Dynemicin A is an anti-cancer
enediyne
In organic chemistry, enediynes are organic compounds containing two triple bonds and one double bond.
Enediynes are most notable for their limited use as antitumor antibiotics (known as enediyne anticancer antibiotics). They are efficient at ...
drug. It displays properties which illustrate promise for
cancer
Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
treatments, but still requires further research.
History and background
Dynemicin A was first isolated from the soil in the
Gujarat State of
India
India, officially the Republic of India (Hindi: ), is a country in South Asia. It is the seventh-largest country by area, the second-most populous country, and the most populous democracy in the world. Bounded by the Indian Ocean on the so ...
. It was discovered to be the natural product of the indigenous bacteria ''
Micromonospora chersina''. The natural product displays a bright purple color due to the
anthraquinone
Anthraquinone, also called anthracenedione or dioxoanthracene, is an aromatic organic compound with formula . Isomers include various quinone derivatives. The term anthraquinone however refers to the isomer, 9,10-anthraquinone (IUPAC: 9,10-dioxoan ...
chromophore structure within it. 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 elucidated the structure in
Japan using
X-ray diffraction studies of triacetyldynemicin A; a closely related compound.
Synthesis
The first reported chemical synthesis of dynemicin was accomplished by Myers and coworkers.
Biosynthesis
Dynemicin A is an antitumor natural product isolated from ''Micromonospora chersina'' which causes DNA strand cleavage. Iwasaki et al. first studied the biosynthetic pathway of Dynemicin A by
13C NMR labeling experiments. Dynemicin A is thought to be biosynthesized separately from two different heptaketide chains originated from seven head-to-tail coupled acetate units, which is then connected to form Dynemicin A. Initially, precursors such as 3 and 4 were proposed to derive from the oleate/crepenynate pathway, as initially put forth for NSC Chrom A biosynthesis. However, recent work by Thorson and coworkers revealed the biosynthesis of the dynemicin enediyne core to be catalyzed by an enediyne polyketide synthase (PKSE) similar to that employed in
calicheamicin biosynthesis.
Mechanism of action
Dynemicin A is specific for
B-DNA, and functions by
intercalating into the minor groove of the
double helix
A double is a look-alike or doppelgänger; one person or being that resembles another.
Double, The Double or Dubble may also refer to:
Film and television
* Double (filmmaking), someone who substitutes for the credited actor of a character
* ...
. For intercalation to occur, the separation between strands, which is usually 3-4
angstroms
The angstromEntry "angstrom" in the Oxford online dictionary. Retrieved on 2019-03-02 from https://en.oxforddictionaries.com/definition/angstrom.Entry "angstrom" in the Merriam-Webster online dictionary. Retrieved on 2019-03-02 from https://www.m ...
, needs to be widened to 7-8
angstroms
The angstromEntry "angstrom" in the Oxford online dictionary. Retrieved on 2019-03-02 from https://en.oxforddictionaries.com/definition/angstrom.Entry "angstrom" in the Merriam-Webster online dictionary. Retrieved on 2019-03-02 from https://www.m ...
to allow enough space for the
ligand
In coordination chemistry, a ligand is an ion or molecule ( functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's elec ...
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
In organic chemistry, a thiol (; ), or thiol derivative, is any organosulfur compound of the form , where R represents an alkyl or other organic substituent. The functional group itself is referred to as either a thiol group or a sulfhydryl gro ...
reduces the molecule the Bergman re-cyclization of the
enediyne
In organic chemistry, enediynes are organic compounds containing two triple bonds and one double bond.
Enediynes are most notable for their limited use as antitumor antibiotics (known as enediyne anticancer antibiotics). They are efficient at ...
proceeds. Second, if a
nucleophilic
In chemistry, a nucleophile is a chemical species that forms bonds by donating an electron pair. All molecules and ions with a free pair of electrons or at least one pi bond can act as nucleophiles. Because nucleophiles donate electrons, they are ...
mechanism is utilized then the retro-Bergman re-cyclization of the
enediyne
In organic chemistry, enediynes are organic compounds containing two triple bonds and one double bond.
Enediynes are most notable for their limited use as antitumor antibiotics (known as enediyne anticancer antibiotics). They are efficient at ...
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 an irreversible double stranded cleavage of the
DNA, leading to cell death. During
in vitro
''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called " test-tube experiments", these studies in biology ...
studies, the molecule showed an increased affinity for the specific 10 base pair sequence CTACTACTTG. However,
in vivo
Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and ...
studies have yet to confirm this phenomenon. Professor Martin Semmelhack of
Princeton University
Princeton University is a private research university in Princeton, New Jersey. Founded in 1746 in Elizabeth as the College of New Jersey, Princeton is the fourth-oldest institution of higher education in the United States and one of the ...
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 vivo studies in mice and rats suggest that the treatment is most effective in
leukemia
Leukemia ( also spelled leukaemia and pronounced ) is a group of blood cancers that usually begin in the bone marrow and result in high numbers of abnormal blood cells. These blood cells are not fully developed and are called ''blasts'' or ...
, breast, and lung cancers. Synthetic alternatives which are more specific to
cancer
Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
cells and leave healthy tissues unharmed are being researched. Other animal models are available, but have proven ineffective and therefore have no human trials currently underway. The
enediyne
In organic chemistry, enediynes are organic compounds containing two triple bonds and one double bond.
Enediynes are most notable for their limited use as antitumor antibiotics (known as enediyne anticancer antibiotics). They are efficient at ...
property of this drug relates to another antibiotic known as
neocarzinostatin
Neocarzinostatin (NCS) is a macromolecular chromoprotein enediyne antitumor antibiotic secreted by ''Streptomyces macromomyceticus''.
It consists of two parts, a labile chromophore (the non-protein molecular entity shown at right) and a 113 ami ...
which is approved for clinical use. As with dynemicin A,
neocarzinostatin
Neocarzinostatin (NCS) is a macromolecular chromoprotein enediyne antitumor antibiotic secreted by ''Streptomyces macromomyceticus''.
It consists of two parts, a labile chromophore (the non-protein molecular entity shown at right) and a 113 ami ...
also interacts with DNA.
References
Notes
* ElSohly, Adel. "Dynemicin A: Molecule in Review." Columbia University. 12 June 2009.
*
* Nicolaou, K. C., S. A. Snyder, A. G. Meyers, and S. J. Danishefsky. "Dynemicin A." Classics in Total Synthesis II: More Targets, Strategies, Methods. Weinheim: Wiley-VCH, 2003. 75–107.
* Schulz-Aellen, Marie-Françoise. "Cancer Drugs." Aging and Human Longevity. Boston: Birkhäuser, 1997. 203-04
* Silverman, Richard B. "Dynemicin A." The Organic Chemistry of Drug Design and Drug Action. Amsterdam: Elsevier Academic, 2004. 381-85
*
*
External links
* https://web.archive.org/web/20100626231055/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#
* https://books.google.com/books?id=PE587tLs3w0C&dq=Bristol-Myers+structure+dynemicin+a&pg=PA76
* https://books.google.com/books?id=7l6IOF2t3vIC&q=dynemycin&pg=PA203
* https://web.archive.org/web/20120405090957/http://smu.edu/catco/pdf/jacs_127_9469.pdf
* https://web.archive.org/web/20121001181112/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
{{Enediynes
Cancer research
Enediynes
Angucyclines
Carboxylic acids
Epoxides
Triols
Nitrogen heterocycles
Heterocyclic compounds with 7 or more rings
Ten-membered rings