Dynemicin A
Encyclopedia
Dynemicin A is an anti-cancer enediyne
drug. It displays properties which illustrate promise for innovative cancer
treatments, but still requires further research.
. It was discovered to be the natural product of the indigenous bacteria, Micromonospora chernisa. The natural product displays a bright purple color due to the anthraquinone
chromophore
structure within Dynemicin A. Initially this compound was isolated for its aesthetic properties as a dye, until further research demonstrated its anti-cancer properties. Shortly after the compound’s discovery, the Bristol-Myers Pharmaceutical Company first elucidated the structure in Japan
. The structure of dynemicin A was determined from X-ray diffraction studies of triacetyldynemicin A; a closely related compound.
synthase
(Dyn E8) and a thioesterase
(DynE7), however the exact mechanism for the complete synthesis of the natural compound is not fully understood. Currently, there are several proposed mechanisms demonstrating the synthesis of Dynemicin A; however they have only been proven in a laboratory setting. These proposed mechanisms have incorporated retrosynthesis to help illustrate the mechanism utilized by the bacterium.
Although several pathways exist for the synthesis of dynemicin A, below is the mechanism suggested by the Bristol-Myers Company. This pathway for the synthesis of dynemicin A is currently the most widely accepted model.
proceeds. Second if a nucleophilic mechanism is utilized then the retro-Bergman re-cyclization of the enediyne
is used. The final products of these two mechanisms are outlined below. When the re-cyclization occurs, the conformational changes and chemical reactions taking place result in a non-reversible double stranded cleavage of the DNA
, leading to in cell death. This mechanism is extremely cytotoxic because prokaryotic and eukaryotic cells alike do not possess a mechanism to repair a double stranded cleavage of their DNA. During in vitro studies the molecule showed an increased affinity for a specific 10 base pair sequence (CTACTACTTG). In vivo studies have yet to confirm this phenomenon. Professor Martin Semmelhack from Princeton University
was the first person to propose the NADPH reduction pathway.
studies in mice and rats suggest that the treatment is most effective in leukemia
, breast and lung cancers. Synthetic alternatives which are more specific to cancer
cells and leave healthy tissues unharmed are being researched. Other animal models are available but have proven ineffective and therefore there are currently no human trials underway. The enediyne
property of this drug relates to another antibiotic known as neocarzinostatin
which is approved for clinical use. As with dynemicin A, neocarzinostatin
also interacts with DNA.
Enediyne
Enediynes are a class of bacterial natural products characterized by either nine- and ten-membered rings containing two triple bonds separated by a double bond. Many of these compounds are capable of undergoing Bergman cyclization...
drug. It displays properties which illustrate promise for innovative 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...
treatments, but still requires further research.
History and background
Dynemicin A was first isolated from the soil in the Gujarat State of IndiaIndia
India , officially the Republic of India , is a country in South Asia. It is the seventh-largest country by geographical area, the second-most populous country with over 1.2 billion people, and the most populous democracy in the world...
. It was discovered to be the natural product of the indigenous bacteria, Micromonospora chernisa. The natural product displays a bright purple color due to the anthraquinone
Anthraquinone
Anthraquinone, also called anthracenedione or dioxoanthracene is an aromatic organic compound with formula . Several isomers are possible, each of which can be viewed as a quinone derivative...
chromophore
Chromophore
A chromophore is the part of a molecule responsible for its color. The color arises when a molecule absorbs certain wavelengths of visible light and transmits or reflects others. The chromophore is a region in the molecule where the energy difference between two different molecular orbitals falls...
structure within Dynemicin A. Initially this compound was isolated for its aesthetic properties as a dye, until further research demonstrated its anti-cancer properties. Shortly after the compound’s discovery, the Bristol-Myers Pharmaceutical Company first elucidated the structure in Japan
Japan
Japan is an island nation in East Asia. Located in the Pacific Ocean, it lies to the east of the Sea of Japan, China, North Korea, South Korea and Russia, stretching from the Sea of Okhotsk in the north to the East China Sea and Taiwan in the south...
. The structure of dynemicin A was determined from X-ray diffraction studies of triacetyldynemicin A; a closely related compound.
Synthesis
The early steps of the synthesis process of dynemicin A are catalyzed by a polyketidePolyketide
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...
synthase
Synthase
In biochemistry, a synthase is an enzyme that catalyses a synthesis process.Following the EC number classification, they belong to the group of ligases, with lyases catalysing the reverse reaction....
(Dyn E8) and a thioesterase
Thioesterase
Thioesterases are enzymes which belong to the Esterase family. Esterases, in turn, are one type of the several hydrolases known.Thioesterases exhibit Esterase activity specifically at a thiol group.Thioesterases or thiolester hydrolases are identified as members of E.C.3.1.2.-Examples:Acetyl-coA...
(DynE7), however the exact mechanism for the complete synthesis of the natural compound is not fully understood. Currently, there are several proposed mechanisms demonstrating the synthesis of Dynemicin A; however they have only been proven in a laboratory setting. These proposed mechanisms have incorporated retrosynthesis to help illustrate the mechanism utilized by the bacterium.
Although several pathways exist for the synthesis of dynemicin A, below is the mechanism suggested by the Bristol-Myers Company. This pathway for the synthesis of dynemicin A is currently the most widely accepted model.
Mechanism of action
Dynemicin A is specific for B-DNA, and functions by intercalating into the minor groove of the double helix. For intercalation to occur the separation between strands which is usually 3-4 angstroms needs to be widened to 7-8 angstroms to allow enough space for the ligand to bind. Given this the DNA must be strained to accommodate the Dynemicin A resulting in an induced fit-like process. Once intercalated within the DNA the epoxide is activated in one of two ways. First, if NADPH or a thiol reduces the molecule the Bergman re-cyclization of the enediyneEnediyne
Enediynes are a class of bacterial natural products characterized by either nine- and ten-membered rings containing two triple bonds separated by a double bond. Many of these compounds are capable of undergoing Bergman cyclization...
proceeds. Second if a nucleophilic mechanism is utilized then the retro-Bergman re-cyclization of the enediyne
Enediyne
Enediynes are a class of bacterial natural products characterized by either nine- and ten-membered rings containing two triple bonds separated by a double bond. Many of these compounds are capable of undergoing Bergman cyclization...
is used. The final products of these two mechanisms are outlined below. When the re-cyclization occurs, the conformational changes and chemical reactions taking place result in a non-reversible double stranded cleavage of the DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
, leading to in cell death. This mechanism is extremely cytotoxic because prokaryotic and eukaryotic cells alike do not possess a mechanism to repair a double stranded cleavage of their DNA. During in vitro studies the molecule showed an increased affinity for a specific 10 base pair sequence (CTACTACTTG). In vivo studies have yet to confirm this phenomenon. Professor Martin Semmelhack from Princeton University
Princeton University
Princeton University is a private research university located in Princeton, New Jersey, United States. The school is one of the eight universities of the Ivy League, and is one of the nine Colonial Colleges founded before the American Revolution....
was the first person to propose the NADPH reduction pathway.
Pharmacological properties
The pharmacological properties of this drug have not yet been fully explored but currently suggest that it may be a more potent anti-cancer agent than other chemotherapeutic drugs. The bacterium is believed to use dynemicin A as an antibacterial agent to help it survive in its niche in the environment. Dynemicin A, as a drug, specifically targets B-DNA and is most effective in rapidly dividing cells. The broad spectrum of the drug prevents current use because it creates unwanted damage in normal healthy tissues. In vivoIn 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...
studies in mice and rats suggest that the treatment is most effective in 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...
, breast and lung cancers. Synthetic alternatives which are more specific to 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 and leave healthy tissues unharmed are being researched. Other animal models are available but have proven ineffective and therefore there are currently no human trials underway. The enediyne
Enediyne
Enediynes are a class of bacterial natural products characterized by either nine- and ten-membered rings containing two triple bonds separated by a double bond. Many of these compounds are capable of undergoing Bergman cyclization...
property of this drug relates to another antibiotic known as neocarzinostatin
Neocarzinostatin
Neocarzinostatin is a macromolecular chromoprotein enediyne antibiotic with anti-tumoral activity secreted by Streptomyces macromomyceticus....
which is approved for clinical use. As with dynemicin A, neocarzinostatin
Neocarzinostatin
Neocarzinostatin is a macromolecular chromoprotein enediyne antibiotic with anti-tumoral activity secreted by Streptomyces macromomyceticus....
also interacts with DNA.
External links
- http://www.columbia.edu/cu/chemistry/groups/synth-lit/MIR2009/2009_06_12-AElsohly-Dynemycin.pdf
- http://www.pdb.org/pdb/explore/pubmedArticle.do?structureId=2XFL#
- http://books.google.com/books?id=PE587tLs3w0C&pg=PA76&lpg=PA76&dq=Bristol-Myers+structure+dynemicin+a&source=bl&ots=X-l9kgIwfu&sig=H6RCeET9W75_KSupYJhxx3gYRsc&hl=en&ei=_CG6TdWJL8rz0gHYusRt&sa=X&oi=book_result&ct=result&resnum=5&ved=0CDgQ6AEwBA#v=onepage&q=Bristol-Myers%20structure%20dynemicin%20a&f=false
- http://books.google.com/books?id=7l6IOF2t3vIC&pg=PA203&lpg=PA203&dq=where+does+dynemicin+a+come+from&source=bl&ots=fcczlI2BvW&sig=mUWUqTwG283RgGvAxUARhqMJNcw&hl=en&ei=GKe0TabeNouO0QGSwPSfCQ&sa=X&oi=book_result&ct=result&resnum=1&ved=0CBYQ6AEwAA#v=onepage&q=dynemycin&f=false
- http://smu.edu/catco/pdf/jacs_127_9469.pdf
- http://smu.edu/catco/pdf/JPC-B_111_8321.pdf
- http://www.britannica.com/EBchecked/media/81/Examples-of-anthraquinone-pigments
- http://www.chem.strath.ac.uk/people/academic/tell_tuttle/research/qmmm