Enantiomeric drug molecules are like the Z-shaped pieces in Tetris—typically, only one of them will be the right fit. In drug discovery, chemists separate these enantiomers, which often exhibit different biological activity from each other, through high-performance liquid chromatography columns packed with specialized chiral stationary phases. But these columns are usually only compatible with either […]
Enantiomeric drug molecules are like the Z-shaped pieces in Tetris—typically, only one of them will be the right fit. In drug discovery, chemists separate these enantiomers, which often exhibit different biological activity from each other, through high-performance liquid chromatography columns packed with specialized chiral stationary phases. But these columns are usually only compatible with either polar or nonpolar solvent mixtures, meaning chemists sometimes have to switch between columns to find the right solvent system. Now, a team of researchers demonstrates a reusable and scalable metal-organic framework (MOF) that can be used to do chiral separations with both polar and nonpolar solvents.
MOFs have been used in chiral separations before, but they haven’t been commercialized for this application, likely because of their poor stability and the high cost of their chiral organic components. To address these issues, José Ramón Galán-Mascarós of the Institute of Chemical Research of Catalonia and colleagues synthesized a water-stable MOF composed of copper atoms linked with modified L-histidine molecules. The enantiomers of a compound each interact slightly differently with the chiral histidine groups, with one slowing down more than the other as they pass through the MOF, allowing the material to separate the two molecules from each other. Histidine is a relatively inexpensive amino acid, and by placing triazole groups on the histidine linkers, researchers were able to increase the metal-nitrogen coordination and boost the MOF’s thermal and chemical stability. Galán-Mascarós’s lab teamed up with Melissa M. Reynolds of Colorado State University and other collaborators to test the performance of the triazole acid metal-organic framework (TAMOF-1) in chiral separations.
The team showed that the TAMOF-1-packed column could separate the enantiomers of the pain-relieving drug ibuprofen and of the infamous medication thalidomide, which was used to treat morning sickness until scientists discovered that one of its enantiomers could cause birth defects.
Using a standard chiral mixture, the team also compared the separation capabilities of the TAMOF-1 column to three commercial chiral columns and found that the TAMOF-1 column performed as well as the others at separating the compounds. However, since most chiral columns can only handle mostly polar or nonpolar solvent mixtures, researchers have to invest in a range of columns to cover a range of different analytes, depending on what solvents will separate them. Using the TAMOF-1 column, however, researchers could switch among solvent systems simply by flushing the column with the appropriate solvent. “We have used these columns many, many times, and we still haven’t worn them out,” Reynolds says.
“The chemistry employed in the synthesis of this new material is easy and flexible enough to allow future chiral MOFs based on modified amino acids, allowing scaled-up synthesis of this and new daughter structures,” says David Fairen-Jimenez of the University of Cambridge. This could expand the range of molecules that could be separated using this technique.
Yong Cui, an expert in metal-organic frameworks at Shanghai Jiao Tong University, says TAMOF-1’s stability, simple preparation, and excellent separation capabilities make it a promising chiral stationary phase for purifying enantiomeric drugs.
Galán-Mascarós and collaborators founded a start-up, Orchestra Scientific, to develop TAMOF-1, which has been synthesized on a 10 kg scale, for commercial use as a stationary phase in chiral chromatographic separations.
This article is reproduced with permission from C&EN (© American Chemical Society). The article was first published on September 16, 2019.