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History and Background
- Dynemicin A was first isolated from the soil in the Gujarat State of India. 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.
Synthesis of Dynemicin A
- The early steps of the synthesis process of Dynemicin A are catalyzed by a polyketide 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.
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 enediyne 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.
- 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, 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.
- ElSohly, Adel. "Dynemicin A: Molecule in Review." Columbia University. 12 June 2009.
- Liew, C. W., A. Scharff, M. Kotaka, R. Kong, H. Sun, I. Qureshi, G. Bricogne, Z. Liang, and J. Lescar. "Induced-fit upon Ligand Binding Revealed by Crystal Structures of the Hot-dog Fold Thioesterase in Dynemicin Biosynthesis." J Mol Bio 404 (2010): 291-306.
- 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
- Tuttle, Tell, Elfi Kraka, and Dieter Cremer. "Docking, Triggering, and Biological Activity of Dynemicin A in DNA: A Computational Study." Journal of the American Chemical Society 127.26 (2005): 9469-484
- Tuttle, Tell, Elfi Kraka, Walter Theil, and Dieter Cremer. "A QM/MM Study of the Bergman Reaction of Dynemicin A in the Minor Groove of DNA." J Phys Chem 111 (2007): 8321-328.