1. Phenylakylamines and Related Compounds 

 

Although the history of khat chemistry goes back more than 100 years, it is still a rather puzzling chapter of natural products chemistry. Its progress was slow and controversial. Owing to the rather sensitive nature of its active principal(s) progress in khat chemistry was largely dependent on two basic factors: approach and methodology. Several attempts have failed or gave inadequate results because of a wrong approach or wrong methodology (or both). Just to mention the most striking and most frequent error in past khat chemistry: several authors overlooked (or were unable to take into account) the fact that khat is consumed in most cases fresh and not as a dried material. Thus one may suspect that any chemical or pharmacological result or conclusion based on a work on the dried plant is not necessarily adequate for the fresh. And we know now that this is, in fact, the case.

 

The history of khat chemistry can be arbitrarily divided into three major periods. The early period started in 1870, when Fliickiger in his paper considered the possibility of the presence of caffeine in khat as a stimulant principle (1). Later Fltickiger and Gerock established that caffeine was, in fact, not present in khat, but found instead an alkaloid they named "katin" (2). Subsequent attempts by several authors (3-7) led to the separation of various similar products under different names (Celastrin, Cathin, Cathinin and Cathidin). One may suspect that, because of lack of appropriate methodology most of them were: (i) impure products or (ii) identical but containing qualitatively and quantitatively varying impurities.

 

A second, and important step forward was Wolfes' work (8), who established the identity of his "cathin" with (+)-norpseudoephedrine (NPE) (1). This result represented the only solid ground for a period of more than 30 years in which several groups (9-17) have taken up the subject without much substantial progress. Some of them (9-10) concluded that NPE was the only alkaloid present in khat in appreciable amounts, whereas most groups found further basic compounds but without any proper characterization or identification (11-17).

 

1 - 3 (see next page)

 

 The present era of khat chemistry started with the work of Brilla (18-19), who was the first to take seriously into account the preference for fresh khat and the observed differences in the CNS stimulant activity of the extracts and that of NPE. Evidence was found that an amine oxalate preparation from the fresh plant showed different physical and chemical characteristics and a stronger effect on locomotor activity than the amine oxalate prepared from a dried khat sample. It was concluded that the oxalate isolated from the fresh plant was an NPE-like compound, possibly a labile precursor, but no structure could be proposed for it. It is quite evident from the data published that both oxalates were mixtures of NPE and the suggested precursor, the dominant component being NPE in the dried plant product and the labile compound in the amine oxalate prepared from the fresh plant material.

Chemical research on khat was taken up again by several groups in the early seventies. On the recommendation of the WHO (20) and the UN Commission on Narcotic Drugs (21) a research programme was initiated at the UN Narcotics Laboratory on the chemical composition of khat involving several major classes of secondary plant products present in the fresh or well preserved material.

 

Independently, Schorno at the University of Bern, Crombie and his coworkers at Nottingham University started analyzing khat for N-containing compounds at about the same time. These separate and later joint efforts have resulted in a rapid progress which is reflected in a number of documents or papers (22-35). Recently, two review papers summarized the results of the UN and Nottingham groups (36-37). Thus, the present paper will mainly present the results published after 1978.

 

The Discovery of Cathione 

 

A simple thin-layer chromatography (TLC) analysis of the methanolic crude extract prepared from fresh or freeze-dried plant samples clearly showed that, besides varying amounts of NPE and other minor amine-type components, an un-identified compound was present in large quantities. This was separated and rapidly identified as (-)- ck-propiophenone (2) (22,24). The trivial name cathinone was proposed and subsequently accepted for it.

 

Somewhat later Schorno came to the same result (29,31) using two different isolation techniques: i) the separation of the oxalate mixture by repeated crystallization; ii) by acetylating the amine base mixture and purifying cathinone acetate on preparative TLC plates (see Figure 1).

 

Cathinone is in many aspects a remarkable natural phenylalkylamine derivative. It is a new natural product, which is quite surprising, considering its structural simplicity. Its rather high instability gives the explanation: as a base it decomposes rather quickly giving rise to a series of decomposition products.This has already been suggested by the UN document (24) and has later been confirmed together with its high recemization liability by other groups (31,40) (see Fig.2.)

Since (-)-cathinone has the same S configuration at its assimetric centre as NPE, it is actually the biosynthetic intermediate of ephedrine postulated by Yamasaki et al., in 1973 (41).Schorno in the meanwhile has presented experimental evidence for this suggestion (42). A detailed study of cathinone and NPE biosynthesis and of their relationship would be of greatest value for a better understanding.

 

The availability of cathinone has prompted renewed interest in its pharmacology. Studies were carried out in several laboratories on synthetic cathinone antipodes and NPE. It was shown that (-)-cathinone is a potent amphetamine-like substance and it has a considerably higher stimulant property than NPE does. Cathinone administration to various animals reproduced most of the effects observed on humans after khat consumption, thus it was concluded that cathinone is the main CNS active principal of fresh khat material (38).

 

Cathinone Synthesis 

 

Synthetic recemic -aminopropiophenone and its optically pure antipodes have been known for almost 100 years, and related synthetic products [e.g. Diethylpropione (4) are present on the drug market mainly as CNS stimulants or anoretac  drugs. This together with the observed CNS activity has suddenly increased interest in synthetic cathinone and resulted in a slightly modified version of the Gabriel synthesis (30), and two stereospecific syntheses published recently by McClure et al. and Berrang et al. (39,40). The Merck Sharp Dohme group used Friedel-Craft's reaction and the acid chlorid of N-protected S-alanine and obtained (S)-cathinone of high otical purity in a fairly good yield (39) (Figure 3). Berrang's groups made use of the easy availability of racemic norephedrine and established a simple route to both cathinone antipodes (40) (Figure 4)

-

Related compounds

 

Early ambiguous data on the presence of further phenylalkylamine-type compounds besides (+)-NPE were substantiated by the isolation and/or identification of four related compounds by the UN and Bern groups using partly different purification and identification methods.

(-)- Norephedrine (3) was found to be always present in both fresh and dried khat samples in varying amounts (31-33, 36). In addition, one more phenylalkylamine derivative (5) (its trivial name: cinnamoylethylalmine) not found before in nature was described after derivatization and gas chromatography - mass spectrometry (GC-MS) analysis from a Kenyan khat sample (36, 43). The compound could not, however, be isolated and characterized definitely and its existence remained questionable until further confirmation. Studies now in progress indicate that the structure proposal was probably correct (43). In this case, compound (5) may become an interesting new contribution to khat chemistry for it has most probably similar CNS stimulant properties as cathinone and it might also serve as a useful chemotaxonomic marker for certain khat types (44).

 

From the strongly basic amine fraction compounds (6) and (7) were also separated and characterized opening the field for speculations on their origin and nature. It was suggested that both may be artefacts formed simply during the extraction-separation and isolation procedure. While this proved to be true for the pyrazine derivative (6) which is a dimerization product of cathinone and could not be traced in the plant material, compound (7) was found to be present in the ethereal oil distilled from the fresh plant material (31). This suggests that it may be formed together with other deamination products (see Figure 2) also in the living plant.

 

2. Sesquiterpene Polyester Alkaloids 

 

From available data it seems evident now that Stockman's (7) Cathidin was the earliest "pioneer" of a second class of N-containing khat extractives: weakly basic, fairly lipophilic polyesters that have repeatedly been overlooked by most investigators because of their non-typical alkaloid nature. Some progress was achieved by Cais et al. (45, 46) who were able to isolate one component of the rather complex mixture and to propose two tentative structures (8a and 8b) for it.

 

In 1974 Luftmann and Spiteller (47) identified the main component of the sesquiterpene polyol core as euonyminol (9) of an old commercial "cathidine" sample.

As a result of a joint effort between the Chemistry Department of the Nottingham University and the UN Narcotics Laboratory a series of pure polyester alkaloids named cathedulins have until now been isolated from a Kenyan and an Ethiopian khat sample (25-28, 33-35). Their molecular weights are in the range from 600 to 1200. They can be subdivided according to their complexity into three groups:

 

1. Low molecular weight esters of a pentahydroxy-sesquiterpene core: cathedulin E2 (=cathedulin K16) (10)

cathedulin E8 (11) 10 - 11

 

2. Medium molecular wieght esters of euonyminol (9) having an evonic acid dilactone bridge:

cathedulin K1 ( 12 ) cathedulin K2 ( IT ) cathedulin K6 ( TT ) cathedulin K15 ( 33. )

12. Cathedulin-K 1 RI = R2 = R3 = Acetyl

13. Cathedulin-K 2 RI = Ho R2 = R3 = Acetyl

14. Cathedulin-K 6 R1 = R2 = Ho R3 = Acetyl

15. Cathedulin-K 15 R1 = R2 = R3 = H

3. High molecular weight, complex of esters of euonyminol:

cathedulin E3 (= cathedulin K11) ( 16) cathedulin E4 ( 17 ) cathedulin E5 ( T ) cathedulin E6 ( rg ) cathedulin K12 ( 20 )

16.. Cathedulin-E 3 (= K-11) R = Acetyl.

 

4. Polyesters with yet unknown structure that have recently been isolated (48):

cathedulin K5

cathedulin K17

cathedulin K 19

 

It is interesting to know that until now no adequate pharmacological testing has been done on these catheduline-type alkaloids due to their extremely poor water solubility and lack of material.

 

3. Volatile Compounds (ethereal oil components) 

 

Khat has a moderate characteristic odour and a weak aromatic taste. Its volatile oil content is fairly low. Quedan (49), and later Schorno (31) obtained a yellow ethereal oil in yields varying from 0.03 to 0.08% depending upon the plant sample. Gas chromatography (GC) and TLC analyses indicated the presence of a number of components, mostly terpenoids ( 21-31 ) but also aromatic-type compounds, such as 7.

 

4. Flavonoids

 

Celastraceae species are rich in flavonol glycosides, e.g. a number of kempferol- and quercetine glycosides have been found in various Euonymus species. Early data indicated the presence of "tannins" in khat, a term which usually covers a complex group of phenolic compounds, frequently also flavonoid-type ones. Indeed, El Sissi et al. (50) identified three flavonols: kempferol (32), quercetine (33) and myricetine ( 34 ) in the hydrolyzed khat extract. Recently, Gellert et al. (51) idolated two dihydroflavonols dihydromyrecetine ( 35 ) and its 3-0-rhamnoside (=Ampelopsine) ( 36 ) from the crude flavonoid mixture of khat.

 

5. Sterols and Triterpenes 

 

Neutral compounds isolated from khat during the UN studies (23) included two ubiquitous sterols and a simple triterpene friedeline ( 37 ) and some of its hydroxylated derivatives as well. In addition, Crombie et al. (33, 37) established, that the red-orange pigmented root bark of the plant contains a series of red triterpene quinones celastrol ( 38 ), pristimerin ( 39 ), iguesterin ( 40 ), and tingenone, a mixture oftingenin A ( T ) and tingenin B ( 42 ).

 

6. FUTURE WORK

 

In spite of the relatively rapid progress in the last 10 years in khat chemistry there is a number of open questions that need further intensive chemical study, just to mention a few:

 

1. Is the list of CNS active components of khat complete ? It is doubtful. Although most physiological activities of fresh khat can be reproduced on animals by cathinone (and/or NPE) administration, the quantative aspect is still far from being complete. In fact, there are indications that, at least in certain khat types, further related compounds might contribute to the overall effectivity of the plant, such as cinnamoilethylamine (5), the nitrogen-free compound (7), or the highly complicated group of polyester alkaloids. It is highly interesting in this respect that a closely related compound cassinine exhibited a pronounced in vivo tranquilizing effect (52). If similar compounds could be found in khat, this would explain why local khat consumers often distinguish between "stimulant" and "calmant" khat varieties/types.

 

2. Much analytical and biosynthetic work is needed for the clarification of such important questions as the chemosystematic aspects of khat types/varieties, the origin and inter-relationship of the phenylalkylamine-type and related compounds. Schorno's group has already made important contributions to this aspect of khat chemistry and no doubt there will be a more intensified research activity on this field.

 

3. The extremely versatile chemical nature and biosynthetic capacity of the Celastraceae family [see (52)] clearly suggests that khat chemistry might still be much more complicated than we today expect it to be. The majority of the weakly basic alkaloids is still unknown, and very little is known about the nitrogen-free/neutral khat components. This leaves large fields of activities still open and might bring, in the near future, significant contributions to out understanding of the "khat puzzle".

 

SUMMARY 

 

The paper gives a review of preparative and synthetic aspects of khat chemistry. It briefly describes the major turning points of the history of the "khat puzzle" with special emphasis on recent findings: the discovery of cathinone and related compounds, the description of high molecular weight polyester alkaloids and neutral substances (flavonoids, sterols, triterpenes and volatile components). It also indicates some important open questions that are suggested as future research subjects.

 

References 

 

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