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September–November 2022

Natural products – mainstream but not always natural

It is generally accepted that advances in natural products chemistry early last century inspired much of what is modern organic chemistry. Each year, peer-reviewed scientific journals publish thousands of articles, and legions of researchers, educators and students attend conferences and seminars showcasing the latest discoveries in basic and applied natural products science, spanning such topics as detection, isolation, characterisation and structure elucidation, biosynthesis and synthesis, chemical ecology and pharmacology, molecular targets and mechanism of action, and much more. Knowledge of natural products has informed our understanding of life, inspired many of the world’s most successful drugs, agrochemicals and biomaterials, and fuelled a revolution in industry, commerce, health care and agriculture.

No longer exclusive to science, awareness of natural products has moved mainstream. Public encounters with natural products as antibiotics (penicillins, tetracyclines), antilipidemics (statins), analgesics (aspirin, opioids), antiparasitics (avermectins), insecticides (pyrethroids, spinosads), herbicides (glufosinate – forerunner to glyphosate) or stimulants (caffeine in coffee, tea and various soft and energy drinks) has had a lasting and profound impact. Natural products make our lives better! As a result, we all know what natural products are – but do we really? Within the world of natural products science lies an inconvenient truth – natural products are not always natural! Before elaborating, consider what we mean by the term ‘natural product’.

It is surprisingly difficult to pin down a working definition of a natural product. Without going down the historical rabbit hole of who said what, when and why, for a large part of the last century natural products were viewed through the binary delimiters of primary versus secondary metabolites, with the former being essential and the latter non-essential to normal growth, development and reproduction. For some, this provided a satisfactory albeit naive circular logic that defined natural products as secondary metabolites, and secondary metabolites as natural products. Equally out of touch with modern thinking, as an undergraduate in the 70s I remember a very senior biochemistry professor advising me that much like non-protein-coding DNA, natural products were nuisance chemistry with no particular purpose – so if I wanted a career in science, it would be best to avoid such molecular detritus. Fortunately, my organic chemistry professors were more enlightened, and the rest is history. Putting aside the primary versus secondary dichotomy, perhaps a safer definition of a natural product is ‘any chemical isolated from a living organism’. But is it really safer? Let me illustrate with an example from my lab.

For several decades, my research team has studied Australian natural products, with a bias towards those of marine origin. One particularly fun project started with a visiting Brazilian student purchasing three fresh mullet (Mugil species) from the local fish shop, from which she excised gastrointestinal tracts and isolated more than 500 chemically distinct fungi. An array of technologies was used to prioritise these fungi in favour of those most likely to produce natural products new to science, with subsequent studies yielding many noteworthy discoveries, including unprecedented Schiff bases such as 1–3 (Org. Lett. 2018, vol. 20, pp. 377–80). Of note, although the dimer 1 and trimer 2 were isolated from a solvent extract of the fungal culture, the monomer 3 was not. We speculated that 3 should be a precursor of 1 and 2, so carefully chemically analysed fresh extracts and proved that 3 was in fact a natural product. Furthermore, during handling and purification, 3 underwent rapid and quantitative acid-mediated transformation to 1 and 2, requiring that the latter be reclassified as artifacts.

While artifacts are not uncommon in the natural products literature, they are often mis-identified as natural products (see Nat. Prod. Rep. 2020, vol. 37, pp. 55–79), so we were pleased with ourselves not to have been fooled (as so many are), or so we thought. In a follow-up study (Marine Drugs 2021, vol. 19, p. 151), we determined that the fungus did not biosynthesise any of the Schiff bases 1–3! Instead, the fungus produced the unprecedented, chemically reactive cryptic natural product N-amino-L-proline methyl ester 4, which it retained in the mycelia. On solvent extraction, 4 was released from the fungal mycelia to encounter 5-hydroxymethylfurfural 5 (produced during autoclave-mediated thermolysis of media carbohydrates) and undergo rapid transformation to the Schiff base 3. These observations also explained why the Schiff bases were only detected in certain culture media – those that were carbohydrate rich and which after autoclaving had high levels of the furan aldehyde 5.

This experience reaffirmed:

  • natural products can be chemically reactive
  • natural products can be cryptic
  • culture media can be a source of reactive chemicals
  • fungi have the option to retain and/or secrete natural products
  • artifacts can form under even the mildest conditions
  • just because a chemical is isolated from an extract doesn’t mean it is natural.

It also prompted the following more inclusive definitions:

  • ‘A natural product is a chemical that originates from, and can be detected in, a fresh extract of a source organism, provided the process of extraction and/or detection does not initiate a chemical transformation that is solely responsible for producing the chemical.’
  • ‘An artifact is a natural product that has undergone a chemical transformation during extraction, handling, storage and/or analysis.’

Notwithstanding, in the eyes of many, a natural product will always be ‘any chemical isolated from a living organism’ – which as definitions go has the appeal of simplicity (even if it sidesteps an inconvenient truth).

Rob Capon FRACI CChem is Professorial Research Fellow and Group Leader in the University of Queensland, Institute for Molecular Bioscience, and Program Leader in the Marine Bioproducts CRC.

Paolo Gamba/Flickr/CC-BY-2.0

Mugil cephalis (flathead grey mullet)

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