How to Overcome Challenges in Complex Natural Product Synthesis

The synthesis of natural products has become a major focus in pharmaceutical and biotechnology research, offering significant potential for novel therapeutic agents and treatment for a broad spectrum of diseases, including cancer, antibiotic-resistant infections, and neurological disorders.

Dr. David Mangelsdorf, a distinguished member of the GL CHEMTEC Scientific Advisory Board, is at the forefront of this field. We recently spoke with Dr. Mangelsdorf to learn more about emerging trends in natural product synthesis and how to confront and overcome related challenges.

Emerging Trends in Natural Product Synthesis

Natural products have been vital in developing therapeutic agents, but their use in pharmaceutical research over the years has been challenged by screening methods. A number of new methodologies and technologies, however, have reignited interest in natural products and sparked further research and development. 

“With new technology, there's been a growing realization that natural products offer a potential treasure trove of compounds with not only medicinal value, but also perhaps chemical engineering value,” Dr.  Mangelsdorf said, highlighting artificial intelligence (AI) and new methodologies for complex natural product synthesis as being particularly exciting.

Let’s take a closer look at each of these developments: 

AI and High-Throughput Screening

High-Throughput Screening (HTS) significantly enhances the speed with which researchers and drug developers can identify potential drug candidates. HTS uses automated systems and miniaturized assays to rapidly evaluate thousands of natural compounds or extracts for biological activity. This enables researchers to quickly test samples for things such as antibacterial or anticancer properties, and to pinpoint promising candidates for further study.

Integrating AI into this process further simplifies and accelerates the identification of therapeutic candidates. AI can analyze vast datasets with precision, uncovering complex synthetic pathways and predicting the efficacy of novel compounds.

“Using artificial intelligence to solve these complex synthetic pathways could be transformative,” Dr. Mangelsdorf said. “Look at all of the other ways that it's being used already, and you can get a sense of its potential impact."

One innovative application of AI is virtual chemistry, which allows researchers to design compounds virtually, reducing the need for extensive physical screening.

“There are programs that allow you to look at the structure of a potential target and virtually screen tens of millions of compounds, identifying potential interactions before synthesizing and testing them,” Dr. Mangelsdorf said, explaining why the global market for AI in drug discovery is forecasted to grow to $13 billion (USD) by 2032 (from $1.5 billion currently). 

New Synthesis Methods and Synthetic Biology 

Advancements such as click chemistry and synthetic biology are helping to overcome the structural complexities of natural products, allowing for more precise and efficient synthesis.

Synthetic biology, in particular, has tremendous potential as it enables scientists to redesign organisms to become efficient producers of complex natural products. A notable example of this is the development of Taxol, a plant-based anti-cancer compound that has led to the creation of more advanced compounds with enhanced medicinal properties.

Gene-editing technology like CRISPR (short for Clustered Regularly Interspaced Short Palindromic Repeats) will also play a valuable role in natural product research. CRISPR allows precise targeting and modification of specific genes in living cells and organisms. By precisely modifying microbial genomes, scientists can enhance the yield or production of desired natural products within the organism itself.

Common Challenges in Complex Natural Product Synthesis

Here are three common challenges posed by natural product synthesis, and how researchers and drug developers are overcoming them:

• The structural complexity of natural products, as mentioned above
• The yield and scalability of small molecule natural products, as it is often difficult to produce sufficient quantities from natural sources and traditional synthetic method
• Getting funding for natural product synthesis projects, as the process can often be “a fishing expedition,” Dr. Mangelsdorf said. 

Leveraging North American Partnerships for Effective Natural Product Synthesis

To overcome these challenges, researchers are embracing a collaborative, multi-disciplinary approach to complement and expand skill sets, access cutting-edge technology, and prove the commercial viability of novel compounds.

As we have covered, many leading drug developers are now leveraging strategic partnerships with contract development and manufacturing organizations (CDMOs), such as GL CHEMTEC, to stay competitive and keep up with the pace of innovation.

“From an academic point of view, we often need chemistry and industry partners that can provide chemical synthesis of compounds that aren't readily available through the Sigma catalog or one of these other chemistry providers,” Dr. Mangelsdorf said, explaining that onshoring and North American chemistry providers have become increasingly popular in this context (and with recent global disruptions).

“Working with specialized providers in North America is definitely an advantage because you can get people together quickly, face-to-face, to solve complex challenges. It’s these kinds of interactions that help form a relationship and make it more collaborative,” he said. 

“Having an experienced partner like GL CHEMTEC, which is based right here in North America, that can not only point us in the right direction but get us to the finish line – that’s beyond valuable.”

GLC: Your Trusted CRO/CDMO Partner

GL CHEMTEC is passionate about your success and committed to solving your most complex chemistry challenges. We offer fast, flexible, cutting-edge solutions to take your medicinal chemistry and early stage small molecule routes to the next level. Our commitment to a collaborative partnership means we scale and adapt precisely to meet your evolving needs.

GL CHEMTEC provides:

• A secure North American alternative to overseas providers, offering R&D labs, Kilo labs and scale-up facilities in the Greater Toronto area
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