New concept of pharmacognosy

    GENERAL CONCEPT OF MODERN PHARMACOGNOSY (2011).
    NEW CLASSIFICATION OF NATURAL COMPOUNDS

    The task I set for myself by proposing a new concept of modern pharmacognosy and a new classification of natural compounds on this site is to familiarize my colleagues in phytochemistry with interesting, significant, and potentially useful events that have occurred in the world of biologically active compounds over the past 10–15 years.

 

    

 

 

    The main trends in the development of phytochemistry as an integral part of pharmacognosy and as an independent science at the present stage are:
– improvement of methods for the isolation and analysis of natural compounds (in particular, the application of gas-liquid and gas chromatography, NMR and PMR spectroscopy);
– isolation of complex natural compound complexes;
– targeted modification of substances to obtain compounds with specified properties.
    In recent decades, pharmacognosy has undergone significant changes, particularly in terms of classification and methods of analysis of natural compounds.
  Thus, the arsenal of analytical methods has been significantly enriched, new “transitional” classes and subclasses of biologically active substances have been discovered, which raises the question of the need to revise the existing classification of natural compounds.
    The basis of such classification should not only be the structure and biosynthetic pathways but also the biogenetic connections between classes and subclasses of biologically active substances (BAS).
    At present, specialists in phytochemistry around the world use classifications of natural compounds based on biosynthetic pathways and the chemical structure of natural substances.
    Thus, the most frequently referenced classifications in modern world phytochemical literature are those of J. Harborne et al. (1999) [Harborne et al., 1999], R. Hansel et al. (1999) [Hansel et al., 1999], and W. Evans (2002) [Evans, 2002], which are based on the aforementioned principles and do not differ significantly (the differences are only within the subclasses of compounds).
    The foundation of all these classifications is the fundamental classification of natural compounds developed and proposed by the German scientist W. Karrer (1958) [Karrer, 1958].
    All of them form the basis of the corresponding textbooks and manuals on pharmacognosy, an important component of which is phytochemistry. Its main provisions are the basis of the classifications used in the countries of the former USSR [Kovalov et al., 2000; Muravyeva et al., 2002].
    The current state of research on natural compounds allows us to assume that the boundaries between the classes of BAS identified at present are quite conditional.
    Thus, a whole series of “transitional” classes of compounds have been discovered to date.
    In particular, these include:
• flavonoid–alkaloids;
• coumarinoalkaloids;
• coumarinoflavonoids;
• xanthochinones;
• flavolignans;
• xantolignans;
• coumarinolignans.

    Let us consider in more detail the formulas of some substances belonging to transitional classes.
    First, these are flavonoid–alkaloids:
– flavanone compounds with diazepine – aquiledin, isoaquiledin, first isolated by Chen, Gao, and Leung in 2001 from the herb of the common columbine Aquilegia vulgaris L. (family Ranunculaceae) [Chen, Gao, Leung, 2001].

– Flavonoid–alkaloids also include flavone compounds with pyrrolidine – ficin and leaves of Ficus pantoniana King (family Moraceae) and dracocephalins A–D from the herb of the rock dragonhead Dracocephalum rupestre Hance (family Lamiaceae), discovered in 2008 [Ren et al., 2008].

– Another flavonoid–alkaloid is the catechin compound with furanopyridine (skitanthin) – copsirichin from the leaves of Kopsia dasyrachis Ridl. (family Apocynaceae) [Harborne, 1999]. Copsirichin has been shown to have immunomodulatory, antitumor activity in cultures of lung carcinoma cells (tyrosine kinase inhibitor IC50 = 25–160 nM), and anti-inflammatory activity.

– In addition to the aforementioned flavonoid aglycones with heterocyclic nitrogen-containing rings, glycosidic forms of flavonoid–alkaloids are also known, namely, catechin glycosides – with pyrrolidine – davalliosides A–C from the rhizomes of Davallia mariesii Moore (family Davalliaceae) [Harborne, 1999].

  The next class of “transitional” compounds is coumarinoalkaloids, for example, toddacoumalone from the roots of Toddalia asiatica (= wild orange) Toddalia asiatica (L.) Lam. (family Rutaceae). As we can see, toddacoumalone is a complex compound built on the basis of coumarin and a quinoline derivative [Ishii et al., 1991].

    Coumarinoflavonoids are also known today – phyllocoumarin from the cladodes of the New Zealand tree Phyllocladus trichomanoides D. Don. (family Podocarpaceae – distant relatives of European conifers, order Pinales, class Pinopsida) [Harborne, 1999].

      In the last decade, xanthochinones have also been discovered (bikaverin from the mycelium of the fungus causing wilt in plants – Fusarium oxysporum Schlecht., class Deuteromycetes, order Sphaeropsidales) [Harborne et al., 1999].

    Flavolignans, xantolignans, and coumarinolignans have been known for quite some time. It can be assumed that other “transitional” compounds will also be discovered in the near future.

    Based on the existence of “transitional” classes, the classification of natural compounds could be presented from a dialectical perspective, taking into account the biogenetic metabolic interconnections between classes of substances, and from a prognostic point of view, suggesting the existence of undetected “transitional” classes of compounds.
    The proposed general classification of natural compounds is presented in the figure. The substances in it are classified into two large groups, as is customary in other well-known classifications:
    – compounds of primary biosynthesis, which are formed in plants as a result of assimilation;
    – compounds of secondary biosynthesis, which are formed in plants as a result of dissimilation.
    Compounds of primary biosynthesis include carbohydrates, lipids, proteins, nucleic acids, enzymes, vitamins, organic acids.
    Compounds of secondary biosynthesis include terpenoids, simple phenols and their derivatives, phenylisoprenoids, polyphenols, alkaloids, thio- and cyanoglycosides, organometallic compounds.
    Arrows indicate biogenetic connections, considering metabolic pathways, between classes and subclasses of compounds, and small print along the arrows indicates the so-called “transitional” classes of substances.
    In this case, we propose for the first time the introduction of the classes “phenylisoprenoids” and “organometallic compounds”.

Fig. 1. General classification of natural compounds.

    In addition to the proposed general classification of natural compounds, we also consider it appropriate to make certain changes in the classifications within some specific classes of substances, in particular, terpenoids, coumarins, flavonoids, alkaloids.
    Thus, terpenoids can be classified into subclasses of hemi– (C5), mono– (C10), sesqui– (C15), di– (C20), sesquiterpene– (C25), tri– (C30), tetra– (C40), polyterpenoids (Cn), as is currently accepted, adding two known subclasses: C35-terpenoids and halogenated acetylene-terpenoids.

    Classification of terpenoids

    Terpenoids
• hemiterpenoids (C5)
• monoterpenoids (C10)
• sesquiterpenoids (C15)
• diterpenoids (C20)
• sesterterpenoids (C25)
• triterpenoids (C30)
• C35-terpenoids
• tetraterpenoids (C40)
• polyterpenoids (Cn)
• halogenated acetylene-terpenoids

    Note. New subclasses proposed for inclusion in the classification are highlighted in bold.

    C35-terpenoids include plagiospirolydes A and B, obtained from the herb of the liverwort Plagiochila moritziana Lindbg. & Gott. [Sp?rle et al., 1989],

as well as cryptotrione from the bark of Cryptomeria japonica (L.f.) D.Don Engl. (family Cupressaceae) [Chen et al., 2010]. For this compound, antitumor activity with an IC50 of 6.44 ± 2.23 μM has been established.

   Over the past 5 years, halogenated acetylene-terpenoids have also been isolated and identified: dactyline, acetylcumazine, deacetylcumazine, which, along with

obtusenin, were isolated from the marine back-gilled mollusk Aplysia dactylomela Rang (= spotted sea hare), class Gastropoda, family Aplysiidae in 2007 [Derby et al., 2007].

    Two years ago, in 2009, a halogenated acetylene-terpenoid laurencin was obtained from the thallus of the red alga Laurencia nipponica Yamada (division Rhodophyta, order Ceramiales, family Rhodomelaceae), which has a structure similar to the aforementioned dactyline and obtusenin [Suzuki et al., 2009].

    The isolation of terpenoid components of essential oils as separate subclasses, as is currently accepted in domestic and Russian textbooks and manuals on pharmacognosy, is considered inappropriate, since essential oils are complex mixtures of substances that may include, in addition to terpenoids, furanocoumarins, simple coumarins, quinones, simple phenols, etc., which are placed in independent classes.

    It should also be noted that glycosides are already known not only for mono-, sesqui-, di-, and triterpenoids but even for hemiterpenoid glycosides, which logically fit into the subclass of hemiterpenoids (C5-terpenoids). These include, for example, (R)–3–ethyl–4–methylpentyl–beta–rutinose from the roots of Streptocaulon griffithii Hook. (family Asclepiadaceae) [Zhang et al., 2008] and others, isolated 3 years ago, in 2008.

    An intermediate link between terpenoids and phenolic compounds is phenylisoprenoids.

    Classification of phenylisoprenoids

    Phenylisoprenoids   
• phenylethanoids (salidroside);
• phenylpropanoids (including – hydroxycinnamic acids);
• phenylbutanoids;
• phenylpentanoids;
• phenylpolyisoprenoids

    Currently, phenylisoprenoids are not classified as an independent class. In some publications on phytochemistry ([Kurkin, 2004] et al.), only phenylpropanoids are distinguished as a separate subclass of compounds. In scientific articles, the term phenylethanoids is encountered when referring to salidroside isolated from the rhizomes of Rhodiola rosea L. and similar compounds.
    However, since at present, in addition to the aforementioned phenylethanoids and phenylpropanoids, phenylbutanoids (agrimonol from the leaves of Agrimonia pilosa Ledeb. [Harborne et al., 1999]), phenylpentanoids (ascolytotoxin from the mycelium of Ascochyta pisi Lib. var. pisi [Harborne et al., 1999]) and phenylpolyisoprenoids (ginkgol, ginkgol acid, bilobal from the fruits of Ginkgo biloba L. and the fruits of Schinus terebinthifolius Raddi [Harborne et al., 1999]) are already known, we propose to combine these subclasses into a separate class of phenylisoprenoids.

    Without stopping separately on the already well-known and mentioned above phenylethanoids and phenylpropanoids (the latter should include hydroxycinnamic acids), we will focus on relatively new compounds – phenylbutanoids, phenylpentanoids, and phenylpolyisoprenoids.
    The subclass of phenylbutanoids includes agrimonol, isolated in 1999 from the leaves of Agrimonia pilosa Ledeb. [Harborne et al., 1999].

  The phenylpentanoids include ascolytotoxin from the mycelium of the pea ascochyta fungus – Ascochyta pisi var. pisi (class Deuteromycetes, order Sphaeropsidales, family Sphaeropsidaceae) [Harborne et al., 1999].

      Very interesting compounds are also phenylpolyisoprenoids, isolated from the fruits of Ginkgo biloba L. and the fruits of Schinus terebinthifolius Raddi (Anacardiaceae) [Harborne et al., 1999], – ginkgol, ginkgol acid, bilobal, and others. These compounds are responsible for the allergic reactions of ginkgo and have a toxic effect in experiments on chicken embryos at concentrations greater than 0.0005% (LD50 equals 1.8 mg/egg, concentration in extract 0.0033%).

    Biogenetically, among phenols, the compounds closest to terpenoids are lignans – derivatives of diphenylpropane.

    The class “Simple phenols and their derivatives,” as is currently accepted, includes phenols, phenolic aldehydes, phenolic ketones, phenolic alcohols, phenolic acids, glycosides of simple phenols (this class of compounds has not undergone significant changes in the last decade).
    The large class “Polyphenols” can be represented as follows: subclasses “Lignans,” “Coumarins,” “Chromones,” “Xanthones,” “Quinones,” “Flavonoids,” “Tannins.” Between subclasses, “transitional subclasses” can logically be placed, as mentioned above (xanthochinones, coumarinoflavonoids, coumarinolignans, xantolignans, flavolignans).

    Based on the recently identified compounds, we propose to make changes to the classification of coumarins and flavonoids.

    In particular, the classification of coumarins could be represented as follows.

    Classification of coumarins

    Coumarins   
• simple and simple substituted coumarins;
• furanocoumarins (= furano-coumarins);
• pyranocoumarins;
• benzocoumarins;
• coumestrols;
• dimeric and condensed coumarins;
• isocoumarins

    Note. New subclasses proposed for inclusion in the classification are highlighted in bold.

    We propose to add a new subclass “Isocoumarins” to the class “Coumarins”.

    Representatives of isocoumarins include melein, 4-hydroxymelein, 6-hydroxymelein, and others, isolated from the wood ants of the genus Camponotus Mayr (family Formicidae) in 2008–2009 [Higgins et al., 2009; Voegtle et al., 2008];

as well as polygonolid from the herb of Polygonum hydropiper L. (1999) [Harborne et al., 1999].

    A new subclass – flavonoid–alkaloids should also be added to the class of flavonoids; their formulas were provided above.
    The subclass of flavonoid–alkaloids should biogenetically precede the class “Alkaloids”.

    Classification of alkaloids

    Alkaloids   
• true
• protoalkaloids (exocyclic)
• pseudoalkaloids (isoprenoid):
        – monoterpenoid,
        – sesquiterpenoid,
        – diterpenoid,
        – triterpenoid (steroidal)

    As we can see, the general classification of alkaloids developed by A.P. Orekhov in 1938 remains unchanged and contains three major groups of alkaloids (true; exocyclic, or protoalkaloids, and isoprenoid, or pseudoalkaloids).

    Based on modern data on the study of alkaloid-bearing plants, the class “Alkaloids” should be supplemented with eight new subclasses (Fig.2).

Alkaloids
– true
– protoalkaloids (exocyclic)
– pseudoalkaloids (isoprenoid): monoterpenoid, sesquiterpenoid, diterpenoid, triterpenoid (steroidal)

True alkaloids

– pyrrolidine
– pyrrolizidine
– tropane
– piperidine
– pyridine
– quinolizidine
– quinoline
– isoquinoline
– indolizidine
– indole
– purine
– imidazole
– acridine
– alkaloids with azepine cycle
– alkaloids with eight-membered cycle
– pyrrole
– naphthyridine
– oxazoles
– peptide
– pyrazole
– quinolizidine

Fig.2. Classification of alkaloids.
Note. New subclasses proposed for inclusion in the classification are highlighted in bold.

   In Fig.2, the classification of true alkaloids is presented according to Evans (2002) and Hansel (1999), and the subclasses highlighted in bold are proposed to be added to their classifications.

1. Thus, the alkaloids with an azepine (7-membered) cycle include balanol, isolated from the fruits of the acorn fungus Verticillium balanoides (Drechsler) Dowsett, J. Reid et Hopkin (class Sordariomycetes, family Plectosphaerellaceae) and Cordyceps ophioglossoides (Ehrh.) Link (class Ascomycetes, order Hypocreales, family Clavicipitaceae) in 2001 [Masse, Morgan, Panek, 2001; Riber, Hazell, Skrydstrup, 2001] (both – division Ascomycetes),

   The second alkaloid with an azepine cycle is drupacin from the fruits of Cephalotaxus fortunei Hook. (family Cephalotaxaceae) and Psoralea drupacea Bge in 2003 [Ye, Wu, 2003].

2. Alkaloids with an eight-membered cycle are represented by ircinols A and B, isolated from marine sponges of the genus Amphimedon – organisms that appeared on planet Earth more than 600 million years ago and are not fully-fledged multicellular animals (phylum Porifera, class Demospongiae, family Niphatidae) in 1994 [Tsuda et al., 1994].

    Another alkaloid with an eight-membered cycle is homalin, obtained from the leaves of the Philippine tree Homalium pronyense Guillaumin (family Flacourtiaceae) in 1999 [Harborne et al., 1999].

3. Among pyrrole alkaloids is magnolamide, isolated from the leaves of Magnolia coco (Lour.) DC. in 1998 [Yu, Chen, Shieh, 1998].

4. The next subclass of alkaloids that we propose to add to their classification is naphthyridine alkaloids, in particular, acanthicypholine from the leaves of Acanthus ilicifolius L. (family Acanthaceae), isolated in 1999 [Harborne et al., 1999].

5. Annuloline from the roots of Lolium multiflorum Lam. (family Poaceae) [Harborne et al., 1999] belongs to the oxazole alkaloids – the 5th new subclass of true alkaloids.

6. The sixth new subclass of true alkaloids is peptide alkaloids – zizyphins A–F from the bark of Zizyphus jujuba Mill. (Rhamnaceae), identified in 2001 [Tripathi et al., 2001]

and aralionins A and B from the bark and leaves of Araliorhamnus vaginata H. Perrier. (Rhamnaceae), known since 1999 [Harborne et al., 1999].

7. Another new subclass of alkaloids is pyrazole alkaloids – vitasomnin, isolated from the roots of the Ayurvedic plant Withania somnifera Dunal (family Solanaceae) in 1999 [Harborne et al., 1999].

8. Finally, the eighth new subclass of true alkaloids that we propose to include in the classification is quinolizidine alkaloids – dioscorin from the roots of various species of Dioscorea, namely, Dioscorea hirsuta M. Martens & Galeotti, D. batatas Decne, D. hispida Dennst., isolated in 1999 [Harborne et al., 1999].

   In the classification of secondary biosynthesis substances, organometallic compounds deserve special mention.
    In particular, they include organosilicon compounds, first isolated from plant raw materials in 2009 – monomethylsilantriol CH3(SiOH)3 and other silanes (herb of Equisetum arvense L. and other species of the genus Equisetum, rhizomes of Calla palustris L. (family Araceae) [Currie, Perry, 2009]),
    as well as compounds containing arsenic (arsenobetaine, isolated from the fruiting bodies of Sparassis crispa (Wulfen) Fr. (division Basidiomycota, class Agaricomycetes, family Sparassidaceae), reported in the scientific literature since 2008 [Rezanka, Siglera, 2008]).

    Thus, based on the wide variety of new natural compounds discovered to date, objective methodological and methodological prerequisites have emerged for revising the existing classification of natural compounds.
    We propose our newly developed dialectical and prognostic classification, which takes into account the current global level of development in phytochemistry and will encompass a significant variety of natural compounds, show their biogenetic connections, expand the boundaries of understanding of BAS classes, and predict new, yet undiscovered classes of BAS.
    There is no doubt that today the clear boundaries between BAS classes are being erased, and many “transitional” classes of compounds have been identified.
    Just as the periodic table allows predicting new undiscovered elements, the proposed biogenetic and prognostic classification allows for the discussion of the existence of new classes of natural compounds.
    Thus, based on the classification we proposed, the existence of such new, undiscovered “transitional” classes of compounds can be predicted, such as:
     • coumarinoquinones;
     • quinonolignans;
     • chromonolignans;
     • chromonquinones;
     • xantocoumarins;
     • xantochromones;
     • chromonoflavonoids.

        Thus, together we can take a glimpse into the future of phytochemistry.

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