Complex Molecule Modifications May Enhance Cancer Drugs

A new method for complex drug molecule modifications has been created at The Scripps Research Institute (TSRI).

This study, published in the journal Science, was prompted after Pfizer needed help synthesizing the molecule bicyclo[1.1.1]pentan-1-amine, which is needed to make a cancer drug candidate.

Researchers used a method called “strain-release amination,” which would enable easier construction of molecules and included molecular probes for biology studies, plastics, and other organic compound materials.

"Most of the previously published synthetic routes require 3 to 5 steps with toxic reagents and yield only tens of milligrams," said PhD student and study co-first author Ryan Gianatassio.

In previous methods, inserting small structures into larger drug molecules can be extremely difficult, and chemists frequently would have to redesign the entire synthesis around the added structure.

"The way they've been doing it is like decorating a Christmas tree by putting the ornaments in place first and then growing the tree around it," said senior investigator Phil S. Baran."In many cases, they just won't pursue that because of the time and labor it would take."

The new method in the current study, however, directly affixed a strained-ring molecule (propellane) to larger existing drug molecules.

"We can make that 5 carbon ring structure of propellane click onto a wide range of drug molecules of a type known as secondary amines -- we call that a propellerization reaction," said Justin M. Lopchuck.

By starting with a stock solution of the propellane, researchers were able to use high-throughput techniques to rapidly elaborate a matrix of amine-containing compounds with the bicyclopentyl moiety, the study authors said. This replaced the need to painstakingly synthesize compounds individually.

Researchers also discovered the new method could be used to attach molecules with precision to specific amino acids on proteins. By doing this it would allow for the creation of new biologic drugs.

"This technique opens up a world of chemistry that academic and commercial laboratories have really wanted to look into but couldn't, due to the technical obstacles," Baran said.

This new information on strain-release amination should enable chemists to use the new method right away.

"People from other pharma companies who have seen early drafts of this paper can't get their hands on the supporting information fast enough," Baran said. "I expect that every company in the business of making drugs will be using this chemistry soon."