Rice University researchers have developed a revolutionary method for making molecules—which could speed up drug synthesis—in a groundbreaking. In addition to simplifying molecular creation, this innovative technique also opens the door for a highly efficient pharmaceutical development process and presents potential solutions to diseases.

Discovery Highlight

Results from the study, which appears in Science, outline a method combining biocatalytic carbon–hydrogen oxidation with radical cross-coupling to simplify the synthesis of piperidines, which are key structural features of many pharmaceuticals. First, a two-step approach is proposed—the enzymatic placement of hydroxyl groups at specific sites on piperidine molecules, allowing for the selective functionalization of these complex, three-dimensional structures. In the second step, carbon-carbon bonds are formed using nickel electrocatalysis in an efficient radical cross-coupling that does away with ‘protective groups’ or expensive catalysts like palladium.

Compared to traditional multi-step processes, which can involve upwards of 7-17 steps, this streamlined method drastically decreases the number of steps needed to synthesize high-value piperidines, down to 2-5 steps. It has proven to be very flexible for the preparation of piperidines that have found utilization in curative natural products and pharmaceuticals, e.g. neurokinin receptor antagonists, anticancer agents and antibiotics. The method unravels challenges to medicinal chemistry, accelerating drug discovery while lowering costs and relying less on expensive metals.

Study’s Methodology

To develop and validate their molecule creation method, the researchers used a combination of advanced analytical tools and innovative methodologies. Thin layer chromatography (TLC) with silica plates and developing agents such as  KMnO₄ and ninhydrin were used to monitor chemical reactions. State-of-the-art systems were employed to confirm molecular structure using liquid chromatography/mass spectrometry (LC/MS) and high-resolution mass spectrometry (HRMS).

The structural properties of synthesized molecules were determined by NMR spectroscopy. Detailed molecular insights were revealed by high-performance systems. The exact molecular structures were determined with exceptional accuracy through X-ray crystallography.

PCR and protein analysis were supported by advanced thermocyclers and spectrophotometers and enzymatic studies were carried out. In addition, the study was expanded through the use of advanced biochemical techniques and biological materials such as expression vectors and electrocompetent E. coli.

Hans Renata and Kenta Yokoi in Renata’s lab at Rice (Credit: Alex Becker/Rice University).

Role of Catalysts

This breakthrough places the finishing touches on an invention that employs catalysts to improve the pace of chemical reactions. Catalysts reduce activation energy and make the rapid synthesis of complex molecules possible. The use of catalysts in this method is novel, and the use of the catalysts allows for the precision of drug discovery, reduces by-products and makes drug discovery more scalable.

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A breakthrough in creating molecules, Rice University’s groundbreaking method is a powerful tool that can revolutionize drug synthesis and discovery. The use of this innovative technique will streamline the pharmaceutical advancement by industries thus uplifting global healthcare outcomes.

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Source: 

1. Becker, A. (2024, December 19). New molecule-creation method a “powerful tool” to accelerate drug synthesis and discovery. Rice News | News and Media Relations | Rice University. https://news.rice.edu/news/2024/new-molecule-creation-method-powerful-tool-accelerate-drug-synthesis-and-discovery 

2. He, J., Yokoi, K., Wixted, B., Zhang, B., Kawamata, Y., Renata, H., & Baran, P. S. (2024). Biocatalytic C–H oxidation meets radical cross-coupling: Simplifying complex piperidine synthesis. Science, 386(6728), 1421–1427. https://doi.org/10.1126/science.adr9368