Discodermolide

Discodermolide

Overview
-Discodermolide is a recently discovered polyketide
Polyketide
Polyketides are secondary metabolites from bacteria, fungi, plants, and animals. Polyketides are usually biosynthesized through the decarboxylative condensation of malonyl-CoA derived extender units in a similar process to fatty acid synthesis...

 natural product
Natural product
A natural product is a chemical compound or substance produced by a living organism - found in nature that usually has a pharmacological or biological activity for use in pharmaceutical drug discovery and drug design...

 found to be a potent inhibitor of 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...

 cell growth. The molecule's carbon skeleton is made up of eight polypropionate
Propionate
The propanoate or propionate ion is C2H5COO− .A propanoic or propionic compound is a salt or ester of propanoic acid....

 and four acetate
Acetate
An acetate is a derivative of acetic acid. This term includes salts and esters, as well as the anion found in solution. Most of the approximately 5 billion kilograms of acetic acid produced annually in industry are used in the production of acetates, which usually take the form of polymers. In...

 units with 13 stereocenters.


Discodermolide was first isolated in 1990 from the Caribbean marine sponge Discodermia dissoluta by chemist Dr. Sarath Gunasekera and biologist Dr. Ross Longley, scientists at the Harbor Branch Oceanographic Institution.
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Encyclopedia
-Discodermolide is a recently discovered polyketide
Polyketide
Polyketides are secondary metabolites from bacteria, fungi, plants, and animals. Polyketides are usually biosynthesized through the decarboxylative condensation of malonyl-CoA derived extender units in a similar process to fatty acid synthesis...

 natural product
Natural product
A natural product is a chemical compound or substance produced by a living organism - found in nature that usually has a pharmacological or biological activity for use in pharmaceutical drug discovery and drug design...

 found to be a potent inhibitor of 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...

 cell growth. The molecule's carbon skeleton is made up of eight polypropionate
Propionate
The propanoate or propionate ion is C2H5COO− .A propanoic or propionic compound is a salt or ester of propanoic acid....

 and four acetate
Acetate
An acetate is a derivative of acetic acid. This term includes salts and esters, as well as the anion found in solution. Most of the approximately 5 billion kilograms of acetic acid produced annually in industry are used in the production of acetates, which usually take the form of polymers. In...

 units with 13 stereocenters.

History


Discodermolide was first isolated in 1990 from the Caribbean marine sponge Discodermia dissoluta by chemist Dr. Sarath Gunasekera and biologist Dr. Ross Longley, scientists at the Harbor Branch Oceanographic Institution. The sponge contained 0.002% of discodermolide (7 mg/434 g of sponge). Since the compound is light-sensitive, the sponge must be harvested at a minimum depth of 33 meters. Discodermolide was initially found to have immunosuppressive and antifungal activities.

Mechanism of action and structure


Discodermolide has been shown to inhibit the proliferation of human cells by arresting the cell cycle
Cell cycle
The cell cycle, or cell-division cycle, is the series of events that takes place in a cell leading to its division and duplication . In cells without a nucleus , the cell cycle occurs via a process termed binary fission...

 in G2-
G2 phase
G2 phase is the 3rd and final subphase of Interphase in the cell cycle directly preceding Mitosis. It follows the successful completion of S phase, during which the cell’s DNA is replicated...

 and M-phase. It hyper-stabilizes microtubule
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...

s, especially prevalent during cell division
Cell division
Cell division is the process by which a parent cell divides into two or more daughter cells . Cell division is usually a small segment of a larger cell cycle. This type of cell division in eukaryotes is known as mitosis, and leaves the daughter cell capable of dividing again. The corresponding sort...

. Hyper-stabilization 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...

 causes cell cycle arrest and cell death by apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...

. Over a variety of cell lines, activity has been measured at IC50 = 3-80 nM.

Discodermolide competes with paclitaxel
Paclitaxel
Paclitaxel is a mitotic inhibitor used in cancer chemotherapy. It was discovered in a U.S. National Cancer Institute program at the Research Triangle Institute in 1967 when Monroe E. Wall and Mansukh C. Wani isolated it from the bark of the Pacific yew tree, Taxus brevifolia and named it taxol...

 for microtubule binding, but with higher affinity and is also effective in paclitaxel- and in epothilone
Epothilone
The epothilones are a new class of cancer drugs. Like taxanes, they prevent cancer cells from dividing by interfering with tubulin, but in early trials epithilones have better efficacy and milder adverse effects than taxanes....

-resistant cancer cells.. Discodermolide also seems to demonstrate a remarkably consistent 3D molecular conformation
Conformation
Conformation generally means structural arrangement and may refer to:*Carbohydrate conformation, the three-dimensional shape of a carbohydrate...

 in the solid-state, in solution and when bound to tubulin; molecules with the conformational flexibility of discodermolide usually present very different conformations in different environments.

Biosynthesis


Many marine-derived polyketides that are often found in sponges cannot be cultured out of their natural environment.Finding the genes responsible for the biosynthesis of a sponge derived polyketides is a difficult task to accomplish because of the sponges’ colonial nature. Scientists are not yet able to culture the sponges; therefore, the genes for the biosynthesis of (+)-discodermolide have not yet been discovered.

Total syntheses


Several total syntheses
Total synthesis
In organic chemistry, a total synthesis is, in principle, the complete chemical synthesis of complex organic molecules from simpler pieces, usually without the aid of biological processes. In practice, these simpler pieces are commercially available in bulk and semi-bulk quantities, and are often...

 have been published to date by Schreiber, Smith, Paterson, Marshall, and Myles. A review of the various synthetic approaches has also been published.

Clinical development


The Harbor Branch Oceanographic Institution licensed (+)-discodermolide to Novartis
Novartis
Novartis International AG is a multinational pharmaceutical company based in Basel, Switzerland, ranking number three in sales among the world-wide industry...

, which began a phase 1 clinical trial
Clinical trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...

 in 2004. Patient accrual was halted due to drug toxicity. Amos B. Smith's research group, in collaboration with Kosan Biosciences
Kosan Biosciences
Kosan Biosciences, Inc. , is a pharmaceutical company which deals with cancer therapeutics medications. The company is currently working on advancing two new classes of anticancer agents through clinical development: heat shock protein 90 inhibitors and epothilones.Their technology platform is...

, has a preclinical drug development program ongoing.

The compound supply necessary for complete clinical trials cannot be met by harvesting, isolation, and purification. As of 2005, attempts at synthesis or semi-synthesis by fermentation
Fermentation (biochemistry)
Fermentation is the process of extracting energy from the oxidation of organic compounds, such as carbohydrates, using an endogenous electron acceptor, which is usually an organic compound. In contrast, respiration is where electrons are donated to an exogenous electron acceptor, such as oxygen,...

 have proven unsuccessful. As a result, all discodermolide used in preclinical studies and clinical trials has come from large-scale total synthesis.

The chemistry of palladium-catalyzed reactions developed by professor Richard F. Heck
Richard F. Heck
Richard Fred Heck is an American chemist noted for the discovery and development of the Heck reaction, which uses palladium to catalyze organic chemical reactions that couple aryl halides with alkenes....

, Ei-ichi Negishi
Ei-ichi Negishi
is a Japanese chemist who has spent most of his career at Purdue University, United States. He is best known for his discovery of the Negishi coupling. He was awarded the 2010 Nobel Prize in Chemistry "for palladium catalyzed cross couplings in organic synthesis" jointly with Richard F. Heck and...

 and Akira Suzuki
Akira Suzuki
Akira Suzuki may refer to:*Akira Suzuki , director and editor of Sailor Suit and Machine Gun among others*Akira Suzuki , creator of the Suzuki reaction*Akira Suzuki ', member of the Japanese rock band The GazettE...

, allowed chemists to carry out key coupling steps on-route to the final product; discodermolide. These three gentelmen were recognized for their ground breaking work with the Nobel prize in 2010.

See also

  • Dictyostatin
  • Epothilone
    Epothilone
    The epothilones are a new class of cancer drugs. Like taxanes, they prevent cancer cells from dividing by interfering with tubulin, but in early trials epithilones have better efficacy and milder adverse effects than taxanes....

  • Eleutherobin
  • Laulimalide
  • Paclitaxel
    Paclitaxel
    Paclitaxel is a mitotic inhibitor used in cancer chemotherapy. It was discovered in a U.S. National Cancer Institute program at the Research Triangle Institute in 1967 when Monroe E. Wall and Mansukh C. Wani isolated it from the bark of the Pacific yew tree, Taxus brevifolia and named it taxol...


External links