The Study of Medicinal Plants: Chemistry, Active Compounds, and Pharmacology

The medicinal properties of any plant are determined by its chemical composition — that is, by the presence within it of particular substances that exert a defined effect on the human body. This truth was already established at the start of the sixteenth century, and it remains the foundation on which the search for new plant-derived remedies rests.

Analysis of an enormous body of evidence has made it possible to identify the pharmacological properties and the range of therapeutic action of many groups of chemical compounds, which are collectively termed active substances. These are the constituents responsible for a plant's healing effect.

The most important active substances include alkaloids, cardiac glycosides, triterpene glycosides (saponins), flavonoids (and other phenolic compounds), coumarins, quinones, xanthones, sesquiterpene lactones, lignans, amino acids, polysaccharides and several other classes of compounds. Each group carries its own characteristic biological signature.

Different classes of active substances answer to different therapeutic tasks. Antiviral activity, for example, is confined to certain groups of flavonoids, xanthones, alkaloids, terpenoids and alcohols; antitumour activity is found among some alkaloids, cyanides, triterpene ketones, diterpenoids, polysaccharides and phenolic compounds. Polyphenolic compounds tend to show hypotensive, spasmolytic, anti-ulcer, choleretic and bactericidal activity.

Many classes of chemical compounds — and many individual substances — have a strictly defined and fairly narrow spectrum of medical and biological activity. Other classes, usually very large ones such as the alkaloids, display an extremely broad and varied range of action, which makes them worthy of many-sided study.

Compounds of this kind deserve wide-ranging medical and biological investigation, above all in the directions recommended by empirical medicine. Advances in analytical chemistry have made it possible to develop simple, rapid procedures — express methods — for detecting the desired classes and individual chemical substances in medicinal plants.

Out of this progress arose the method of mass chemical analysis, otherwise known as chemical screening (from the English word screening — sifting or sorting through a sieve), which quickly became standard practice in prospecting work. It is often applied to hunt for the wanted compounds by analysing every plant of the region under study.

What is the chemical screening method?

Chemical screening yields its most effective results when it is combined with data on a plant's use in empirical medicine and with attention to its taxonomic position. Together these three lines of evidence sharply raise the odds of finding a genuinely useful species.

Experience shows that almost every plant used in empirical medicine contains classes of biologically active compounds already known to science. For that reason the search for the substances we need should first be directed, in a targeted way, at plants that have in some manner already revealed pharmacological or chemotherapeutic activity.

The express method can be paired with a preliminary selection of promising species, varieties and populations based on organoleptic assessment and on the analysis of ethnobotanical data, which indirectly point to the presence of the substances of interest. This narrows a vast flora down to a manageable shortlist before a single test tube is filled.

A selection approach of this kind was widely used by Academician N. I. Vavilov when assessing the quality of the starting material of various useful plants drawn into breeding and genetic research. During the years of the first five-year plans, the same route guided the search across the flora of the USSR for new rubber-bearing plants.

Surveying more than 1,400 plant species enabled Academician A. P. Orekhov and his students, by 1960, to describe about 100 new alkaloids and to set up in the USSR the production of those needed for medical purposes and for the control of agricultural pests. Screening thus fed directly into industrial pharmacology.

The Institute of Chemistry of Plant Substances of the Academy of Sciences of the Uzbek SSR examined about 4,000 plant species, identified 415 alkaloids and established the structure of 206 of them for the first time. Expeditions of the All-Union Institute of Medicinal Plants (VILR) surveyed 1,498 species of the Caucasus, 1,026 species of the Far East, and many plants of Central Asia, Siberia and the European part of the USSR.

In the Far East alone, 417 alkaloid-bearing plants were found, among them the semi-shrub securinega, which contains the new alkaloid securinine — an agent with a strychnine-like action. By the end of 1967 the structure of 4,349 alkaloids had been described worldwide.

The next stage of the search is an in-depth, many-sided evaluation of the pharmacological, chemotherapeutic and antitumour activity of the isolated individual substances, or of the total preparations that contain them. It has to be noted that, both nationally and worldwide, chemical research runs well ahead of the capacity for thorough medical and biological testing of the new compounds discovered in plants.

The structure of 12,000 individual compounds isolated from plants has now been established, and unfortunately many of them have not yet undergone medical and biological study. The bottleneck lies not in finding molecules but in verifying what they can do in the body.

Of all classes of chemical compounds the alkaloids are unquestionably the most significant: 100 of them are recommended as important medical agents — among them atropine, berberine, codeine, cocaine, caffeine, morphine, papaverine, pilocarpine, platyphylline, reserpine, salsoline, securinine, strychnine, quinine, cytisine and ephedrine.

Most of these preparations came out of searches founded on chemical screening. Yet the one-sided development of the method is troubling, since in many institutes and laboratories it has been reduced to hunting only for alkaloid-bearing plants, leaving other valuable classes overlooked.

It must not be forgotten that, alongside alkaloids, new biologically active plant substances belonging to other chemical classes are discovered every year. Whereas before 1956 the structure of only 2,669 non-alkaloid natural plant compounds was known, in the following five years (1957–1961) a further 1,754 individual organic substances were found in plants.

The number of chemical substances with an established structure has now reached 7,000, which together with the alkaloids amounts to more than 12,000 plant substances. Chemical screening is slowly emerging from its "alkaloid period" and beginning to embrace a wider chemical landscape.

Of the 70 groups and classes of plant substances known at present (Karrer et al., 1977), screening is carried out for only about 10 classes, because reliable and rapid express methods for detecting the other compounds in plant raw material are lacking. Drawing new classes of biologically active compounds into chemical screening is an important reserve for raising the pace and effectiveness of the search for new plant-derived drugs.

The development of methods for rapidly locating single chemical substances — for example berberine, rutin, ascorbic acid, morphine and cytisine — is likewise very important. In the creation of new medicinal preparations the greatest interest attaches to secondary compounds, the so-called substances of specific biosynthesis, many of which possess a broad spectrum of biological activity.

What therapeutic roles do the main compound classes play?

Alkaloids are approved for use in medical practice as analeptics, analgesics, sedatives, hypotensives, expectorants, choleretics, spasmolytics, uterine agents, central-nervous-system stimulants and adrenaline-like preparations. Their versatility is precisely what makes the class so heavily studied.

Flavonoids strengthen the walls of capillaries, lower the tone of the smooth muscle of the intestine, stimulate the secretion of bile and enhance the detoxifying function of the liver; some of them also have spasmolytic, cardiotonic and antitumour action. Many polyphenolic compounds serve as hypotensive, spasmolytic, anti-ulcer, choleretic and antibacterial agents.

Antitumour activity has been noted in cyanides (such as those contained in peach seeds), triterpene ketones, diterpenoids, polysaccharides, alkaloids, phenolic and other compounds. More and more preparations are being created from cardiac glycosides, amino acids, alcohols, coumarins, polysaccharides, aldehydes, sesquiterpene lactones and steroidal compounds.

Long-known chemical substances often find medical application when some medical or biological activity has only recently been discovered in them and a rational method of manufacturing preparations has been worked out. Beyond flagging promising new objects for study, chemical screening also makes it possible to:

• reveal correlations between a plant's taxonomic position, its chemical composition and its medical and biological activity;
• clarify the geographic and ecological factors that promote or hinder the accumulation of particular active substances in plants;
• determine the significance of biologically active substances for the plants that produce them;
• detect chemical races within plants that differ hereditarily from one another in the presence of particular active substances.

All of this can be exploited when choosing ways to steer the processes taking place within a plant. Screening, in other words, is not only a filter but a source of biological insight.

The availability of fast, cheap and yet sufficiently accurate express methods makes it tempting to undertake an urgent, total evaluation of every plant of the flora of the USSR and of the whole world for the presence of alkaloids, triterpene and steroid saponins, quinones, flavonoids, cardiac glycosides, tannins and other principal classes of active substances.

Such a sweep would quickly weed out the unpromising species — those that contain no biologically active substances at all, or contain them only in small quantities — and concentrate effort where it counts.

Why must different plant organs be analysed separately?

Different organs of the same plant frequently differ not only in the quantity of active substances they hold but also in their qualitative composition. A leaf and a root of one species may effectively belong to different chemical worlds.

For instance, the alkaloid sinomenine is present only in the herb of the Dahurian moonseed, while cytisine occurs only in the fruits of the lance-leaved thermopsis and is absent from its above-ground parts until flowering ends — whereas in the alternate-flowered thermopsis, cytisine is present in large amounts in the above-ground parts at every phase of the plant's development.

For this reason, to obtain a full picture of the chemical composition of any plant, at least four of its organs should be analysed: the underground parts (roots, rhizomes, bulbs, tubers); the leaves and stems (in herbs the leaves are always richer in active substances than the stems); the flowers (or inflorescences); and the fruits and seeds. In woody and shrubby plants the active substances are often concentrated in the bark of stems and roots, and sometimes only in the seedlings or in certain parts of the flower, fruit and seed.

The alkaloid triacanthine, for example, is present in significant amounts only in the unfurling leaves of the three-thorned honey locust, while in the other phases of development it is practically absent from all organs of that plant. Timing an analysis wrongly can therefore make an active plant look inert.

It is easy to calculate the scale this creates. To draw up a complete list of the alkaloid-bearing plants of the flora of the USSR — some 20,000 species — would require no fewer than 160,000 analyses (20,000 species × 4 organs × 2 developmental phases), which amounts to roughly 8,000 working days for a single analytical technician.

About the same amount of time would be needed to determine the presence or absence, across every plant of the flora, of flavonoids, coumarins, cardiac glycosides, tannins, polysaccharides, triterpene glycosides and each of the other classes of chemical compounds — if the analyses were carried out without any preliminary weeding-out of plants on one ground or another.

The complication runs deeper still. Identical organs, in the same phase of development, may contain the wanted active substances in one district and lack them in another. Alongside geographic and ecological factors — the influence of temperature, humidity, insolation and the like — this can reflect the existence of special chemical races within a given plant that are entirely indistinguishable by morphological features.

All of this greatly complicates the task and would seem to place the completion of a preliminary chemical survey of the flora of the USSR — let alone of the entire globe — in the distant future. The arithmetic alone is daunting.

Yet knowing certain regularities allows the work to be simplified considerably. In the first place, it is by no means necessary to examine every organ in every phase of development. It is enough to analyse each organ in its optimal phase, when it contains the greatest amount of the substance under study.

Earlier research has established, for example, that leaves and stems are richest in alkaloids during the budding phase, bark during the spring flow of sap, and flowers at the phase of their full opening. Fruits and seeds, admittedly, may contain different alkaloids in different amounts when ripe and unripe, and so should where possible be examined twice. Knowledge of these regularities markedly simplifies the preliminary chemical evaluation of plants.

A total survey of every species is an effective approach, yet it is still work carried out blind. The real question is whether one can distinguish groups of plants that presumably contain a given class of chemical compounds from those that certainly do not — without even performing the simplest chemical analysis.

In other words, can the chemical composition of plants be judged by eye? As the next section of this booklet will show, in broad outline the answer to that question is yes — and it is this predictive shortcut that turns an impossible census into a practical search.