New method automates the production of small-molecule active pharmaceutical ingredients
The research and development of novel small-molecule compounds for therapeutic applications requires an enormous amount of time, resources and work.
Dr. Liu Chenguang (left) and Assistant Professor Wu Jie (right) are part of the NUS team that developed the automated technology for making pharmaceutical compounds. Image source: National University of Singapore.
Now, a research team from the National University of Singapore (NUS) has given traditional chemical synthesis a new twist and identified a new way to automate the production of small molecules suitable for pharmaceutical use.
The new technique could be used for molecules that are generally manufactured by manual processes, thereby reducing the manpower required.
The researchers who succeeded in making this technological innovation were led by Assistant Professor Wu Jie from the NUS Department of Chemistry and Associate Professor Saif A. Khan from the NUS Department of Chemical and Biomolecular Engineering.
In demonstrating the new method on a pharmaceutical molecule called Prexersatib, which is used in cancer therapy, the NUS researchers achieved a fully automated six-step synthesis with an isolated yield of 65% in less than 32 hours.
In addition, the new method effectively generated 23 prexasertib derivatives in an automated manner, demonstrating their potential for drug discovery and design. The results, which were first published in the journal Nature Chemistry on April 19, 2021, could be used to produce a wide range of pharmaceutical molecules.
Simplifying the manufacture of pharmaceutical compounds Compound
New developments in end-to-end flow synthesis are rapidly expanding the potential of automated syntheses of low molecular weight pharmaceutical compounds in flow reactors.
There are also well-defined production techniques for several molecules, such as oligonucleotides and peptides, which have repeating functional units. However, due to various problems such as
The novel automated method developed by NUS researchers integrates a number of chemical synthesis methods. These include solid-based synthesis, in which molecules are chemically bound and can grow on an insoluble carrier material, and continuous flow synthesis, in which chemical reactions are carried out in an optimized process.
The new process, known as solid phase synthesis flow (SPS flow), helps develop the target molecule on a solid support material while the reaction reagent passes through a fixed bed reactor. Computer automation controls the entire process.
Compared to predominant automated processes, the SPS flow technology enables broader reaction patterns as well as a longer linear, continuous automated production of pharmaceutical compounds.
The team tested the new method on Prexasertib, a cancer-inhibiting molecule, because it can adhere suitably to the solid resin used as a carrier material. The researchers’ experiments showed a 65% yield after 32 hours of constant automated execution.
This process is an improvement over the prevailing technique of making Prexasertib, which takes more or less about a week and also requires an elaborate six-step manual process and cleaning process to achieve a yield of up to 50%.
The latest technology also enables synthetic changes early in the process itself, thus enabling greater structural diversification compared to conventional techniques that only allow late diversification of the common core structure of a molecule.
Using a computer-based chemical recipe file, the researchers effectively created 23 derived molecules of Prexasertib. The resulting derivatives are molecules in which the parts of the molecular structure are slightly different from the actual molecule.
The ability to easily obtain these derivatives is critical during the drug discovery and design process, as understanding the relationship between molecular structures and their activities plays an important role in the selection of promising clinical candidates.
Saif A. Khan, Associate Professor, Department of Chemical and Biomolecular Engineering, National University of Singapore
Create new opportunities in drug development
The NUS researchers now plan to further demonstrate the versatility of their SPS flow method by conducting additional studies that incorporate top-selling pharmaceutical molecules.
Our new technology offers a simple and compact platform for the automated on-demand synthesis of a drug molecule and its derivatives. We estimate that 73 percent of the 200 top-selling small molecule drugs could be made using this technology.
Wu Jie, Associate Professor, Department of Chemistry, National University of Singapore
The researchers’ upcoming studies will focus on the development of a portable and fully automated system for manufacturing active pharmaceutical ingredients on a larger scale that is suitable for manufacturing. This system will use the recently developed lead optimization method to accelerate the drug discovery process.
Journal reference:
Liu, C., et al. (2021) Automated synthesis of Prexasertib and derivatives, made possible by solid-phase synthesis in continuous flow. Nature chemistry. doi.org/10.1038/s41557-021–00662-w.
Source: https://nus.edu.sg/
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