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The Future Of Natural Products Chemistry: Marine Novel Compounds

Created 08.17.11 by Chivas Owle
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Historically, this is how most pharmaceutical agents were discovered. In ancient times, great civilizations used what the local plants and animals provided for them. Until the 1920’s, virtually all remedies were discovered through trial and error using the local products that were available. Once more scientific forms of investigation became available, many individual compounds were isolated from extracts used by indigenous populations.Many of the most commonly used drugs in the world such as aspirin, atropine, colchicine, digoxin, and many more were discovered this way. This process defined modern natural products chemistry for decades and indeed this sort of novel compound discovery continues to this day, and for good reason. Much research remains – the vast majority of terrestrial plants and animals have not been studied for any medicinal use.

The primary benefit of using compounds produced in nature is that they are “prescreened” through the process of natural selection and serve some purpose already. The trick is to figure out what that function is and if it can be harnessed for our benefit. This is the principle concern of researchers who gather organisms, perform organic chemistry techniques to isolate the individual compounds that are produced by the organism, describe their structure, and run assays to determine biological actions.

From Land to Sea: Researching Marine Compounds

Dr. Valerie Paul conducting field research

More recently, research has branched out to include an area previously untapped area: the ocean. The ocean is a vast untapped reservoir of biological and chemical diversity. Each milliliter of seawater collected near the surface of the ocean contains about one million microbes. The same amount of water collected from the ocean floor contains about one billion microbes. And this is only considering microbes! The ocean is home to a variety of life forms including fish, algae, snails, sponges, reefs, bacteria, and much, much more. Medicinal chemists have only just begun to explore the potential of this amazing source of natural compounds.

Many of the agents discovered so far from marine sources are under investigation for anti-cancer activity. This is primarily because the National Cancer Institute finances much of the research in this field. However, the National Institute of Health recently set up grants for the purpose of screening marine compounds against a much larger assay of potential uses, including antibiotic, antimalarial, anti-HIV, and much, much more. This is an exciting prospect in the quest for new pharmaceutical agents to treat a variety of conditions.

The relatively new practice of using the ocean to procure specimens has provided researchers with a whole new group of organisms with which to isolate compounds. Because these compounds are so different from terrestrial sources, new techniques had to be developed in order to isolate and describe them.

Challenges of Working With Marine Natural Products

One major problem working with chemicals produced in nature is the available supply. Collecting enough material for research is often challenging. Often the only practical solution is large-scale collection and extraction of the organism that produces the compound of interest.

An alternative to large-scale collection can be to study the predator-prey relationships. One example of this is in the mollusk/macroalga relationship. Collecting mollusks rather than macroalga can increase yield by a factor of 10,000. This is because the mollusks eats the macroalga and concentrates the compounds produced by the macroalga. While each macroalga may only produce a small amount of the material in question, the mollusks will consume many macroalga. As it continues to devour more and more macroalga, the mollusk will naturally begin to accumulate the compounds of the macroalga. This is why the compound of interest may be found in much greater quantities if the researcher concentrates on extracting from the predator rather than the prey.

Another unique challenge in marine natural products is determining the true producer of a particular compound. Whenever bulk extractions are run on large samples, there is a possibility that the compounds isolated may come from multiple sources. For example, when running extractions on large batches of sponges, there is a high probability that the batch will also contain at least some cyanobacteria. The challenge for the researcher is to determine which compounds are produced by the sponge and which ones are produced by the bacteria. Thankfully the products of cyanobacteria are often distinctive enough chemically to allow the researcher to determine the true producer of the compound without the need for further testing.

Conclusion

The field of marine natural products chemistry is one of the most promising in the continued search for new pharmaceutical agents. Interested parties are encouraged to learn more about this exciting field from trade journals such as The Journal of Natural Products or Drug Discovery Today, by visiting marine ecology exhibits, or by contacting research groups in this field such as The Smithsonian Martine Research Station or Harbor Branch Oceanographic Institute.

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Comments

  1. Chemist says:

    Only in academic circles are natural products still being researched. Major drug companies have completely abandoned studying these molecules due to their horrendous bio-availability and poor off-target profiles. A few exceptions exist, but their molecules were discovered decades ago.

    To say that “The field of marine natural products chemistry is one of the most promising in the continued search for new pharmaceutical agents” is just simply wrong. Natural products are slowly becoming an artifact of the 20th century. I guess it’s a good excuse to go scuba diving during regular work hours, though.

  2. AdonisDNA says:

    … and the pharmaceutical company lawyers have a hard time patenting naturally occurring substances.

  3. Chivas Owle says:

    Thanks for the thoughtful responses guys! I disagree about the future of Natural Products Chemistry – our best days are not behind us yet ;) but I love the discourse. Keep the comments coming.

  4. R2 says:

    Until we master the art of designing drugs from scratch (ha!) we will, at the very least, continue to look towards naturally occurring compounds as a source of inspiration for new drugs. It’s not as if we have to discover compounds in a ready-to-market form in order for them to be potentially useful.

  5. nxijasusce says:

    , , , ,

  6. Chris Stratton says:

    The opinion that I have encountered thus far in dealing with doctors (I am in the military, shadowing as many medical professionals as I can prior to discharge and med school entrance) is one of general distrust for naturally occurring remedies – not just “home brew,” “back woods” treatments.

    How does the fielding of bio-marine medicines differ from the already established genre of homeopathic treatments presently talked down upon by today’s physician? I have a hard time differentiating between the two. What is the deciding factor? Is it the stigma that is attached to homeopathic remedies that today’s doctors distrust, or the application (or mis-application, as it were) by patients?

    1. RJ Herrmann says:

      Good point, Chris. Since much new technology these days draws heavily from biomimicry, it’s odd that the medical profession still kicks and screams about something they cannot control. The general public would rather have something natural from a provider that treats them as an individual, with theory and philosophy soundly proven, not, for example, the cut and burn of cancer therapy. The reason people see alternative health providers is that they don’t see results and so often get worse instead of better.

  7. Chivas Owle says:

    Chris,

    Excellent question. Finding compounds in nature to treat illnesses is not homeopathy. Not even close. Virtually every medicine you know of has a basis in nature. It is how we find medicinal compounds. We run biological assays on naturally occurring compounds to discover their function; if the function can be used medicinally we explore them as potential drug candidates. The only difference is that looking in marine environments for inspiration is relatively new. Very few drug therapies have been designed from scratch, medicinal chemists rely on natural compounds for inspiration on new drug therapies. The process is long and complicated, but it is how drugs are discovered (mostly).

    Homeopathy, herbal remedies, and other types of treatment are a different field altogether and are far outside the scope of this article. The doctors have good reason to be skeptical of them, to put it mildly. I won’t explain homeopathy here, but google the term and educate yourself about what it entails. Herbal remedies may or may not be effective, they lack scientific evidence for their use. They have other issues as well, far outside the scope of this article.

    If you have more questions, feel free to ask! Hope you liked the article. ;)

    1. RJ Herrmann says:

      And I guess you’re an authority on how homeopathy works? Leave homeopathy to people that understand it and have studied it. It’s older than any drug you have used in ‘modern’ pharmacy. Homeopathic remedies are far more gentle, are prescribed individually, and don’t have side effects. What happens when someone takes digitoxin (digoxin) and overdoses? The homeopathic remedy digitalis does not kill. It heals. This from nature, Chivas.

  8. Brett Friedler says:

    An interesting read. What would be the major differences between compounds derived from a marine organism versus a terrestrial organism?

  9. Chivas Owle says:

    Brett,

    Another excellent question! That one is hard to pin down exactly. It might be like saying, how is Mexican food different from Chinese food? They are both food, right? But they are not the same exact thing. It is similar in the field of natural products chemistry. The marine environment is a relatively new avenue to explore to find compounds that can be used medicinally. Plus aquatic life is extremely diverse. With that diversity comes extra opportunities to discover novel compounds.

    Does that answer your question?

  10. Medical Student says:

    Sounds like the Chemist has it all figured out… I’m surprised cancer and AIDS still exist with Chemists like this around…

    Truth is no one knows where the next cure will come from and that’s why we’re all still looking. I think marine animals can provide us with many untapped resources. Nice article Chivas.

  11. Chemist says:

    “Until we master the art of designing drugs from scratch (ha!) we will, at the very least, continue to look towards naturally occurring compounds as a source of inspiration for new drugs.”

    Not to be too snarky, but this statement would be met with an eye roll from any non-academic medicinal chemist. The number one source of new medicines is proprietary compound libraries. Major pharmaceutical companies have literally millions of molecules (that they have established synthetic access to) which they screen against biological targets in the early phases of drug discovery programs. The groups who are looking toward natural products for “inspiration” are academic or, at best, very small biotechs that occupy a niche in the discovery market. Look up the work of Stuart Schreiber to see how valuable natural products are as inspiration for drugs… look at how many molecules this work has put into the clinic since the 1990’s (a mere handful, most of which went nowhere). Granted, natural products were an incredibly valuable resource until the 90’s, their relevance has since waned substantially.

    Drug discovery is DRIVEN by drug-like molecules, which you don’t find in nature. They are largely man-made, boring looking, and modular from a synthetic chemist’s perspective. With the possible exception of infectious diseases (amphoTerrible, anyone?), the future of small molecular therapeutics is in well-understood, selective and safe molecules. And these molecules are almost never derived from natural product scaffolds.

    Natural products are beautiful and academically fascinating in many, many ways. But they’re also awfully difficult to optimize and much more valuable as biological tools than therapeutics themselves. This research is definitely valuable, but saying they are the future of medicine is over-selling them.

    Also, patenting natural products wouldn’t be a problem at all. If you identify the novel use for a substance, you can patent it. Period. Intellectual property has nothing to do with Pharma’s disinterest in these compounds.

    So what then is the future of pharmaceuticals, you ask? it’s virtual screening, molecular modelling, and transition-metal catalyzed cross couplings. Those 3 technologies are what will bring us the cures of tomorrow.

    1. E says:

      while I think Pharma agrees with you Chemist, if you look at the percentage of ALL approved small molecule drugs since 1981 (Newman and Cragg, 2012) you’ll find that only 36% are purely synthetic drugs, the rest (the entire rest) owe something to natural products- even if its just their pharmacophore. Now you might say that might have been the case before the 90’s, but if you look at it over time you’ll find that’s not the case. In 2011, 50% of approved small molecules were either natural products or natural product derivatives (doesn’t include synthetic molecules with NP inspired pharmacophores). Yes, Pharma has turned away from Natural Products, but not because they arent productive- but because its more expensive and slower and also certain amount of hubris. I work closely in this field, and it looks as if the tides are chaning a bit as Pharma jettisons R&D programs (which became less productive- perhaps because they turned away from NPs) and looks to smaller biotechs and academia for partnerships.

  12. Chemist says:

    If you’re interested in more discussion on this topic from both sides, I recommend this blog post and the paper cited within:

    http://pipeline.corante.com/archives/2010/07/12/natural_products_not_the_best_fit_for_drugs.php

    Anyway, no discussion of natural products is complete without some banter form a medicinal chemist, so I was just trying to provide that perspective. The author gracefully welcomed the discourse, and I applaud him for that. Keep up the good work.

  13. R2 says:

    “The number one source of new medicines is proprietary compound libraries. Major pharmaceutical companies have literally millions of molecules (that they have established synthetic access to) which they screen against biological targets in the early phases of drug discovery programs.”

    And where did these compound libraries come from? Not to suggest that they all have natural sources or inspirations, but some certainly do. I don’t doubt that the techniques you mention are useful, but to this point they seem to have been more useful in tweaking existing classes of medications rather than creating new ones.

    I don’t want to discount the importance of evolutionary drug improvements entirely, but I fail to see them creating the type of revolutionary changes in medicine that products with natural origins have made. You may be right that the “best days” of natural products chemistry are in the past, but based on what they’ve given us so far and how many of them have yet to be explored, I think it would be premature to give up on them entirely.

  14. Chivas says:

    Wow, thanks for all the comment guys! And Chemist I very much appreciate your prescriptive, as well as your link. Very interesting link. If you ever want to write an article that focuses on how drugs are developed from sources other than nature, I for one would be happy to read it (as I am sure others would as well)!

    I realize my reply is a bit late, lol.

  15. Candra says:

    Malucass, a province in Indonesia have incredible source of marine Medicinal product but, there was no any chemist to explore it. Banda sea, is the deepest sea in Indonesia, need much more researcher to reveal the secret inside it.

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