Nuclear Magnetic Resonance Reveals New Drug Compounds

In 1971 President Nixon declared a “war on cancer”, when signing the National Cancer Act into US law.1 Since then, researchers, funding agencies, outreach groups, and clinicians have made great progress towards eradicating this devastating set of diseases.

Breast cancer is a prime example of this monumental effort. Vast amounts of resources have been poured into breast cancer research and awareness efforts over the past several decades, greatly improving survival rates.2 However, the war is far from won. Over 40,000 US women died from breast cancer in 2014, and nearly 600,000 Americans died of cancer in 2016.3,4 These statistics highlight a continued need for the development of effective drugs to treat the many forms of cancer.

The development of novel drug compounds is highly complex and costly. Pharmaceutical companies amass their compounds by the million into giant libraries – and guard them closely – with the hopes that one may be the key to a new drug for FDA approval. These libraries are incredibly expensive to build, maintain, and utilize. By starting with natural compounds researchers can avoid using countless molecules with no relevant biological activity.

Colony cyanobacteria. Credit: RomanenkoAlexey/Shutterstock.com

Thus, many researchers venture out into the wild to find plants, fungi, and bacteria that may contain chemicals with therapeutic potential. The famous story of the discovery of penicillin describes how Dr. Alexander Flemming discovered the anti-bacterial compound when his experiment was accidentally contaminated with mould.5

Another example are the statins, a remarkably successful class of drugs used to reduce blood cholesterol levels, the first of which was discovered in a bacterial species. Many drugs currently used to treat patients were originally found in nature, some of which have been modified to improve stability, efficacy, or safety.

One major contributor to these drug discovery efforts has been the cyanobacteria. Named for their color, these filamentous blue-green bacteria are known to produce toxic chemicals. Dr. Chen Zhang and a group of researchers from the University of California, San Diego, traveled to the Pacific island of Saipan, in the Northern Islands of Mariana, where they encountered a purple colored cyanobacteria of the species cf. Caldora penicillata.7

Marine environments have produced a number of natural products used in drug development efforts, and cytoxic compounds have been previously described in cyanobacteria.8,9 Dr. Zhang found one such natural product, called curacin D, present in extracts from his sample from Saipan. The researchers also found a novel compound, which had never been previously described.

After giving it the name laucysteinamide A, Dr. Zhang and his colleagues used nuclear magnetic resonance (NMR) and other laboratory techniques to determine the structure and biological activity of this compound. Their results were published in the journal Marine Drugs in April of 2017.

By using both Bruker ALPHA-P FTIR and Bruker 600 MHz NMR spectrometers, the authors were able to determine the chemical structure and conformation of laucysteinamide A, which they determined to be an analog of the previously described bacterial metabolite somocystinamide A.10 Due its structural similarity to this known cytotoxic agent, the researchers sought to determine the potential of laucysteinamide A as an anti-cancer agent.

The authors found that while the complete bacterial extract was highly toxic to brine shrimp, the new compound, once isolated, was only weakly toxic to human cancer cells. Most of the toxicity of the complete extract was thought to be dependent upon the presence of curacin D, which is known to be highly potent against cancer cells.11

Although the result was not as exciting as the researchers would have hoped, their findings highlight the importance of NMR technology. Having determined the structure of Laucysteinamide A, it could be modified to enhance its anti-cancer efficacy through rational drug design efforts.

By enabling researchers to quickly and confidently identify novel compounds, Bruker instruments improve the rational drug design process, saving time and resources. Bruker NMR technologies allow researchers to avoid the costly and cumbersome process of developing and screening a library of molecules of which not a single compound may have relevant potency.

Using NMR to determine the structure of drug compounds and biological targets, researchers can focus on improving drugs that are already known to be relevant to the disease state being studied. The versatile, yet precise, technique of NMR helps researchers in the fight against cancer every day, and one day Bruker instruments may help us win the war.

References:

  1. “National Cancer Act of 1971.” National Cancer Institute. https://www.cancer.gov/about-nci/legislative/history/national-cancer-act-1971.
  2. “Cancer Stat Facts: Female Breast Cancer.” National Cancer Institute. https://seer.cancer.gov/statfacts/html/breast.html.
  3. “Breast Cancer Statistics.” Centers for Disease Control and Prevention. https://www.cdc.gov/cancer/breast/statistics/index.htm.
  4. "Cancer Statistics." National Cancer Institute. https://www.cancer.gov/about-cancer/understanding/statistics.
  5. Tan, Siang Yong, and Yvonne Tatsumura. Alexander Fleming (1881–1955): Discoverer of Penicillin. Singapore Medical Journal. 2015;56:366–367.
  6. Endo, Akira. The Origin of the Statins. International Congress Series 1262. 2004:3-8.
  7. Zhang, Chen, Naman CB, Engene N, et al. Laucysteinamide A, a Hybrid PKS/NRPS Metabolite from a Saipan Cyanobacterium, Cf. Caldora Penicillata. Marine Drugs. 2017;15:1-11.
  8. Blunt JW, Copp BR, Keyzers RA, et al. Marine natural products. Nat Prod Rep. 2015;32:116–211.
  9. Williams PG, Yoshida WY, Moore RE, et al. Isolation and structure determination of obyanamide, a novel cytotoxic cyclic depsipeptide from the marine cyanobacterium Lyngbya confervoides. J Nat Prod. 2002;65:29–31.
  10. Nogle, L.M.; Gerwick,W.H. Somocystinamide A, a novel cytotoxic disulfide dimer from a Fijian marine cyanobacterial mixed assemblage. Org. Lett. 2002, 4, 1095–1098.
  11. Marquez B, Verdier-Pinard P, Hamel E, et al. Curacin D, an antimitotic agent from the marine cyanobacterium Lyngbya majuscula. Phytochemistry. 1998;49:2387–2389.

About Bruker

Bruker is market leader in analytical magnetic resonance instruments including NMR, EPR and preclinical magnetic resonance imaging (MRI).

Bruker's product portfolio in the field of magnetic resonance includes NMR, preclinical MRI ,EPR and Time-Domain (TD) NMR.

In addition Bruker delivers the world's most comprehensive range of research tools enabling life science, materials science, analytical chemistry, process control and clinical research.

Bruker is also the leading superconductor magnet and ultra high field magnet manufacturer for NMR and MRI solutions.


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Last updated: Aug 10, 2017 at 6:36 AM

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