Researchers in chemistry and biology take compounds through various stages to make sure they are safe and effective – see how and read our free special collection.

Chemistry is the art of making molecules and understanding what they do. Around the world, many chemists are making and discovering new molecules every day. However, probably the best chemist in the world is nature. Plants, insects, fungi and bacteria all contain thousands of chemical compounds, and many of them are bio-active, which means they interact with living matter to cause diseases or, even better, cure diseases. For this reason a lot of scientific activity is aimed at finding, isolating, identifying and copying natural products.

Take, for example, the search for a new medicine. Although other methods are now proving successful, many first-in-class drugs (drugs that treat a medical condition with a new and unique mechanism) have been developed from compounds found in plants using phenotypic screens (screens that provide a measurable signal but for which you don’t know the underlying mechanism of action).

So what are the steps to turn a plant into a medicine?

Isolation: What compounds are in this plant?

Isolation methods are often based on quite old techniques. A simple first step can be grinding a plant in a mortar, adding a liquid and filtering to separate the soluble from insoluble. Further isolation can be done using various chromatography techniques. These techniques are based on the principal that dissolved compounds pass through a filter at different speeds. Other common techniques are distillation (in which individual compounds are removed from a heated liquid as they reach boiling point) and solvent extraction, which relies on some compounds being more soluble in one liquid than another.

Analysis: What is this compound?

So you have your compound, but what is it? And what does it do?  An analytical chemist has many tools for finding this out. One of the most important is the published literature. Chemical databases allow a scientist to navigate through the massive number of publications and find relevant information. It is relatively easy to work out the molecular weight and elements in a compound. The structure, however, is very complex: enter the compound C6H8O2 in a chemical database, for example, and you will find 746 possible compounds.

To determine what a compound is, it is not only necessary to know which atoms it contains but how they are arranged and bonded together. This affects such properties as acidity and solubility as well as the ability of one compound to  interact with another. Identification can involve analytical techniques such as X-ray crystallography, spectroscopy, spectrometry, chromatography and computer modelling (chemoinformatics).

What does this compound do?

The simplest way to test this is in vitro (meaning “in glass” but now usually “in plastic”). This may involve introducing the compound to living material (such as cells ) or protein under laboratory conditions and monitoring the effect. Does the compound stop fungal growth on the cells? Are the cells prevented from growing? Are first results promising? Then the compound can  be tested in vivo: in live organisms under laboratory conditions (genetically modified mice or zebra fish are two organisms often used for this type of testing).

Synthesis: How can we make this in the laboratory?

One of the disadvantages of using plants as a raw material for medicine is maintaining a supply:  the plant may be difficult to grow and, since the compounds are often found in very low concentrations, extraction may be costly. The first patient to be treated with penicillin (which is derived from fungi) died not because the medicine was harmful but because the supply ran out.

To study the compounds in depth, and perhaps even test as a new medicine, large quantities are required. Many scientists work on natural product synthesis: producing compounds found in nature in the laboratory. These natural products can have very complex structures and sometimes over twenty chemical reactions are needed before an exact copy of the natural product is made successfully. There is a wide body of literature on various methods of synthesis.

Can we make it work better?

So you have a compound with promising properties. Maybe there are similar molecules that work even better. Could it be improved? How can you find this out? By extensive series of tests comparing slightly similar compounds (using a semi-automated process combining high throughput synthesis and high throughput screening is the most efficient way. Examples of ways you can alter a compound are:

• Add extra atoms or groups of atoms or take away groups.
• Exchange one group of atoms for another.

An example of exchanging one group of atoms for another is Myriocin. This compound is derived from a white fungus used in Chinese medicine as a tonic. Working from the original compound (shown as 1 in the figure), Fujita and colleagues designed a much simpler structure which was more effective The simplified Myriocin in the figure was further optimized (by Adachi and co-workers) to produce the compound FTY720 (or fingolimod), which looked to be a promising medicine to prevent rejection of skin grafts.

High throughput screening is usually done on library of compounds all with different structures. These libraries are often a starting point for scientists looking for new medicines.

Biochemistry and chemical biology: How does this compound work?

The way a compound works can be extremely complex. A  molecule can act as a  barrier to another compound: it can block chemical signals sent to a cell or send out false messages by mimicking another compound. To understand how a drug works in a human body, it is first necessary to understand how compounds in cells work. This is the role of the biochemist. A chemical biologist will use this knowledge to study what happens when a compound not usually found in the body is introduced into a human cell. If you can find a compound which will, for example, act only on cancer cells but leave healthy cells alone then you have a potentially useful basis for a drug. Bioorganic and Medicinal Chemistry Letters features a set of Digests, short articles that look into the ways various chemicals act on the human cells.

Can we make this more easily? More cheaply? More quickly?

Synthesis is often complex; if a simpler method can be found, it could save millions in production costs and reduce the price of the medicine. Chemists try to find ways that require fewer steps, allow cheaper starting materials and produce less waste. For example, carrying out several chemical conversions at the same time, called “one-pot synthesis,” can be very efficient.

Clinical trials: This cures the disease but will it kill the patient?  

No medicine can be sold without being thoroughly tested. Government and industry have strict protocols for this. Testing on humans begins with small groups (phase 1 clinical trials). Even at this stage, when the chemical first discovered in a plant, has been optimized to make the drug more effective, it may well be that clinical testing shows that the drug is not effective. Two more phases of testing with increased numbers of patients take place before a drug can be sent to the relevant medical authorities for approval for use. Even after a medicine has been released to the market it is monitored to make sure that it is safe (pharmacovigilance).

What next? Publication!

Scientists who make a discovery often publish it. Publication not only shows who discovered this product but also allows others to elaborate on your work and take it in new directions. For example, the Myriocin shown above was first developed into drug to suppress rejection of skin grafts and organ transplants but found not to be so effective.

That might have been the end of the story, but research is never wasted. The work done on discovering how the seemingly unsuccessful drug FTY720 worked showed a new biologic pathway (the way chemicals act on cells to cause changes in the cell), and that this pathway could be used to suppress autoimmune reactions. So FTY720 proved to be not a failed medicine for skin grafts but rather was developed into a successful pill to stabilise the condition of multiple sclerosis patients.

Peter Bernstein, Digest Editor for Bioorganic and Medicinal Chemistry comments: In this article the use of natural products combined with phenotypic screening has been highlighted as a source of new drugs. Historically, this has been a fertile approach to drug discovery but over the last 10-20 years it had been overshadowed by other, target driven, approaches, especially where the structure of the biological target [enzyme, receptor, transporter) is known. Recently the application of newer isolation and screening techniques has reinvigorated the use of natural products as leads and recent analyses demonstrate that this area is alive and well and remains one of the tools in the drug discoverer’s armamentarium.

Special collection: the road to pharmaceutical discovery

To celebrate the work of these scientists, Elsevier is making a collection of papers about the various stages of pharmaceutical discovery freely available until Dec 2017.

Isolation

• Kiyofumi Ninomiya et al: Carnosic acid, a new class of lipid absorption inhibitor from sage, Bioorganic & Medicinal Chemistry Letters (April 2004)
• Jiřı́ Slanina et al: New and facile method of preparation of the anti-HIV-1 agent, 1,3-dicaffeoylquinic acid, Tetrahedron Letters (May 2001)
• Dongyan Li et al: Two new adamantyl-like polyprenylated acylphloroglucinols from Hypericum attenuatum choisy, Tetrahedron Letters (April 2015)

Analysis

• Soon Young Shin et al: Polyphenols bearing cinnamaldehyde scaffold showing cell growth inhibitory effects on the cisplatin-resistant A2780/Cis ovarian cancer cells, Bioorganic & Medicinal Chemistry (March 2014)
• Tetsuro Fujita et al: Simple compounds, 2-alkyl-2-amino-1,3-propanediols have potent immunosuppressive activity, Bioorganic & Medicinal Chemistry Letters (April 1995)
• Mark J Wigglesworth et al: Increasing the delivery of next generation therapeutics from high throughput screening libraries, Current Opinion in Chemical Biology (June 2015).

Molecular libraries

• Pravin Patil et al: MCR synthesis of a tetracyclic tetrazole scaffold, Bioorganic & Medicinal Chemistry (June 2015)

Example of how the use of a compound can change

• Frédéric J Zécri: From Natural Product to the First Oral Treatment for Multiple Sclerosis: The Discovery of FTY720 (Gilenya™)?, Current Opinion in Chemical Biology (June 2016)

How does this chemical work?

• G. Richardson et al: Non-electrophilic modulators of the canonical Keap1/Nrf2 pathway, Bioorganic & Medicinal Chemistry Letters (June 2015)
• Patrick Cyr et al: Recent progress on nuclear receptor RORγ modulators, Bioorganic & Medicinal Chemistry Letters (September 2016)
• Freek J. Janssen, Mario van der Stelt: Inhibitors of diacylglycerol lipases in neurodegenerative and metabolic disorders, Bioorganic & Medicinal Chemistry Letters (August 2016)
• Edward J. Hennessy: Selective inhibitors of Bcl-2 and Bcl-xL: Balancing antitumor activity with on-target toxicity, Bioorganic & Medicinal Chemistry Letters (May 2016)
• Hengmiao Cheng et al: Recent progress on third generation covalent EGFR inhibitors, Bioorganic & Medicinal Chemistry Letters (April 2016)

Synthesis

• Kunitomo Adachi et al: Design, synthesis, and structure-activity relationships of 2-substituted-2-amino-1,3-propanediols: Discovery of a novel immunosuppressant, FTY720 Bioorganic & Medicinal Chemistry Letters (April 2005)
• Vijay Nair, T.D. Suja: Intramolecular 1,3-dipolar cycloaddition reactions in targeted syntheses, Tetrahedron (December 2007)
• Bahador Karami et al: A one-pot, three-component synthesis of new pyrano[2,3-h]coumarin derivatives, Tetrahedron Letters (March 2012)
• Gordon M. Cragg, David J. Newman: Natural products: A continuing source of novel drug leads
• Biochimica et Biophysica Acta – General Subjects  ( June 2013)

Contributor

A medicinal chemist, Dr. Peter Bernstein has over 30 years of successful drug discovery, scientific and project leadership. He has experience in a wide set of target types and therapeutic areas. This is documented by his more than 200 publications, presentations and patents, which also serve to provide him recognition in the broader scientific community.

While specializing in delivery of small molecule clinical candidates, he has also worked on and led teams ranging from target identification/project initiation to post-launch product support. In addition, he has experience with portfolio and project evaluations, due diligence evaluations and training.

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Author

Joanna Aldred is an Editorial Manager at Elsevier working on  the Tetrahedron journals. Based in Amsterdam, she has over 25 years experience in publishing and works closely with the editors, publishers and authors. She is an occasional contributor to Elsevier’s Pharma R&D Today blog.

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Twitter: @JoannaMAldred

Drug discovery: how RELX helps

RELX has developed several information solutions that facilitate drug discovery and development at all stages:

Reaxys Medicinal Chemistry offers structure–activity relationship profiles, data from in vivo animal studies, in vitro metabolic profiles, and in vitro efficacy, pharmacokinetic, toxicity and safety data.

Reaxys makes it easier to find relevant literature, retrieve precise compound property and reaction data, so that the information can be incorporated into research workflows.

Embase is a highly versatile, multipurpose and up-to-date biomedical database covering the most important international biomedical literature from 1947.

PharmaPendium  is a  source of searchable FDA/EMA drug approval documents and comparative drug safety, pharmacokinetic, efficacy and metabolizing enzyme and transporter data, to help with: risk assessments of a drug candidate’s toxicity; assessments of a drug candidate’s PK parameters and properties and allows better assessment of the best animal model to use.

Elsevier’s Pathway Studio aids interpretation of experimental data to give a more complete picture of the underlying biology of diseases, responses to drugs, and a wide range of biological processes.

QUOSA PV is a pharmacovigilance workflow management tool that centralizes the discovery of critical adverse event information in various types of literature.

Elsevier publishes various journals in this field, including: Bioorganic and Medicinal Chemistry, Bioorganic and Medicinal Chemistry Letters, The European Journal of Medicinal Chemistry and Drug Discovery Today (see www.ScienceDirect.com).