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Shedding some light on the 5-8-5 scaffold
August 2018
by Kelsey Kaustinen  |  Email the author
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TALLAHASSEE, Fla.—While compound screening libraries are a familiar staple within the drug development industry, some scientists prefer to turn to natural products instead. Such compounds can offer not just new options with proven bioavailability—and sometimes better efficacy than synthetic counterparts—but also answers as to ideal or optimized molecular structures. Along those lines, looking at natural products closely has revealed some interesting repetitions—among them, the carbocyclic 5-8-5 fused ring system, a molecular structure that could have significant therapeutic potential.
 
The 5-8-5 scaffold consists of two five-sided molecular rings that are fused to a central eight-sided ring. The issue with this particular scaffold is that despite its prevalence in nature, recreating it synthetically is very difficult. But a new technique identified by a team from Florida State University (FSU) could be the answer to overcoming those difficulties.
 
The researchers’ work—detailed in the study “Modular access to functionalized 5-8-5 fused ring systems via a photoinduced cycloisomerization reaction,” which appeared in Chemical Science—not only identified a new way to produce the 5-8-5 ring structure, but the process is also much faster.
 
“The benefit of natural products is they have many tidal centers, and so as a general starting point, they’re not really like anything you’d find in a typical screening library,” says James Frederich, an assistant professor in the Department of Chemistry and Biochemistry and lead author of the recent study. “I think the opportunities for natural products just as an inspiration for the development of fully synthetic compounds is really high, and I think really requires trained synthetic chemists to look at those problems.”
 
“We’re really interested in the fact that this particular scaffold is found within a number of bioactive natural products that have functional properties that are important in human cell culture,” he adds. “There’s about 30 natural products that harbor this scaffold, and maybe six or seven of them are identified with on-target type of activity in human cell culture, so we looked at the basis of that scaffold as sort of a privileged scaffold that could be built off of. After some investigation, it seems like there are many ways to make one specific natural product in those groups, but no really good direct modular entry point for that type of scaffold. And so that became the first initial goal of our program—in the longer term, of course—to use that chemistry to access a number of these natural products and maybe track down more detailed biochemistry once they’re in hand.”
 
The current approaches for replicating the 5-8-5 scaffold demand extremely long synthesizing times with high temperatures and transition metal catalysts.
 
Frederich confirms that the current methods for synthesizing 5-8-5 scaffolds are the primary hindrance to exploring this structure’s potential, explaining that “Our best-yielding reaction on a gram scale takes 48 hours or 52 hours to go to completion, so the first real issue to use this chemistry was to cut down on that time.”
 
By contrast, the FSU approach is primarily triggered by ultraviolet light. Cyclization substrates are accessed with a two-step assembly scheme, and once the substrate is present, the scaffold is exposed to ultraviolet light to encourage ring formation.
 
“The use of UV light is particularly convenient as it avoids the need for high temperatures or costly catalysts,” Frederich said.
 
“From our perspective, the overarching goal was to use certain members of the 5-8-5 system, in particular those that are known to stabilize protein-protein interaction in vitro and in vivo, and how they use that sort of evolved biological efficacy to target that protein-protein interaction problem,” he tells DDNews. “And I think these have been notoriously difficult drug targets to go after. In many cases, people look at trying to create small-molecule inhibitors of protein-protein interactions, and really the best way to do that is to mimic the endogenous ligands, and so typically people make peptidomimetics, or small molecules that mimic proteins’ secondary structures to try and access where the protein binds. That has its challenges, although I think it’s become more tractable.”
 
Code: E081802

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