Jan 22 2020
Natural products are used to extract several drugs. However, it is crucial for chemists to first identify the structure and stereochemistry of natural products before they can be exploited. This can be highly difficult, specifically if the molecules have very few hydrogen atoms and when it is not possible to crystallize them.
Measuring the residual chemical shift anisotropy in a liquid crystalline medium. The method was used to determine the stereochemistry of spiroepicoccin A, a recently discovered natural product. The novel natural product was isolated from the deep-sea fungus Epicoccum nigrum, which can be found at depths of more than 4,500 m. Image Credit: Songhwan Hwang, FMP.
Researchers at the Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP) have invented a new NMR-based technique that makes the analysis simple and generate results that are more accurate. The study has been reported in the Journal of the American Chemical Society.
Antibiotics, cancer drugs, and painkillers all contain natural products that play a vital role in about 60% of all FDA-approved drugs. Specifically promising are sources such as plants, sessile marine organisms, and fungi. This is because several of them have chemical defenses to thwart predators. But it is very difficult to identify potential drug candidates.
Firstly, it is essential for scientists to identify the exact structure and stereochemistry (how atoms are spatially arranged) of the molecules. Chemists cannot produce the molecules and develop them into drugs without this information. Furthermore, the structure is crucial in determining whether or not the molecule has already been discovered.
Apart from the X-ray diffraction technique, which can be used only in the case of crystallizable molecules, nuclear magnetic resonance (NMR) spectroscopy is often used by chemists to determine the structure. In this context, the “residual chemical shift anisotropy,” an NMR-based parameter, has gained significance most recently.
Research works performed in the last two to three years have revealed that this parameter enables the structure and stereochemistry of organic molecules to be determined very accurately. But this necessitates special instruments, which are not available in all laboratories, to be used. Moreover, there are also laborious analysis methods involved in data analysis.
Simplified Method Produces More Accurate Results
At present, scientists at the Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP) have come up with a new technique that can be used to measure the residual chemical shift anisotropy in a much more simple and effective manner.
Collaborators from Brazil (Universidade Federal de Pernambuco) and China (Chinese Academy of Sciences, Institute of Oceanology, and South Central University for Nationalities) also contributed to this study.
The NMR-based method we have developed enables chemists to determine the stereochemistry of novel natural products with greater accuracy and efficiency. Furthermore, the method is very easy to use, making it accessible to all chemists.
Dr Han Sun, Chemist and Study Lead Author, Leibniz-Forschungsinstitut für Molekulare Pharmakologie
As part of the experiment, natural products are combined with a commercially available peptide with an AAKLVFF sequence. Upon dissolving in methanol, the peptides change into liquid crystals, making the orientation of the natural products weak under the magnetic field.
This particular orientation enables us to measure the residual chemical shift anisotropy of the molecules as a parameter, which in turn provides accurate information about their structure and stereochemistry.
Dr Han Sun, Chemist and Study Lead Author, Leibniz-Forschungsinstitut für Molekulare Pharmakologie
From the example of thalidomide, it can be observed how crucial it is to accurately identify the stereochemistry of compounds. The thalidomide compound not only has a sedative effect (hypnotic) but also an adverse developmental effect, caused by its two mirror-image forms (S)-thalidomide and (R)-thalidomide.
Analysis of Exotic Natural Products from the Ocean
In this study, the team used spiroepicoccin A, a natural product that has not been explored before. The Chinese collaborators isolated spiroepicoccin A from marine microorganisms. Obtained from a depth of over 4500 m, this substance has only a few hydrogen atoms bonded to its stereocenters, making it highly difficult to determine even using well-known NMR methods.
However, the new measurement technique enabled the structure and stereochemistry of the natural product to be unraveled without any ambiguity.
Even though our method enables us to measure only the relative and not the absolute stereochemistry as yet, our work makes an important contribution to simplifying the determination of challenging natural products.
Dr Han Sun, Chemist and Study Lead Author, Leibniz-Forschungsinstitut für Molekulare Pharmakologie
Pharmaceutical companies are already excited “because the method accelerates the development of new drugs, which is also our aim.”