The discovery and development of new small molecule compounds for therapeutic use involves a considerable investment of time, effort and resources. Giving a new twist to conventional chemical synthesis, a team of researchers from the National University of Singapore (NUS) has developed a way to automate the production of small molecules suitable for pharmaceutical use. The method can potentially be used for molecules that are typically produced by manual processes, thereby reducing the labor required.
The research team that achieved this technological breakthrough was led by assistant professor Wu Jie of the Department of Chemistry NUS as well as Associate Professor Saif A. Khan of the NUS Department of Chemical and Biomolecular Engineering.
By demonstrating the new technique of prexersatib, a drug molecule used in the treatment of cancer, the NUS team performed a fully automated six-step synthesis with an isolated yield of 65% in 32 hours. In addition, their technique also successfully produced 23 derivatives of prexasertib in an automated fashion, indicating the potential of the method for drug discovery and design.
The results, which were first published in the journal Chemistry of nature on April 19, 2021, can potentially be applied to the production of a wide range of pharmaceutical molecules.
Simplify the production of pharmaceutical compounds
Recent advances in end-to-end continuous flow synthesis are rapidly expanding the capabilities of automated syntheses of small molecule pharmaceutical compounds in flow reactors. There are well-defined production methods for molecules such as peptides and oligonucleotides that have repeating functional units. However, it is difficult to perform multistep continuous flow synthesis of active pharmaceutical ingredients due to problems such as incompatibilities of solvents and reagents.
The new automated technique developed by the NUS research team combines two chemical synthesis techniques. These include continuous flow synthesis, where chemical reactions are carried out in a continuous process, and solid support synthesis, in which molecules are chemically bonded and grown on an insoluble support material.
Their new technique, called solid phase synthesis flow, or SPS flow, allows the target molecule to be grown on a solid support material as the reaction reagent flows through a packed bed reactor. The whole process is controlled by computer automation. Compared to existing automated techniques, the SPS-flow method allows for broader reaction models and longer linear end-to-end automated synthesis of pharmaceutical compounds.
The researchers tested their technique on prexasertib, a cancer-inhibiting molecule, due to its ability to be attached to a solid resin that was used as a support material. Their experiments showed a 65 percent efficiency after 32 hours of continuous automated runtime. This is an improvement over the existing method of producing prexasertib which takes about a week and requires a manual process and a six-step purification procedure to produce a yield of up to 50 percent.
The new method also allows for synthetic modifications early in the process, allowing for greater structural diversification compared to traditional methods which only allow late-stage diversification of a molecule’s common basic structure. Using a computerized chemical recipe file, the team succeeded in producing 23 molecules derived from prexasertib. The derivatives produced are molecules whose parts of the molecular structure differ slightly from the original molecule.
“The ability to readily obtain these derivatives is crucial 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,” said explained Assistant Professor Khan.
Create new opportunities for drug development
The NUS team plans to further showcase the versatility of its SPS-flow technique by conducting more research integrating top-selling pharmaceutical molecules.
“Our new technique presents a simple and compact platform for the automated synthesis on demand of a drug molecule and its derivatives. We estimate that 73% of the top 200 selling small molecule drugs could be produced using this technique, ”said Professor Wu.
Future studies by the team will target the development of a fully automated and portable system for the production of active pharmaceutical ingredients on a larger scale, suitable for manufacturing. The system will apply the new lead optimization technique to speed up the drug discovery process.