Natural products, or their close derivatives, make some of our most potent medicines, among which macrocycles with their large carbon-rich ring systems are one class. The size and complexity of macrocycles has made it difficult to emulate and build on Nature’s success in the laboratory. By completing a complex molecular synthesis of these compounds attached to a unique identifying DNA strand, the Chemists of the University of Basel have built a rich collection of natural product-like macrocycles that can be mined for new medicines as the researchers report in the scientific journal “Angewandte Chemie”.
Natural evolution has created an incredible diversity of small molecular structures that perturb living systems and are therefore used as drugs in medicinal applications. Although several dozen approved medicines are macrocyclic structures, nearly all of these are natural products or close derivatives.
To find new lead compounds in drug research, huge libraries with diverse structures are required – or simply put, rich collections of molecules. Medicinal chemists have failed to imitate Nature’s approach to bioactive macrocyclic molecules – and their long syntheses precluded the creation of large screening libraries, which are essential for identifying drug leads.
A challenge for synthetic chemistry
Researchers at the chemistry department of the University of Basel have now completed a total synthesis of over one million macrocycles that incorporate structural elements often observed in natural biologically active macrocycles.
The synthesis is based on the split-and-pool principle: Before a synthesis step, the whole library is split. Then each fraction is coupled with one of various building blocks and the newly built molecules are labeled with a covalently attached DNA sequence. Before the next synthesis step all fractions are pooled again.
This leads to the cross combination of all diversity elements. Each combination is attached to a specific DNA barcode. Through this approach all 1.4 million members of the pooled library could be screened in a single experiment. Next generation DNA sequencing on the selected libraries could then identify macrocycles that bind target proteins.
Macrocycles are unlikely yet potent drugs
Most small molecule drugs are hydrophobic molecules (“water repellants”) with a low molecular weight (less than 500 daltons). Because of this, these drugs tend to slip without problem through cell membranes, exposing them to the great majority of disease-relevant proteins.
Macrocycles buck this trend because they are often extremely large (more than 800 daltons) by medicinal chemistry standards, and yet they passively diffuse through cell membranes.
Researchers speculate that this special property of natural macrocycles derives from their ability to adapt their spatial structure (conformation) depending on the medium.
Hence in the largely water-based environment of the blood stream and cell interior the macrocycles would expose their more water compatible (hydrophilic) groups to remain soluble. Once the hydrophobic cell membrane is encountered a conformational shift could allow the molecules to expose their hydrophobic face, making them soluble in membranes and hence capable of passive diffusion.
New applications possible
Given their unique properties, macrocycles are conspicuously under-represented in medicinal chemistry. This is largely due to the synthetic challenge of creating a large collection of macrocycles for screening. With the help of a barcoding DNA strand the Gillingham group has overcome this hurdle by developing an efficient seven-step synthesis of a natural product-like macrocycle library all pooled in one solution.
“With a large diverse collection of macrocycles available for screening, a more data-rich investigation of the properties of these extraordinary molecules can begin”, comments Dennis Gillingham. “This might reveal future medicinal applications, targets or active principles.”
Prof. Dr. Dennis Gillingham, University of Basel, Department of Chemistry, Tel. +41 61 267 11 48, email: email@example.com
Cedric Stress, Basilius Sauter, Lukas Schneider, Timothy Sharpe, Dennis Gillingham
A DNA‐encoded chemical library incorporating elements of natural macrocycles
Angewandte Chemie International Edition (2019), doi: 10.1002/anie.201902513
Reto Caluori | Universität Basel
Sweet beaks: What Galapagos finches and marine bacteria have in common
20.02.2020 | Max-Planck-Institut für Marine Mikrobiologie
Social networks reveal dating in blue tits
20.02.2020 | Max-Planck-Institut für Ornithologie
The operational speed of semiconductors in various electronic and optoelectronic devices is limited to several gigahertz (a billion oscillations per second). This constrains the upper limit of the operational speed of computing. Now researchers from the Max Planck Institute for the Structure and Dynamics of Matter in Hamburg, Germany, and the Indian Institute of Technology in Bombay have explained how these processes can be sped up through the use of light waves and defected solid materials.
Light waves perform several hundred trillion oscillations per second. Hence, it is natural to envision employing light oscillations to drive the electronic...
Most natural and artificial surfaces are rough: metals and even glasses that appear smooth to the naked eye can look like jagged mountain ranges under the microscope. There is currently no uniform theory about the origin of this roughness despite it being observed on all scales, from the atomic to the tectonic. Scientists suspect that the rough surface is formed by irreversible plastic deformation that occurs in many processes of mechanical machining of components such as milling.
Prof. Dr. Lars Pastewka from the Simulation group at the Department of Microsystems Engineering at the University of Freiburg and his team have simulated such...
Investigation of the temperature dependence of the skyrmion Hall effect reveals further insights into possible new data storage devices
The joint research project of Johannes Gutenberg University Mainz (JGU) and the Massachusetts Institute of Technology (MIT) that had previously demonstrated...
Researchers at Chalmers University of Technology, Sweden, recently completed a 5-year research project looking at how to make fibre optic communications systems more energy efficient. Among their proposals are smart, error-correcting data chip circuits, which they refined to be 10 times less energy consumptive. The project has yielded several scientific articles, in publications including Nature Communications.
Streaming films and music, scrolling through social media, and using cloud-based storage services are everyday activities now.
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.
12.02.2020 | Event News
16.01.2020 | Event News
15.01.2020 | Event News
20.02.2020 | Life Sciences
20.02.2020 | Life Sciences
20.02.2020 | Communications Media