Definition

The definition of the term alkaloid is not a simple one, and is in many cases a source of academic controversy. Difficulties with the definition of such a group of secondary and natural molecules as alkaloids stem from similarities of alkaloids with other secondary compounds. Attempts to define the term "alkaloid" originated at the time of the discovery of these compounds. Friedrich Sertürner, an apothecary's assistant from Westphalia, first isolated morphine (Figure 1), one of the most important alkaloids in the applied sense1. This was in 1805, and proved a significant step forward in chemistry and pharmacology2'3'4. Using the method developed by Friedrich Sertürner, the pharmacists Pierre Joseph Pelletier and Joseph Benaime Caventou isolated, from 1817 to 1821, a remarkable range of other alkaloids (Figure 2), such as brucine (a close relative of strychnine), febrifuge, quinine, caffeine and veratrine1'5. The term "alkaloid" was

NCH3
Acido Oleico

Figure 1. Contemporary scheme of morphine. Friedrich Sertürner, who first isolated this alkaloid in an impure form in 1805, did know that it was converted from the pathway of tyrosine, Tyr. The correct morphine structure was determined by Gulland and Robinson in 1923. Moreover, even 200 years after Sertürner's isolation, scientists are still discussing the synthesis of this alkaloid from a molecular point of view. This is a good example of the scientific evolution of knowledge of alkaloids.

Figure 1. Contemporary scheme of morphine. Friedrich Sertürner, who first isolated this alkaloid in an impure form in 1805, did know that it was converted from the pathway of tyrosine, Tyr. The correct morphine structure was determined by Gulland and Robinson in 1923. Moreover, even 200 years after Sertürner's isolation, scientists are still discussing the synthesis of this alkaloid from a molecular point of view. This is a good example of the scientific evolution of knowledge of alkaloids.

first mentioned in 1819 by W. Meißner, an apothecary from Halle. He observed that these compounds appeared "like alkali", and so named them alkaloids6.

For the biologist, the alkaloid is a pure and perfect natural product. From the biological point of view, the alkaloid is any biologically active and heterocyclic chemical compound which contains nitrogen and may some pharmacological activity and, in many cases, medicinal or ecological use7. This definition, as a relatively wide one based on application, can be criticized as inexact. However, it presents a general picture of what kinds of compound are under consideration. The biological and chemical nature of this group of compounds leads to the conclusion that each definition of alkaloids is either too broad or too narrow. A short exact definition is not possible without a long list of exceptions8'9'10'11'12'13'14'15'16'17'18'19'20'21'22'23'24. Sometimes, to avoid presenting this list of exceptions, the basic characteristics of alkaloids are given in the definition. Winterstein and Tier8 stressed that these compounds had such characteristics as (1) greater or lesser toxicity, which acts primarily on the central nervous system (CNS), (2) the basic character of a chemical construction, (3) heterocyclic nitrogen as an ingredient, (4) a synthesis from amino acids or their immediate derivatives and (5) a limited distribution in nature.

In another definition, Waller and Nowacki16 mentioned many characteristics of alkaloids. They especially drew attention to the fact that alkaloids have nitrogen in the molecule and are connected to at least two carbon atoms. Moreover, this compound has at least one ring in the molecule, and its ring is not necessarily heterocyclic. The authors also stated that alkaloids could not be structural units of macromolecular cellular substances, vitamins or hormones. More recently, Sengbush25 simply stressed that alkaloids are a group of nitrogen-containing bases and that most of them are drugs.

The most important points for the biologist are that alkaloids are a special group of chemicals that are active at different cellular levels of organisms, and

Definition Miscellaneous Alkaloid
H
Quinine

Febrifuge Strychnine

Figure 2. Some alkaloids isolated by pharmaceutists Pierre Joseph Pelletier and Joseph Beiname Caventou during 1817-1821. They did not know the exact structures. Their compounds thus isolated are combinations of alkaloids rather than one pure alkaloid.

that they take part in the biological processes of plants, animals and microorganisms.

For the medical scientist, the term "alkaloids" means any group of nitrogenous substances of vegetable origin, often of complex structure and high molecular mass26. Moreover, it is important that alkaloids are often heterocycles, and may have primary, secondary or tertiary bases, or may contain quaternary ammonium groups. Certainly, the fact that alkaloids are only slightly soluble in water but soluble in ethanol, benzene, ether and chloroform is also extremely important, and highlighted in the medical definition. This long definition also notes that alkaloids exhibit some general characteristics which are revealed by the coloration or precipitation of alkaloid reagents. Finally, medicine draws attention to the fact that alkaloids create intense physiological action, and they are widely used in the medical fields as curative drugs. Some alkaloids can also be highly toxic, even in very small doses26. In the database of the National Library of Medicine it is possible to find the definition of alkaloids, according to which these compounds are nitrogenous bases and occur in animal and vegetable kingdoms, while some of them have been synthesized27. Another electronic database also provides a definition of alkaloids, stating that an alkaloid is a nitrogenous organic compound which has pharmacological effects on humans and other animals, and whose name is derived from the world alkaline28. As can be seen, the definition of alkaloids in the field of medicine also offers parameters of "may be", "often", "slightly" and "highly", which are not exact. This is typical of the scientific and practical fields, where alkaloids are well known and used in the bettering of human health, but where the term remains relatively difficult to define exactly and concisely.

Chemistry has provided a definition of alkaloids in purely chemical terms. Chemists stress that alkaloids are any group of complex heterocyclic nitrogen compounds, which have strong physiological activity, are often toxic, and retain their own basic chemical properties. It is also stated that there are a few exceptions to this definition29. In another chemical definition, it is stated only that alkaloids are nitrogen-containing compounds derived from plants and animals30. Later, chemists stressed that alkaloids were biogenic, nitrogen-containing and mostly N-heterocyclic compounds. In this definition it is also stated that amino acids, peptides, nucleosides, amino sugars and antibiotics are not considered as to be alkaloids31.

Inspite of differences between the research fields of biology, medicine and chemistry, and the fact that there remain some differences of accentuation in alkaloid definitions, such definitions are very similar, indeed almost identical. Scientists are recognizing the vital importance of these products for biology, medicine and chemistry. What has been learnt about alkaloids from the last 200 years of studies? It is fascinating that alkaloids are just a product of nature, and a very small unit of global nature both in the material sense and in processes as they occur. They are just a product of living cells, for other living cells. The alkaloid is a product of chemical molecules for the production of other molecules. It is synthesized, playing its own role in the metabolism after that. The alkaloid represents perfection in much the same way as perfection appears in life and nature. This is the reason why alkaloids were and are a fascinating subject of study. This is also the reason why definitions of these groups of molecules, provided by scientists of biology, medicine and chemistry, are acceptably imperfect. However, alkaloids are recognized as a large group of compounds with biological, pharmacological or physiological and chemical activity. Without alkaloids, stupendous achievements in the battle against malaria, leukaemia and cancer as well as Parkinson disease would be not possible. The pharmaceutical drug industry has succeeded in the use of natural plant alkaloids for the development of anti-malarian agents (quinine and chloroquinine), anticancer agents (taxol, vinblastine and vincristine) and agents promoting blood circulation in the brain (vincamine) (Figure 3). Many alkaloids can influence an animal's nervous system, providing possible changes in the functionality of the organism. The activity of alkaloid molecules on a psychomental level (opium latex, papaverine, morphine, cocaine) is one of natural phenomena in the process of species self-protection, and the interactions between producers (plants) and consumers (herbivores). It is also a good example of natural selection mechanisms and results. Nowadays, there are more than 8000 natural compounds and their derivatives recognized as alkaloids. Each year, scientists around the Globe discover at least 100 new molecules. They frequently occur as acid salts, but some also occur in combination with sugars whereas, others appear as amides or esters. Alkaloids can also be quaternary salts or tertiary amine oxides23.

Alkaloids can be classified in the terms of their (1) biological and ecological activity; (2) chemical structures and (3) biosynthetic pathway. From the point of

Taxol

Structure Vinblastine Alkaloid

Vinblastine

Vinblastine

ho oh h3co'

h co2ch3 cho

Vincristine

Figure 3. Schemes of taxol, vinblastine, vincristine and vincamine.

h3co'

h co2ch3 cho

Vincristine

Figure 3. Schemes of taxol, vinblastine, vincristine and vincamine.

ho oh ho co2ch3

Vincamine ho co2ch3

Vincamine view of biological activity23, it is possible to divide alkaloids into (1) neutral or weakly basic molecules (e.g., lactams such as ricinine, certain N-oxides such as indicine), (2) animal-derived alkaloids (e.g., anuran, mammalian and arthropod alkaloids), (3) marine alkaloids, (4) moss alkaloids, (5) fungal and bacterial alkaloids and (6) non-natural alkaloids (structurally modified or analogues).

Nowadays, the group of compounds mentioned as non-natural alkaloids is growing especially rapidly as a result of bio-organic and stereochemistry research. Pharmacological research and the drug industry rapidly advance and promote the most promising new molecules for possible production applications. This is necessary since the sources of infections (micro-organisms) are constantly changing their species and infection ability, becoming resistant to medicines and antibiotics.

Alkaloids are generally classified by their common molecular precursors, based on the biological pathway used to construct the molecule. From a structural point of view, alkaloids are divided according to their shapes and origins. There are three main types of alkaloids: (1) true alkaloids, (2) protoalkaloids and (3) pseudoalkaloids. True alkaloids and protoalkaloids are derived from amino acids, whereas pseudoalkaloids are not derived from these compounds (Table 1).

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