After helping develop a new approach for organic synthesis -- carbon-hydrogen functionalization -- scientists at Emory University are now showing how this approach may apply to drug discovery. Nature Catalysis published their most recent work -- a streamlined process for making a three-dimensional scaffold of keen interest to the pharmaceutical industry.
"Our tools open up whole new chemical space for potential drug targets," says Huw Davies, Emory professor of organic chemistry and senior author of the paper.
Graphic shows the dirhodium catalyst developed used to synthesize a 3D scaffold of keen interest to the pharmaceutical industry. The Davies lab has published a series of major papers on dirhodium catalysts that selectively funcitonalized C-H bonds in a streamlined manner.
Credit: Davies Lab/Emory University
Davies is the founding director of the National Science Foundation's Center for Selective C-H Functionalization, a consortium based at Emory and encompassing 15 major research universities from across the country as well as industrial partners.
Traditionally, organic chemistry has focused on the division between reactive molecular bonds and the inert bonds between carbon-carbon (C-C) and carbon-hydrogen (C-H). The inert bonds provide a strong, stable scaffold for performing chemical synthesis with the reactive groups. C-H functionalization flips this model on its head, making C-H bonds become the reactive sites.
The aim is to efficiently transform simple, abundant molecules into much more complex, value-added molecules. Functionalizing C-H bonds opens new chemical pathways for the synthesis of fine chemicals -- pathways that are more direct, less costly and generate less chemical waste.
The Davies lab has published a series of major papers on dirhodium catalysts that selectively functionalize C-H bonds in a streamlined manner.
The current paper demonstrates the power of a dirhodium catalyst to efficiently synthesize a bioisostere of a benzene ring. A benzene ring is a two-dimensional (2D) molecule and a common motif in drug candidates. The bioisostere has similar biologicial properties to a benzene ring. It is a different chemical entity, however, with a 3D structure, which opens up new chemical territory for drug discovery.
Previous attempts to exploit this bioisostere for biomedical research have been hampered by the delicate nature of the structure and the limited ways to make them. "Traditional chemistry is too harsh and causes the system to fragment," Davies explains. "Our method allows us to easily achieve a reaction on a C-H bond of this bioisostere in a way that does not destroy the scaffold. We can do chemistry that no one else can do and generate new, and more elaborate, derivatives containing this promising bioisostere."
The paper serves as proof of principle that bioisosteres can serve as fundamental building blocks to generate an expanded range of chemical entities. "It's like getting a new Lego shape in your kit," Davies says. "The more Lego shapes you have, the more new and different structures you can build."
Zachary Garlets, a former member of the Davies lab who currently works for the biopharmaceutical firm Bristol-Myers Squibb, is first author of the paper. The project was a collaboration between the Davies lab and computational chemists from UCLA (Jacob Sanders and K.N. Houk) and medicinal chemists from Novartis Institutes for Biomedical Research (Hasnain Malik and Christian Gampe).
The paper follows another recent demonstration of the potential for generating novel scaffolds relevant to pharmaceutical research using the method. That work, a collaboration between Emory chemists and AbbVie, was published in the journal Chem.
Carol Clark | EurekAlert!
Blocking the iron transport could stop tuberculosis
02.04.2020 | University of Zurich
Discovery of life in solid rock deep beneath sea may inspire new search for life on Mars
02.04.2020 | University of Tokyo
90 million-year-old forest soil provides unexpected evidence for exceptionally warm climate near the South Pole in the Cretaceous
An international team of researchers led by geoscientists from the Alfred Wegener Institute, Helmholtz Centre for Polar and Marine Research (AWI) have now...
The bacteria that cause tuberculosis need iron to survive. Researchers at the University of Zurich have now solved the first detailed structure of the transport protein responsible for the iron supply. When the iron transport into the bacteria is inhibited, the pathogen can no longer grow. This opens novel ways to develop targeted tuberculosis drugs.
One of the most devastating pathogens that lives inside human cells is Mycobacterium tuberculosis, the bacillus that causes tuberculosis. According to the...
An international team with the participation of Prof. Dr. Michael Kues from the Cluster of Excellence PhoenixD at Leibniz University Hannover has developed a new method for generating quantum-entangled photons in a spectral range of light that was previously inaccessible. The discovery can make the encryption of satellite-based communications much more secure in the future.
A 15-member research team from the UK, Germany and Japan has developed a new method for generating and detecting quantum-entangled photons at a wavelength of...
Together with their colleagues from the University of Würzburg, physicists from the group of Professor Alexander Szameit at the University of Rostock have devised a “funnel” for photons. Their discovery was recently published in the renowned journal Science and holds great promise for novel ultra-sensitive detectors as well as innovative applications in telecommunications and information processing.
The quantum-optical properties of light and its interaction with matter has fascinated the Rostock professor Alexander Szameit since College.
Researchers at the University of Zurich show that different stem cell populations are innervated in distinct ways. Innervation may therefore be crucial for proper tissue regeneration. They also demonstrate that cancer stem cells likewise establish contacts with nerves. Targeting tumour innervation could thus lead to new cancer therapies.
Stem cells can generate a variety of specific tissues and are increasingly used for clinical applications such as the replacement of bone or cartilage....
02.04.2020 | Event News
26.03.2020 | Event News
23.03.2020 | Event News
02.04.2020 | Physics and Astronomy
02.04.2020 | Information Technology
02.04.2020 | Health and Medicine