Scientists have developed a new technique called phosphorus-fluoride exchange (PFEx), expanding the field of click chemistry by using phosphorus as a chemical connector to construct complex molecules. This advance could potentially contribute to the discovery of effective drugs for cancer treatment and the creation of new materials with useful properties such as flame retardancy or antimicrobial effects, while maintaining environmental sustainability as phosphorus bonds can be easily broken during recycling.
Diversity is an essential path to discovery for chemists like Professor John Moses of Cold Spring Harbor Laboratory (CSHL). The wider the range of molecules they investigate, the better the chances of identifying something of value. Recent advances by Moses’ lab allow them to rapidly construct a large number of complex molecules. Moses hopes that among these molecules will be new and effective cancer treatments.
Together with K. Led by Barry Sharpless, a two-time Nobel laureate, Moses’ lab developed a chemical transformation called phosphorus fluoride exchange, or PFEx. PFEk efficiently joins chemical building blocks together to form new molecules, in a reliable process known as click chemistry. Click chemists already offers chemists a powerful set of tools. As the latest addition to that toolkit, PFX takes a cue from biology and uses phosphorus as a chemical connector.
Shoujun Sun, seen here, is a postdoctoral fellow in Professor John Moses’ lab at Cold Spring Harbor Laboratory. Sun led the new Moses lab study that marks a significant breakthrough in the field of click chemistry. Credit: Moses Laboratory/Cold Spring Harbor Laboratory
Inside cells, phosphorus gives structure to DNA and holds together essential energy storage molecules. It is a versatile connector. It can easily bond multiple chemical groups. These groups can be arranged around the phosphorus hub to create three-dimensional shapes.
Moses says, “Nature has recognized its importance — it is a privileged group.” If we’re trying to make drugs that interact with biology, we shouldn’t ignore that fact.”
Chemists can now use PFEk to join many different chemical components around a single phosphorus hub. By incorporating more phosphor connectors, they can build even more complex molecules. “Now we decorate this three-dimensional connection. And that will give us access to some new chemical space,” says CSHL researcher Joshua Homer. “When you access a new space, you access a new function.”
The power and potential of PFE-based chemistry lies in its ability to rapidly and reliably assemble complex molecules using sustainable laboratory science. The illustration above shows how PFEx is compatible with other click chemistry connections, including the 2022 Nobel Prize-winning CuAAC reactions. Credit: Moses Lab/Cold Spring Harbor Lab
PFX reactions can even allow drugs to latch on to their targets inside the body. Moses’ team has already begun investigating PFEk as a source of cancer therapy. One of the advantages of this approach is that researchers can optimize the reactivity of molecules involved in PFE reactions. This could ensure that potential drugs only interact with their intended targets, reducing the risk of side effects.
The researchers expect their new type of click chemistry to help create materials with useful properties. For example, PFEk can be used to incorporate flame retardants or antimicrobials into new surfaces. Moses says PFEk materials will have an important advantage over the “forever chemicals” found in many products today. Phosphorus bonds are not overly stable. This means that they can be easily broken down when the product is ready for recycling.
Reference: “Phosphorus Fluoride Exchange: Multidimensional Catalytic Click Chemistry from Phosphorus Binding Hubs” by Shoujun Sun, Joshua A. Homer, Christopher J. Smedley, King-King Cheng, K. Barry Sharpless and John E. Moses, June 7, 2023, Chem.
DOI: 10.1016/j.chempr.2023.05.013
The study was funded by the National Cancer Institute, Cold Spring Harbor Laboratory, Northwell Health, FM Kirby Foundation, Sunshine Foundation, SJ Edwards, Starr Foundation, Wassily Family Foundation, La Trobe University and the National Institutes of Health.