New synthesis methods enhance 3D chemical space for drug discovery

February 11, 2020

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.

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."
-end-
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.

Emory Health Sciences

Related Science Articles from Brightsurf:

75 science societies urge the education department to base Title IX sexual harassment regulations on evidence and science
The American Educational Research Association (AERA) and the American Association for the Advancement of Science (AAAS) today led 75 scientific societies in submitting comments on the US Department of Education's proposed changes to Title IX regulations.

Science/Science Careers' survey ranks top biotech, biopharma, and pharma employers
The Science and Science Careers' 2018 annual Top Employers Survey polled employees in the biotechnology, biopharmaceutical, pharmaceutical, and related industries to determine the 20 best employers in these industries as well as their driving characteristics.

Science in the palm of your hand: How citizen science transforms passive learners
Citizen science projects can engage even children who previously were not interested in science.

Applied science may yield more translational research publications than basic science
While translational research can happen at any stage of the research process, a recent investigation of behavioral and social science research awards granted by the NIH between 2008 and 2014 revealed that applied science yielded a higher volume of translational research publications than basic science, according to a study published May 9, 2018 in the open-access journal PLOS ONE by Xueying Han from the Science and Technology Policy Institute, USA, and colleagues.

Prominent academics, including Salk's Thomas Albright, call for more science in forensic science
Six scientists who recently served on the National Commission on Forensic Science are calling on the scientific community at large to advocate for increased research and financial support of forensic science as well as the introduction of empirical testing requirements to ensure the validity of outcomes.

World Science Forum 2017 Jordan issues Science for Peace Declaration
On behalf of the coordinating organizations responsible for delivering the World Science Forum Jordan, the concluding Science for Peace Declaration issued at the Dead Sea represents a global call for action to science and society to build a future that promises greater equality, security and opportunity for all, and in which science plays an increasingly prominent role as an enabler of fair and sustainable development.

PETA science group promotes animal-free science at society of toxicology conference
The PETA International Science Consortium Ltd. is presenting two posters on animal-free methods for testing inhalation toxicity at the 56th annual Society of Toxicology (SOT) meeting March 12 to 16, 2017, in Baltimore, Maryland.

Citizen Science in the Digital Age: Rhetoric, Science and Public Engagement
James Wynn's timely investigation highlights scientific studies grounded in publicly gathered data and probes the rhetoric these studies employ.

Science/Science Careers' survey ranks top biotech, pharma, and biopharma employers
The Science and Science Careers' 2016 annual Top Employers Survey polled employees in the biotechnology, biopharmaceutical, pharmaceutical, and related industries to determine the 20 best employers in these industries as well as their driving characteristics.

Three natural science professors win TJ Park Science Fellowship
Professor Jung-Min Kee (Department of Chemistry, UNIST), Professor Kyudong Choi (Department of Mathematical Sciences, UNIST), and Professor Kwanpyo Kim (Department of Physics, UNIST) are the recipients of the Cheong-Am (TJ Park) Science Fellowship of the year 2016.

Read More: Science News and Science Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.