug substances of natural origin as well...
focused on the investigation and identification of medically important plants and animals in the terrestrial environment, although many marine organisms were used in Traditional Chinese Medicine
Traditional Chinese medicine
Traditional Chinese Medicine refers to a broad range of medicine practices sharing common theoretical concepts which have been developed in China and are based on a tradition of more than 2,000 years, including various forms of herbal medicine, acupuncture, massage , exercise , and dietary therapy...
. With the development of the open-circuit self-contained underwater breathing apparatus or SCUBA
Aqua-lung
Aqua-Lung was the original name of the first open-circuit free-swimming underwater breathing set in reaching worldwide popularity and commercial success...
in the 1940s, some chemists turned to more pioneering work looking for new medicines in the marine environment. In the United States, the road has been long for the first FDA approval of a drug directly from the sea, but in 2004, the approval of ziconotide isolated from a marine cone snail has paved the way for other marine-derived compounds moving through clinical trials.
With 79% of the earth’s surface covered by water, research into the chemistry of marine organisms is relatively unexplored and represents a vast resource for new medicines to combat major diseases such as 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...
, AIDS
AIDS
Acquired immune deficiency syndrome or acquired immunodeficiency syndrome is a disease of the human immune system caused by the human immunodeficiency virus...
or malaria
Malaria
Malaria is a mosquito-borne infectious disease of humans and other animals caused by eukaryotic protists of the genus Plasmodium. The disease results from the multiplication of Plasmodium parasites within red blood cells, causing symptoms that typically include fever and headache, in severe cases...
. Research typically focuses on sessile organisms or slow moving animals because of their inherent need for chemical defenses. Standard research involves an extraction of the organism in a suitable solvent followed by either an assay of this crude extract for a particular disease target or a rationally guided isolation of new chemical compounds using standard chromatography
Chromatography
Chromatography is the collective term for a set of laboratory techniques for the separation of mixtures....
techniques.
Marine Organisms as Sources of Natural Products
Over 70% of the earth's surface is covered by oceans which contain 95% of the earth's biosphere. It was over 3500 million years ago that organisms first appeared in the sea. Over time, they have evolved many different mechanisms to survive the various harsh environments which include extreme temperatures, salinity, pressure,different levels of aeration and radiation, overcoming effects of mutation, and combating infection, fouling and overgrowth by other organisms. Adaptations to survive the different environments could be by physical or chemical adaptation. Organisms with no apparent physical defense, like sessileSessility (zoology)
In zoology, sessility is a characteristic of animals which are not able to move about. They are usually permanently attached to a solid substrate of some kind, such as a part of a plant or dead tree trunk, a rock, or the hull of a ship in the case of barnacles. Corals lay down their own...
organisms, are believed to have evolved chemical defenses to protect themselves. It is also believed that the compounds would have to be extremely potent due to the dilution effect of seawater. This has been described to be analogues to pheromones but with the purpose of repelling instead of attracting. As well, predators have evolved chemical weapons in order to paralyze or kill prey. Conus magus
Conus magus
Conus magus, common name the magical cone, is a species of sea snail, a marine gastropod mollusk in the family Conidae, the cone snails and their allies.Like all species within the genus Conus, these snails are predatory and venomous...
is an example of a cone snail that has a poisoned harpoon-like projectile which it uses to paralyze prey like small fish. Some organisms, like the Viperfish
Viperfish
A viperfish is a saltwater fish in the genus Chauliodus, with long, needle-like teeth and hinged lower jaws. They grow to lengths of 30 to 60 cm . Viperfish stay near lower depths in the daytime and shallow at night. Viperfish mainly stay in tropical and temperate waters...
, are believed to attract small fish or prey by using it's photophore
Photophore
A photophore is a light-emitting organ which appears as luminous spots on various marine animals, including fish and cephalopods. The organ can be simple, or as complex as the human eye; equipped with lenses, shutters, color filters and reflectors...
.
Many different marine organisms have been explored for bioactive compounds. Some vertebrate animals include fish, sharks and snakes. Some examples of invertebrates are sponges, coelenterates, tunicates, echinoderms, corals, algae, molluscs and bryozoans. Some microorganisms include bacteria, fungi and cyanobacteria.
True Producer
There is an ongoing debate on what organisms are the actual true producers of some compounds. About 40% of the biomass of sponges can be from microorganisms. It's not surprising that some compounds may actually be produced by symbiotic microorganisms rather than the host.Biological Diversity in Marine Environments
Marine environments are considered more biologically diverse than terrestrial environments. Thirty-two different animal phyla are represented in the oceans of the 33 recognized phyla. Fifteen different phyla are represented only in marine environments while only 1 is elusively terrestrial. Marine phyla also contain functionally unique organisms such as filter feeders and sessile organisms which have no terrestrial counterpart. Also, marine autotrophs are more diverse than their terrestrial counterparts. Marine autotrophs are believed to stem from at least 8 ancient clades while terrestrial organisms mainly stem from one clade, EmbyrophytaEmbryophyte
The land plants or embryophytes, more formally Embryophyta or Metaphyta, are the most familiar group of plants. They are called 'land plants' because they live primarily in terrestrial habitats, in contrast with the related green algae that are primarily aquatic. The embryophytes include trees,...
. Marine environments may contain over 80% of the world's plant and animal species. The diversity of coral reefs can be extraordinary with species diversity reaching 1000 species per meter squared. The greatest marine tropical biodiversity is reported to be in the Indo-Pacific Ocean.
Sample Collection Technological Requirements
Collecting marine samples can range from very simple and inexpensive to very complicated expensive. Samples from near or on shores are readily accessible via beach combing, wading or snorkelingSnorkeling
Snorkeling is the practice of swimming on or through a body of water while equipped with a diving mask, a shaped tube called a snorkel, and usually swimfins. In cooler waters, a wetsuit may also be worn...
. Sample collection from deep water can be completed via dredging however, this is a very invasive technique which destroys the local habitat, does not allow for repeated sampling from the same location and compromises sample integrity. Corers
Box corer
The Box corer is a marine geological sampling tool for soft sediments in lakes or oceans. It is deployed from a research vessel with a deep sea wire and suitable for any water depth...
can be used for sediment sample collection from deep locations quickly, easily and inexpensively. SCUBA diving
Scuba diving
Scuba diving is a form of underwater diving in which a diver uses a scuba set to breathe underwater....
was introduced in the 1940s however, it was not widely used until it became popular in the 1970s. SCUBA diving is limited in the duration that divers can spend underwater when conducted from the surface. If prolonged dives were necessary, a underwater laboratory could be used. Aquarius
Aquarius (laboratory)
The NOAA Aquarius Reef Base is an underwater habitat located in the Florida Keys National Marine Sanctuary, adjacent to Conch Reef. It is one of the few underwater research facilities in the world dedicated to science...
is the only underwater laboratory dedicated to marine science. For sample collection from depths that cannot be achieved by SCUBA diving, submersibles
Submersible
A submersible is a small vehicle designed to operate underwater. The term submersible is often used to differentiate from other underwater vehicles known as submarines, in that a submarine is a fully autonomous craft, capable of renewing its own power and breathing air, whereas a submersible is...
may be used. Sample collection by submersibles can be extremely expensive with costs for a submersible, support ship, technicians and support staff ranging between $10,000 to $45,000 per day.
Chemical Compound Isolation
For the isolation of biologically active compounds from organisms, several different steps need to be completed. The different steps required to obtain a biologically active compound are: ExtractionExtraction (chemistry)
Extraction in chemistry is a separation process consisting in the separation of a substance from a matrix. It may refer to Liquid-liquid extraction, and Solid phase extraction....
, chromatographic purification
Chromatography
Chromatography is the collective term for a set of laboratory techniques for the separation of mixtures....
, dereplication, structure elucidation and bioassay
Bioassay
Bioassay , or biological standardization is a type of scientific experiment. Bioassays are typically conducted to measure the effects of a substance on a living organism and are essential in the development of new drugs and in monitoring environmental pollutants...
testing. The steps do not have to follow that particular order and many steps may be completed simultaneously. In the first step, the sample may be triturated
Trituration
Trituration is the name of several different methods of processing materials. Trituration is also the name of the process for reducing the particle size of a substance by grinding, as by grinding of powders in a mortar with a pestle. Trituration additionally refers to the production of a...
and extracted
Liquid-liquid extraction
Liquid–liquid extraction, also known as solvent extraction and partitioning, is a method to separate compounds based on their relative solubilities in two different immiscible liquids, usually water and an organic solvent. It is an extraction of a substance from one liquid phase into another liquid...
with a suitable solvent or macerated. Some solvents used are methanol
Methanol
Methanol, also known as methyl alcohol, wood alcohol, wood naphtha or wood spirits, is a chemical with the formula CH3OH . It is the simplest alcohol, and is a light, volatile, colorless, flammable liquid with a distinctive odor very similar to, but slightly sweeter than, ethanol...
:chloroform
Chloroform
Chloroform is an organic compound with formula CHCl3. It is one of the four chloromethanes. The colorless, sweet-smelling, dense liquid is a trihalomethane, and is considered somewhat hazardous...
, ethanol
Ethanol
Ethanol, also called ethyl alcohol, pure alcohol, grain alcohol, or drinking alcohol, is a volatile, flammable, colorless liquid. It is a psychoactive drug and one of the oldest recreational drugs. Best known as the type of alcohol found in alcoholic beverages, it is also used in thermometers, as a...
, acetonitrile
Acetonitrile
Acetonitrile is the chemical compound with formula . This colourless liquid is the simplest organic nitrile. It is produced mainly as a byproduct of acrylonitrile manufacture...
, or others. The purpose is to remove organic compounds that have a medium polarity which are considered more "drug-like"
Druglikeness
Druglikeness is a qualitative concept used in drug design for how "druglike" a substance is with respect to factors like bioavailability. It is estimated from the molecular structure before the substance is even synthesized and tested...
. Ideally,polar compounds like salts
Salt
In chemistry, salts are ionic compounds that result from the neutralization reaction of an acid and a base. They are composed of cations and anions so that the product is electrically neutral...
, peptides
Peptide
Peptides are short polymers of amino acid monomers linked by peptide bonds. They are distinguished from proteins on the basis of size, typically containing less than 50 monomer units. The shortest peptides are dipeptides, consisting of two amino acids joined by a single peptide bond...
, sugars
Carbohydrate
A carbohydrate is an organic compound with the empirical formula ; that is, consists only of carbon, hydrogen, and oxygen, with a hydrogen:oxygen atom ratio of 2:1 . However, there are exceptions to this. One common example would be deoxyribose, a component of DNA, which has the empirical...
as well as very non-polar compounds like lipids
Lipid
Lipids constitute a broad group of naturally occurring molecules that include fats, waxes, sterols, fat-soluble vitamins , monoglycerides, diglycerides, triglycerides, phospholipids, and others...
are left behind to simplify chromatography since they are not generally considered "drug-like". Drying of the sample could be completed before extraction by lyophilisation to remove any excess water and therefore limit the amount of highly polar compounds extracted.
The next step depends on the methodology of individual laboratories. Bioassay-guided fractionation is a common method to find biologically active compounds. This involves testing the crude extract or preliminary fractions from chromatography in an assay or multiple assays, determining what fractions or crude extracts show activity in the specific assays, and further fractionating the active fractions or extracts. This step is than repeated where the new fractions are tested and the active fractions are further fractionated. This continues until the fraction only contains one compound. Dereplication is ideally performed as early as possible to determine if the active compound has been previously reported in order to prevent "rediscovering" a compound. This can be performed using Liquid Chromatography- Mass Spectrometry
Liquid chromatography-mass spectrometry
Liquid chromatography–mass spectrometry is an analytical chemistry technique that combines the physical separation capabilities of liquid chromatography with the mass analysis capabilities of mass spectrometry. LC-MS is a powerful technique used for many applications which has very high...
(LC-MS) data or Nuclear Magnetic Resonance
Nuclear magnetic resonance
Nuclear magnetic resonance is a physical phenomenon in which magnetic nuclei in a magnetic field absorb and re-emit electromagnetic radiation...
(NMR) data obtained in the biological assay-guided process and than comparing the information to that found in databases of previously reported compounds.
Structure elucidation is performed by using NMR data obtained of the compound and High Resolution Mass Spectrometry (HR-MS) Data. Tandem Mass Spectrometry
Tandem mass spectrometry
Tandem mass spectrometry, also known as MS/MS or MS2, involves multiple steps of mass spectrometry selection, with some form of fragmentation occurring in between the stages.-Tandem MS instruments:...
can also be useful, especially for large molecules like glycolipids
Glycolipid
Glycolipids are lipids with a carbohydrate attached. Their role is to provide energy and also serve as markers for cellular recognition.-Metabolism:...
, proteins
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
, polysaccharides
Polysaccharide
Polysaccharides are long carbohydrate molecules, of repeated monomer units joined together by glycosidic bonds. They range in structure from linear to highly branched. Polysaccharides are often quite heterogeneous, containing slight modifications of the repeating unit. Depending on the structure,...
or peptides
Peptide
Peptides are short polymers of amino acid monomers linked by peptide bonds. They are distinguished from proteins on the basis of size, typically containing less than 50 monomer units. The shortest peptides are dipeptides, consisting of two amino acids joined by a single peptide bond...
. Completed characterization for publication purposes may require Infrared (IR)
Infrared spectroscopy
Infrared spectroscopy is the spectroscopy that deals with the infrared region of the electromagnetic spectrum, that is light with a longer wavelength and lower frequency than visible light. It covers a range of techniques, mostly based on absorption spectroscopy. As with all spectroscopic...
, Ultraviolet-visible (UV-vis)
Ultraviolet-visible spectroscopy
Ultraviolet-visible spectroscopy or ultraviolet-visible spectrophotometry refers to absorption spectroscopy or reflectance spectroscopy in the ultraviolet-visible spectral region. This means it uses light in the visible and adjacent ranges...
, specific rotation
Specific rotation
In stereochemistry, the specific rotation of a chemical compound [α] is defined as the observed angle of optical rotation α when plane-polarized light is passed through a sample with a path length of 1 decimeter and a sample concentration of 1 gram per 1 millilitre. It is the main property used to...
and melting point
Melting point
The melting point of a solid is the temperature at which it changes state from solid to liquid. At the melting point the solid and liquid phase exist in equilibrium. The melting point of a substance depends on pressure and is usually specified at standard atmospheric pressure...
data. Obtaining a crystal structure
Crystal structure
In mineralogy and crystallography, crystal structure is a unique arrangement of atoms or molecules in a crystalline liquid or solid. A crystal structure is composed of a pattern, a set of atoms arranged in a particular way, and a lattice exhibiting long-range order and symmetry...
via 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...
can greatly accelerate and simplify structure elucidation however, obtaining crystals can be quite difficult.
There are many different bioassays available for testing. There are anticancer
Anticarcinogen
An anticarcinogen is any chemical which reduces the occurrence of cancers, reduces the severity of cancers that do occur, or acts against cancers that do occur, based on evidence from in vitro studies, animal models, epidemiological studies and/or clinical studies.Preventative anticarcinogens act...
, antimicrobial
Antimicrobial
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...
, antiviral
Antiviral drug
Antiviral drugs are a class of medication used specifically for treating viral infections. Like antibiotics for bacteria, specific antivirals are used for specific viruses...
, 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....
, antiparasitic, anticholesterolemic
Hypolipidemic agent
Hypolipidemic agents, or antihyperlipidemic agents, are a diverse group of pharmaceuticals that are used in the treatment of hyperlipidemias. They are called lipid-lowering drugs or agents.- Classes of hypolipidemic drugs :...
, and many other differ assays. For MTT assay
MTT assay
The MTT assay and the MTS assay are colorimetric assays for measuring the activity of enzymes that reduce MTT or close dyes to formazan dyes, giving a purple color. A main application allows to assess the viability and the proliferation of cells...
and cytosolic
Cytosol
The cytosol or intracellular fluid is the liquid found inside cells, that is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondrion into compartments....
Lactate dehydrogenase (LDH)
Lactate dehydrogenase
Lactate dehydrogenase is an enzyme present in a wide variety of organisms, including plants and animals.Lactate dehydrogenases exist in four distinct enzyme classes. Two of them are cytochrome c-dependent enzymes, each acting on either D-lactate or L-lactate...
release are common 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:...
or cell viability assays
Viability assay
A viability assay is an assay to determine the ability of cells or tissues to maintain or recover its viability. For example, examining the ratio of potassium to sodium in cells indicates viability because if cells do not have high intracellular potassium and low intracellular sodium: the...
.
Supply Issue
A common problem that plagues drug development is obtaining a sustainable supply of the compound. Compounds isolated from invertebrates can be difficult to obtain in sufficient quantity for clinical trials. Synthesis is an alternate source of the compound of interest if the compound is simple otherwise, it is generally not a viable alternative. Aqua culture is another alternative if the organism is readily grown otherwise, it may not be good sustainable source of a compound. Also, the small quantity the compound is usually found in from organisms makes this alternative even more expensive. For example, ET-743 can be isolated from the tunicate Ecteinascidia turbinata with a yield of 2 g per ton. This would require thousands of tons of tunicate to be grown and extracted to produce the kilograms of ET-743 that would be required for the treatment of thousands of people. Some success has been had in producing compounds of interest from microorganisms. Microorganisms can be used as a sustainable source for the production of compounds of interest. They can also be used for the production of intermediates so that semisynthesis can be used to produce the final compound. This has been achieved for ET-743 with the production of the intermediate Safracin B from Pseudomonas fluoresens and the subsequent semisynthesis into ET-743. This is currently the industrial production method for the production of Yondelis.Compounds from Marine Sources in Clinical Level
Approved drug
In the United States, the FDA approves drugs. Before a drug can be prescribed, it must undergo an extensive FDA approval process. This process involves first testing the drug on animals or in medical labs. If found to be safe by the FDA and approved for the next phase of study, the drug is then...
Cytarabine
Cytarabine, or cytosine arabinoside, is a chemotherapy agent used mainly in the treatment of cancers of white blood cells such as acute myeloid leukemia and non-Hodgkin lymphoma. It is also known as Ara-C...
Nucleoside
Nucleosides are glycosylamines consisting of a nucleobase bound to a ribose or deoxyribose sugar via a beta-glycosidic linkage...
DNA polymerase
A DNA polymerase is an enzyme that helps catalyze in the polymerization of deoxyribonucleotides into a DNA strand. DNA polymerases are best known for their feedback role in DNA replication, in which the polymerase "reads" an intact DNA strand as a template and uses it to synthesize the new strand....
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...
Vidarabine
Vidarabine or adenine arabinoside is an antiviral drug which is active against herpes simplex and varicella zoster viruses.- How the drug was discovered :...
Antiviral drug
Antiviral drugs are a class of medication used specifically for treating viral infections. Like antibiotics for bacteria, specific antivirals are used for specific viruses...
Peptide
Peptides are short polymers of amino acid monomers linked by peptide bonds. They are distinguished from proteins on the basis of size, typically containing less than 50 monomer units. The shortest peptides are dipeptides, consisting of two amino acids joined by a single peptide bond...
N-type calcium channel
The N-type calcium channel is a type of voltage-dependent calcium channel. Like the others of this class, the α1 subunit forms the pore through which calcium enters the cell and determines most of the channel's properties...
Analgesic
An analgesic is any member of the group of drugs used to relieve pain . The word analgesic derives from Greek an- and algos ....
Eribulin
Eribulin is an anticancer drug marketed by Eisai Co. under the trade name Halaven. Eribulin mesylate was approved by the U.S. Food and Drug Administration on November 15, 2010, to treat patients with metastatic breast cancer who have received at least two prior chemotherapy regimens for late-stage...
Macrolide
The macrolides are a group of drugs whose activity stems from the presence of a macrolide ring, a large macrocyclic lactone ring to which one or more deoxy sugars, usually cladinose and desosamine, may be attached. The lactone rings are usually 14-, 15-, or 16-membered...
Microtubule
Microtubules are a component of the cytoskeleton. These rope-like polymers of tubulin can grow as long as 25 micrometers and are highly dynamic. The outer diameter of microtubule is about 25 nm. Microtubules are important for maintaining cell structure, providing platforms for intracellular...
Lovaza
Lovaza is a brand name prescription drug fish oil capsule developed by GlaxoSmithKline and approved by the U.S. Food and Drug Administration to lower very high triglyceride levels. It is an Omega-3 fatty acid. It is a dietary supplement that has been purified, chemically altered, branded, and been...
Omega-3 fatty acid
N−3 fatty acids are essential unsaturated fatty acids with a double bond starting after the third carbon atom from the end of the carbon chain....
Triglyceride
A triglyceride is an ester derived from glycerol and three fatty acids. There are many triglycerides, depending on the oil source, some are highly unsaturated, some less so....
-Synthesizing Enzymes
Hypertriglyceridemia
In medicine, hypertriglyceridemia denotes high blood levels of triglycerides, the most abundant fatty molecule in most organisms. It has been associated with atherosclerosis, even in the absence of hypercholesterolemia . It can also lead to pancreatitis in excessive concentrations In medicine,...
Trabectedin
Trabectedin is an anti-tumor drug. It is sold by Zeltia and Johnson and Johnson under the brand name Yondelis. It is approved for use in Europe, Russia and South Korea for the treatment of advanced soft tissue sarcoma. It is also undergoing clinical trials for the treatment of breast, prostate,...
EU Approved only
Tunicate
Tunicates, also known as urochordates, are members of the subphylum Tunicata, previously known as Urochordata, a group of underwater saclike filter feeders with incurrent and excurrent siphons that is classified within the phylum Chordata. While most tunicates live on the ocean floor, others such...
Alkaloid
Alkaloids are a group of naturally occurring chemical compounds that contain mostly basic nitrogen atoms. This group also includes some related compounds with neutral and even weakly acidic properties. Also some synthetic compounds of similar structure are attributed to alkaloids...
Brentuximab vedotin
Brentuximab vedotin is an antibody-drug conjugate approved to treat anaplastic large cell lymphoma and Hodgkin lymphoma. The U.S...
Mollusca
The Mollusca , common name molluscs or mollusksSpelled mollusks in the USA, see reasons given in Rosenberg's ; for the spelling mollusc see the reasons given by , is a large phylum of invertebrate animals. There are around 85,000 recognized extant species of molluscs. Mollusca is the largest...
Antibody-drug conjugate
Antibody-drug conjugates are a new type of targeted therapy, used for example for cancer. They consist of an antibody linked to a payload drug . Hence, they are a type of immunoconjugate and often an immunotoxin.The antibody causes the ADC to bind to the target cancer cells...
(MM Auristatin E)
Monomethyl auristatin E
Monomethyl auristatin E is a synthetic antineoplastic agent. Because of its toxicity, it cannot be used as a drug itself; instead, it is linked to a monoclonal antibody which directs it to the cancer cells...
CD30
CD30, also known as TNFRSF8, is a cell membrane protein of the tumor necrosis factor receptor family and tumor marker.This receptor is expressed by activated, but not by resting, T and B cells. TRAF2 and TRAF5 can interact with this receptor, and mediate the signal transduction that leads to the...
and Microtubules
Aplidine
Aplidine, also known as dihydrodidemnin B, is a chemical compound extracted from the ascidian Aplidium albicans. It is currently undergoing clinical trial testing...
Depsipeptide
A depsipeptide is a peptide in which one or more of the amide bonds are replaced by ester bonds.Depsipeptides have often been used in research to probe the importance of hydrogen bond networks in protein folding kinetics and thermodynamics. They are also found in nature as natural products...
RAC1
Ras-related C3 botulinum toxin substrate 1 also known as Rac1 is a protein that in humans is encoded by the RAC1 gene. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some of these variants has not been determined.- Function :Rac1 is...
and JNK
C-Jun N-terminal kinases
c-Jun N-terminal kinases , were originally identified as kinases that bind and phosphorylate c-Jun on Ser-63 and Ser-73 within its transcriptional activation domain. They belong to the mitogen-activated protein kinase family, and are responsive to stress stimuli, such as cytokines, ultraviolet...
Activation
GTS-21
GTS-21 is a drug that acts as a partial agonist at neural nicotinic acetylcholine receptors. It binds to both the α4β2 and α7 subtypes, but activates only the α7 to any significant extent....
Worm
The term worm refers to an obsolete taxon used by Carolus Linnaeus and Jean-Baptiste Lamarck for all non-arthropod invertebrate animals, and stems from the Old English word wyrm. Currently it is used to describe many different distantly-related animals that typically have a long cylindrical...
Alpha-7 nicotinic receptor
The alpha-7 nicotinic receptor, also known as the α7 receptor, is a type of nicotinic acetylcholine receptor, consisting entirely of α7 subunits....
Schizophrenia
Schizophrenia is a mental disorder characterized by a disintegration of thought processes and of emotional responsiveness. It most commonly manifests itself as auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking, and it is accompanied by significant social...
Fungus
A fungus is a member of a large group of eukaryotic organisms that includes microorganisms such as yeasts and molds , as well as the more familiar mushrooms. These organisms are classified as a kingdom, Fungi, which is separate from plants, animals, and bacteria...
Diketopiperazine
Diketopiperazines are a class of cyclic organic compounds that result from peptide bonds between two amino acids to form a lactam. They are the smallest possible cyclic peptides....
Nudibranch
A nudibranch is a member of what is now a taxonomic clade, and what was previously a suborder, of soft-bodied, marine gastropod mollusks which shed their shell after their larval stage. They are noted for their often extraordinary colors and striking forms...
Glembatumumab vedotin
Glembatumumab vedotin is an antibody-drug conjugate that targets cancer cells expressing transmembrane glycoprotein NMB ....
Salinosporamide A
Salinosporamide A is a potent proteasome inhibitor used as an anticancer agent that recently entered phase I human clinical trials for the treatment of multiple myeloma only three years after its discovery. This novel marine natural product is produced by the recently described obligate marine...
Bacteria
Bacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...
CD70
CD70 is a ligand for CD27.-External links:...
and Microtubules
Bryostatin
Bryostatins are a group of macrolide lactones first isolated in the 1960s by George Pettit from extracts of a species of bryozoan, Bugula neritina. The structure of bryostatin 1 was determined in 1982. Until today 20 different bryostatins have been isolated. Bryostatins are a potent modulators of...
Bryozoa
The Bryozoa, also known as Ectoprocta or commonly as moss animals, are a phylum of aquatic invertebrate animals. Typically about long, they are filter feeders that sieve food particles out of the water using a retractable lophophore, a "crown" of tentacles lined with cilia...
Protein kinase C
Protein kinase C also known as PKC is a family of enzymes that are involved in controlling the function of other proteins through the phosphorylation of hydroxyl groups of serine and threonine amino acid residues on these proteins. PKC enzymes in turn are activated by signals such as increases in...
Alzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
Alcyonacea
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...
Eicosanoid
In biochemistry, eicosanoids are signaling molecules made by oxidation of twenty-carbon essential fatty acids, ....
Wound healing
Wound healing, or cicatrisation, is an intricate process in which the skin repairs itself after injury. In normal skin, the epidermis and dermis exists in a steady-state equilibrium, forming a protective barrier against the external environment...
αIncludes natural products or natural product derivatives or analogues;
βNumber of active trials/number of total trials from http://www.clinicaltrials.gov/ as of July 2011
External links
- Medicine from the Sea at Cluster of Excellence "Future Ocean"
- Marine Pharmacology: The Clinical Pipeline by Mayer,A.M.S at Midwestern University