Stuart R. Gallant, MD, PhD

Before there was a pharmaceutical industry, humans looked to plants as source of medicines.  Today’s post focuses on medicines derived from plants and how they are different and unique.

Drug Discovery From Plants

There are two chief methods of drug discovery from plants:

• Traditional Medicinal Practices:  Humans have for thousands of years used plants, along with animals, fungi, minerals, and other starting materials, to make medicines.  To be sure, some of these medicines provide more of a psychological comfort than a cure.  Nevertheless, many current medicines started from traditional practices.  Examples include quinine from cinchona tree bark as a treatment for malaria and the muscle relaxant tubocurarine isolated from a traditional South American hunting poison.
• Screening:  In screening of plant extracts, in vitro testing is performed to assess medicinal activity.  For instance, historically many cancer treatments were discovered by screening candidates versus cancer cell lines and looking for evidence of inhibition of cancer.

However, the ways that chemicals from plants can appear in licensed pharmaceuticals are quite extensive:

• Natural Products:  The chemical derived from the plant can be used in a purified form as the active ingredient of a drug product.  An example is paclitaxel, discovered in 1971, a drug derived from Pacific yew bark and used in treating certain cancers.  Another example is pilocarpine, which has been used to treat glaucoma for more than a century, a drug made from plants within the genus Pilocarpus.
• Botanical Drugs:  The plant material may be used in an impure (but nevertheless controlled) pharmaceutical form to produce a drug.  An example is crofelemer a purified oligomeric proanthocyanidin, used to treat certain diarrheal conditions, purified from the sap of a South American tree Croton lechleri.
• Natural Product Derived:  A semisynthetic version of the plant-derived chemical can be produced to optimize the pharmaceutical effect.  Considering the following atropine related drugs shows how fertile this approach to drug development can be:
  • Atropine:  occurs naturally in Nightshade plants; discovered in 1833; used to treat certain types of nerve agent and pesticide poisoning.
  • Scopolamine:  also from certain Nightshades; isolated in 1880, and now used for motion sickness.
  • Ipratropium bromide (Atrovent):  patented in 1966; made by treating atropine with isopropyl bromide; a potent bronchodilator used to treat asthma and chronic obstructive pulmonary disease (COPD).
  • Hyoscine butylbromide (scopolamine butylbromide, sold as Buscopan):  a modified scopolamine that targets various types of muscle spasm (esophageal spasms, bladder spasms, renal colic), patented in 1950.
  • Tiotropium bromide (Spiriva):  a further modification to Atrovent which allows longer (24 hour) brochodilation.
• Synthetic with Natural Product Pharmacophore:  A synthetic drug onto which the active portion of the natural product is grafted.

When all these possible drug types are considered, the number of approved drugs is quite large [1]:

(Note:  Newman and Cragg’s list includes all products which are natural, not merely plants.  For example, the sea squirt derived anti-cancer drug Plitidepsin is included on the list.)  There was some falloff of natural product drugs after then 1990s when many pharmaceutical companies shift toward “target-based” approaches based in knowledge of disease mechanisms.  However, the fall off was far from substantial.  For instance, there were more licensures of these categories of natural products in 2017 than there were in 1982, 1990, or 1991.  Knowledge of natural product chemistry remains a valuable skill even in the 2020s.

Overview of Plant Chemistry

Plants engage in metabolism and photosynthesis.  The basic equation of photosynthesis is:

CO₂  +  2H₂O  + photons  ®  [CH₂O]  +  O₂  +  H₂O

However, plants are far more than photosynthesis machines.  Plants engage in a spectrum of behaviors that require complex chemistry:

• Reproduction
• Repair of injuries
• Resistance to fungal and bacterial infections
• Repulsion of insect and animal predators
• Signaling to other plants
• Suppression of plant competitors
• Attraction of helpful insects and animals
• Resistance to environmental stressors, for example cold resistance in high latitude plants, UV resistance in high altitude plants, and resistance to extremes of pH or salinity.

Some important plant chemistries that support these goals include lipids, alkaloids, phenolics, and terpenoids.

Lipids

Plants require oils and waxes for purposes including:

• Formation of hydrophobic barrier of biological membranes
• Energy reserve
• Role as various secondary compounds, including pigments

Plant oils having well known health benefits include linoleic acid:

and linolenic acid:

Alkaloids, Phenolics, and Terpenoids

Alkaloids, phenolics, and terpenoids are used for a range of purposes in modulating a plant’s interactions with its environment:

• Deterrence of predation by animals and insects
• Repulsion of bacteria and fungi
• Phenolics and terpenoids provide scent and color to allow plants to attract pollinators and other helpful animals and plants

These classes are truly massive with 12,000 alkaloids, 10,000 phenolics, and 25,000 terpenoids identified to date and large numbers awaiting identification.

Alkaloids

Alkaloids are used by plants to deter predation, as poisons, as antimicrobials, and to deter germination of neighboring plant competitors.  Many animals have evolved an aversion to bitter tastes in food because alkaloids often taste bitter in solution.

The theme of alkaloid chemistry is that these molecules include several ring structures with one or more nitrogen.  Major classes of alkalkoids include:  imidazole, isoquinoline, piperidine, protopine, purine, pyridine, pyrrolidine, pyrrolizidine, quinazoline, quinoline, quinolizidine, steroidal, terpenoid indole, and tropane alkaloids.

An example is quinoline:

which is a parent structure of quinine a malaria medication derived from cinchona tree bark:

The tropane class includes:

• Scopolamine (from jimson weed) which is used as an antinausea medication, but can also cause toxic anticholineric effects like tachycardia and blurred vision.
• Hyoscyamine (from henbane) which is used for GI applications, control of excessive mucous secretions, and other indications.
• Cocaine (from coca leaves) which is a widely used drug of abuse which increses alertness and elevates heart rate and blood pressure.

Individual members of the alkaloids are synthesized from various amino acids, for instance the isoquinoline group begins with tyrosine, and the quinoline group begins with tryptophane and anthranilic acid.  A wide range of chemistries are used to create a vast library of alkaloids in the plants.  For instance, the amino acid tyrosine is converted to tyramine by decarboxylation—the resulting product is one of the two toxic compounds present in mistletoe.

Phenolics

Phenolics serve many functions in plants including:  scents, pigments, poisons, deterrents for herbivores, signaling compounds to other plants, and antimicrobials.  The basic structure is that of phenol:

Vanillin is the primary component extracted from vanilla bean:

Quercetin brings about red wine headache by blocking the enzyme that allows conversion of aldehyde to acetate (aldehyde dehydrogenase) [2].  Quercetin acts as a kind of sunblock for grapes, protecting them against strong sunlight:

Terpenoids

Terpenoids play a role in photosynthesis, electron transport, growth regulation, and attraction and repulsion.  Structurally, they consist of one or more isoprene:

combined head-to-tail, head-to-head, or head-to-middle.  In addition to plants, animals, bacteria, fungi, and algae synthesize terpenoids.

Beta-carotene and lycopene are examples:

Beta carotene is a red orange pigment synthesized by fungi, as well as plants.  Lycopene is a bright red pigment found in tomatoes and other fruits and vegetables.  Not all terpenoids are linear, for example the monoterpenoid menthol:

Menthol acts as a local anesthetic and as a counter irritant.

Natural Variety Within A Single Plant

Plants rarely produce a single active molecule of a given structure.  Plants naturally create a family of molecules for any function that they find useful.  Some examples:

• Valerian root produces valerenic acid, acetoxy valerenic acid, and hydroxy valerenic acid.
• Plants produce polyphenols in complex mixtures (monomers, dimers, trimers…) with variants in each degree of polymerization.  Trimers in cinnamon include:  Lindetannin, Aesculitannin B, Cinnamtannin B1, Cinnamtannin D1, as well as minor trimers.

This natural structural variety offers benefits:

• Some variants may have unique selectivity for certain disease states.
• Other variants may be able to overcome resistance in the case of resistant bacterial strains or resistant cancer cells.

An Example:  Guava Leaf

Guava leaf is commonly used in traditional medicine.  Often extracts (i.e., “teas” prepared by soaking leaves in hot or boiling water) are used after allowing time to cool as topical treatments for skin inflammations of various origins.  It is possible to imagine that such extracts would have both anti-bacterial and anti-fungal properties.

Laboratory preparations from guava leaves have been analyzed for chemical composition. Some of the constituents include flavonoids, including glycosides of quercetin, including quercetin 3-O-α-L-arabinopyranoside [3]:

This is a variant of the phenolic chemical found in wine grapes which was discussed above as playing a role in shielding the grape from the rays of the sun.  Triterpenic acids, including guavenoic acid:

The aqueous and organic extracts of guava plant material have shown antimicrobial activity—three compounds are implicated:  guajaverine, psydiolic acid, and the flavonoid compound guaijaverin.  Depending on your point of view, this could be seen as an example of the importance of studying traditional medicinal practices or on the utility of screening extracts versus microbial populations (as well as cancer cell lines) to look for possible new active pharmaceuticals.

Toxicity

One persistent idea is that “it’s natural, it can’t be toxic.”  To a certain extent, there is truth in this bias.  Many natural molecules have been encountered by animals over evolutionary time.  As a result, the liver has developed mechanism for detoxification and elimination of many natural molecules.  In contrast, many synthetic molecules have characteristics which the liver has not encountered—so the potential to form a toxic breakdown product is proportionally higher for some synthetic molecules.

However, plant chemicals are not inherently safe.  Consider amygdalin, a toxic glycoside derived from phenylalanine:

Sale of apricot pits, a source of amygdalin, has been banned in some countries because cancer patients have been eating them in hopes of curing their disease in a natural way.  Many of these patients have ended up sick, and some have died.  (Note:  There is no evidence of benefit in the consumption of amygdalin for any disease state.)

It is important to conduct property safety studies on any new active ingredient for safety, as well as efficacy.  This applies to natural and synthetic drug candidates.

Practicalities of Drug Discovery From Plants

Screening versus well characterized cell lines remains an important technique for natural product discovery.  With the growth and increased availability of cell lines for disease indications such as cancer, CNS, cardiovascular, GI, dermatology, nephrology, and other areas, discovery of plant activity as well as mechanism of action has never been cheaper or easier.

However, many of the skills that went with natural drug discovery are no longer practiced widely.  Finding a drug discovery laboratory that regularly works with plant materials can be important to the success of a discovery program.

One important concern in drug discovery is intellectual property.  Some countries have laws governing the exploitation of regional plant species.  Before beginning a drug discovery program, consider the source of any starting materials and whether there are intellectual property implications.

CROs

Contract research organizations (CROs) have many specialized skills that can speed drug discovery.  In natural product drug discovery, some skills to consider are:

• Sourcing of raw materials
• Evaluation of ethnobotanical knowledge that could help the discovery program
• Techniques of extraction of the full range of molecules from flowers, leaves, bark, and other materials without compromising activity
• Economical and efficient purification of candidates
• The full range of analytical chemical techniques for identifying active molecules, particularly chromatographic and mass-spec techniques
• Preparation of small manufacturing lots for early animal studies

An experienced CRO partner such as Planta Analytical (www.plantaanalytica.com) can save many times the cost of a CRO research contract by speeding work up and eliminating wasted effort and time.

Conclusions

Plants make an uncountably large number of potential pharmaceutical ingredients—many of which are naturally evolved to have specific interactions with animal nervous, cardiac, pulmonary, musculoskeletal, and digestive systems.  Several decades after many large pharmaceutical companies abandoned natural product research, chemicals with natural origins continue to be important in new drug discovery.  For those involved in drug discovery in the natural products area, the pond remains just as large and there just as many fish swimming in it, but many of the fishermen have left the pond.  That means that the ratio of potential natural product block busters to research dollars has gone up dramatically in recent decades, and this area will remain active on into future years.

[1] Newman, D. J. and Cragg, G. M.  “Natural Products as Sources of New Drugs over the Nearly Four Decades from 01/1981 to 09/2019,” J. Nat. Prod. 83, 3, 770–803 (2020).

[2] Devi, A., et al.  “Inhibition of ALDH2 by quercetin glucuronide suggests a new hypothesis to explain red wine headaches,” Scientific Reports 13, 19503 (2023).

[3] Ngbolua, K., et al.  “A review of the Phytochemistry and Pharmacology of Psidium guajava L. (Myrtaceae) and Future direction,” Discovery Phytomedicine, 5, 7-13 (2017).

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