The Alkaloids of Vinca, minor

The alkaloids so far isolated from V. minor (Table II) are quite different from those of the two other well-investigated species, V. rosea 

It should be noted that in the group C bases, just as for the ebum-amine-vincamine group, compounds turn up with different stereochemistries thus, in V. minor there is also found the levo form of racemic vincadifformine first isolated from V. difformis (Table III). Since rac-vincadifformine has recently been reported (86) from V. minor, it is just possible that it might be an artifact produced from the true natural product, the levo form, during its isolation. 

Crude extracts of V. minor have shown a hypotensive effect in experimental animals (76) which is believed to be owing almost entirely to its vincamine content (77), and success has been claimed for clinical studies in middle Europe of purified alkaloid extracts (78). Besides this property, vincamine also has a curare-like property (79) and is known to induce strychnine-like convulsions in rabbits (80). The ability of vincamine to reduce blood sugar in an acute test in rats is apparently not because of the inhibition of hepatic glycogenolysis (81). The medicinal uses of V. minor have recently been reviewed (82). 

Almost all the alkaloids isolated from V. minor are derived from the type III moiety 41) belonging to the vincamine, Aspidosperma, and quebrachamine subclasses. In this sense there is more uniformity among the alkaloids of V. minor than the other Vinca species. The alkaloids are also unusual in that amongst the three subclasses are found racemic alkaloids, namely, d(-eburnamine (vincanorine), dZ-A-methylquebrach-amine d -vincadifformine and its dZ-l-methyl derivative (minovine) (see Table II). 

From the physical and analytical data 16-epivincamine could have differed from vincamine in the position of the hydroxyl and/or methoxy-carbonyl or was simply a stereoisomer. That the latter was true followed from its reduction to a diol with lithium aluminum hydride oxidation of which furnished 1-eburnaminone. Heating 16-epivincamine in dry 

19-Oxo-l-vincadi3ormine [minorieine (36, 39) base VM-15 (39, 40)] ll-Methoxy-19-oxo-Z-vincadifformine [minoricein (39)] 

The conformation of vincaminorine and its C-16 epimer, vincaminor-eine, represents an interesting problem in this particular azabicyclo-dodecene system, the final structure being determined by a consideration of the NMR-spectra and rates of methiodide formation (35, 36). Of particular interest is the opinion that a peak at 6.25 ppm in the NMR-spectrum of vincaminorine representing one proton is due to the C-16 proton being strongly deshielded by N-4, as indicated below (see also Chapter 9 of this volume). As a result of a mass spectrometric examination and other considerations the epimeric configuration at C-16 has been proposed (37). 

---

Epivincamine (mp 181°-185° Mp—36° in CHCI3) has been found among the alkaloids of Vinca minor L. and it was very similar in its IR- and UV-spectra to vincamine 23). The mass spectrum with peaks at M, M-15, M-18, M-29, M-47, M-59, M-70, and the intense peak at M-102 were nearly identical with those of vincamine differing somewhat in the intensity of some peaks and mainly in the peak at m/e 266 which in vincamine is found at m/e 267. Reduction of the alkaloid gave 16-epivincaminol which after oxidation with periodic acid furnished (— )-eburnamonine. Another proof for the C-16 isomerism was obtained... 

Echitoveniline (102), 11-methoxyechitoveniline (103), and 11-methoxyechitovenidine (104) are three new alkaloids from the fruits of Alstonia venenata R. Br. (135,136), although the leaves are a better source of 103. In consonance with these structures, ester exchange with sodium methoxide affords (-)-19R-minovincinine (80) from 102, and (—)-19/ -ll-methoxyminovincinine, a minor alkaloid of Vinca minor (137), from 103 and 104. 

Among the examples of monoindole bases being discussed, vincamine (109) is the principal alkaloid of Vinca minor L. and has received some notoriety because it apparently causes some improvement in the abilities of sufferers of cerebral arteriosderosis (78). It is believed that this is the result of increasing cerebral blood flow with the accompanying increase in oxygenation of tissue as a result of its action as a vasodilator. 

An unusual variant in this group of alkaloids is afforded by vinoxine (69), an alkaloid of Vinca minor first isolated in 1967. The structure (69) may very simply be imagined to arise by fission of the C-6—C-7 bond in pleiocarpamine or 16-epipleiocarpamine. 

Continuing their work on the isolation of alkaloids of Vinca minor Dopke et al. (10) obtained a new amorphous / -anilinoacrylate alkaloid... 

Catharanthus ovalis Mgf. contains a wide variety of indole alkaloids, of which 24 have recently been isolated from the aerial parts. " These include serpentine, alstonine, and 16-epi-pleiocarpamine this last base had not been encountered previously in the genus Catharanthus. Pleiocarpamine has been found in the trunk and root bark of Hunteria congolana Pichon, and 2,7-dihydropleiocarp-amine in the root bark. " The Nfoxide of 16-cpi-pleiocarpamine occurs in the leaves of Vinca minor and isoreserpinine in ViVicn herbacea. ... 

Vincamine (CV) [1089], one of the monoterpenoid-derived indole alkaloids of Vinca minor L., which are quite different in chemical structure from the alkaloids occurring in Vinca rosea, is of interest mainly on account of its ability to produce a sustained h5q)otension - a property also characteristic of the total alkaloids of Vinca rosea [1090-1092]. A number of the studies with vincamine... 

Boyadzhiev L and Yordanov B. Pertraction of Indole Alkaloids from Vinca minor L. Sep Sci Tech, 2004 39(6) 1321-1329. Coucouvanis D. Dell Rosa and Jay Pike recognition and transport of amphiphilic molecules by a new class of inorganic ditopic receptors. The synthesis of M- Bu - salphen-3n-cr-n complexes and their use (M = Mn,Fe, n = 6) in the transport of tryptophan and serotonin across bulk liquid membranes. Comptes Rendus Chimie, 2003 6(3) 317-327. 

Aspidofractinine (146), the parent member of this third large subgroup of alkaloids of the aspidospermine group, does not occur widely, and the only recent report of its occurrence is in the stem bark and root bark of Hunteria elliottii Pichon (12). Its Na-methyl (147) and Na-methyl-14,15-didehydro (148) derivatives are new alkaloids, which have been found in the roots of Vinca sardoa (67). The ester alkaloids occur much more widely, and several new sources have been reported for (—)-kopsinine (149), (-)-venalstonine (150), (-)-venalstonidine (151), and several minor alkaloids (152-160) (Table I). Of the six reported isolations of 15a-hydroxykopsinine (154), one (16) does not spedfy the configuration of the hydroxyl group. Since it is described as a known alkaloid, it is presumed to be 15a-hydroxykopsinine, because 15/3-hydroxykopsinine is unknown as a natural product. 

Note Other alkaloids found in the vtncamine fraction of Vinca minor L. are vincine, vincuminine and vincinine ... 

Crespi et al. (715) patented the production of vincamine and epivin-camine by means of cell cultures of V. minor. Yields of 3.3 and 0.9 g/liter, respectively, were claimed for the two alkaloids. Two other patents have been reported concerning the production of Vinca alkaloids (Table XLIII). 

Aerial parts of vinca minor were treated with 25% NH4OH for 30 minutes, extracted with CHCI3, the concentrated extract was reextracted with 2% tartaric acid adjusted to pH 9.0 with 25% NH4OH, and alkaloids were extracted with CHCI3, dissolved in HOAc and titrated with HCIO4 by using crystal violet indicator. 

The enzyme responsible for the stereospecific condensation of trypt-amine and secologanin 34) was called strictosidine synthase, and its presence was demonstrated by Treimer and Zenk 194) in a number of indole alkaloid-producing plants, including Amsonia salicifolia, Catharanthus roseus, Ochrosia elliptica, Rauwolfia vomitoria, Rhazya orientalis, Stem-madenia tomentosa. Vinca minor, and Voacanga africana. Enzyme activity as high as 1698 pkat/mg protein was observed for O. elliptica. No... 

Vincamine, vinblastine and vincristine are very important clinic alkaloids. They are produced naturally by plants vincamine by Vinca minor, and vinblascine and vincristine by Madagascar periwinkle Catharanthus roseus). The vindoline synthesis pathway starts with strictosidine and, via dehydrogeissoschizine, preakuammicine, stemmadenine and tabersonine, is converted to vindoline and vincristine (Figure 42). Conversion from vindoline to vinblastine is based on the NADH enzyme activity. Vinblastine and vincristine are very similar alkaloids. The difference is that vincristine has CHO connected to N, whereas vinblastine in the same situation has only CO3. This synthetic structural differences influence their activity. Vinblastine is used to treat Hodgkin s disease (a form of lymphoid cancer), while vincristine is used clinically in the treatment of children s leukaemia. Vincristine is more neurotoxic than vinblastine. 

Further variants on the terpenoid indole alkaloid skeleton (Figure 6.82) are found in ibogaine from Tabemanthe iboga, vincamine from Vinca minor, and ajmaline from Rauwolfia serpentina. Ibogaine is simply a C9 Iboga type alkaloid, but is of interest as an experimental drug to treat heroin addiction. In a number of European countries, vincamine is used clinically as a vasodilator to increase cerebral blood flow in cases of senility, and ajmaline for cardiac arrhythmias. Ajmaline... 

Majvinine, a minor alkaloid of the aerial parts of Vinca major, is a new alkaloid, which proves to be 10-methoxy-7Va-methylvellosimine (162).92... 

Vinca minor, cultivated in Georgia, USSR, has been shown to contain ( )-vincadifformine and vincine, both already known to occur in this species, together with apovincamine and 11-methoxyvincadifformine.92 Voaphylline, voaphylline hydroxyindolenine, and 11-hydroxytabersonine have been isolated from the leaves of Tabernanthe pubescens,43/ and 5,22-dioxokopsane (177) from the root bark of Alstonia venenata R. Br. 93 this is the first report of an alkaloid of the heptacyclic kopsine group in this species. 

Under this heading is discussed the chemistry of those alkaloids, isolated from Vinca species (principally V. minor), that are closely related to eburnamine and its congeners. A table of Vinca alkaloids is given elsewhere (see Chapter 12). 

The Vinca minor alkaloids vincadine (II-A) and vincaminoreine (II-B) are the 3-carbomethoxy- and 3-carbomethoxy-Aa-methyl derivatives, respectively, of ( + )-quebrachamine (10a). The same plant also contains ( + )-indolic-A-methylquebrachamine (10b). 

Through a biomimetic approach, tabersonine is also the semisynthetic precursor of vincamine, a Eburna alkaloid isolated from Vinca minor, and is used for cerebral insufficiency in Europe. Tabemanthe iboga has a long history of use as a stimulant in tropical Africa its main active principle is ibogaine, a controlled substance in many countries (Fig. 40). It is being actively investigated in the United States for its potential to induce opium addiction withdrawal. 

Vincamine is an alkaloid extracted from the plant Vinca minor. Ethyl apovincaminate is a related synthetic ethyl ester of vincaminic acid. These drugs have spasmolytic effects similar to those of reserpine, but also have metabolic effects, including, in high doses, inhibition of phosphodiesterase. Although increased cerebral blood flow has been reported after the intravenous administration of vincamine, there have been no reliable studies of blood flow after oral medication. Improvement in scores on some psychometric tests have been obtained in some patients with cerebrovascular disease, but no clear-cut practical benefit has been demonstrated. 

Diphosphoglycerate (2,3 DPG, 14), a naturally occurring material that increases in people with anemia, was reported to inhibit the second phase of platelet aggregation.55 The inhibitory effect was potentiated by dipyridamole and Vinca minor alkaloids. 

The structure (94) for vincatine from Vinca minor was arrived at by mass spectral examination of the alkaloid and its lithium aluminium hydride reduction product (95), which has since been synthesised (Scheme 14). It is the first oxindole alkaloid with an aspidospermine aliphatic skeleton. 

Despite only a minor difference in the chemical structures of vinblastine and vincristine, the clinical effects differ considerably. Surprisingly there is no clinical evidence of cross resistance between them, or with radiation and other presently known oncolytic agents. The rise and fall of the blood activity level of vincristine is steeper than that of vinblastine.The dosage requirements of both alkaloids differ markedly the weekly intravenous dose of vinblastine for humans is 0.1—0.2 mg per kg, that of vincristine, however, is approximately one tenth of this. Concerning the side-effects, vincristine shows more neurotoxic effects and vinblastine is considered to have more potency in bone-marrow depression. This is not without consequences on human therapy therapy is limited by bone-marrow depression with vinblastine and neuromuscular effects, with vincristine. Early symptoms of side-effects are vomiting, fever, and exanthemes. Late symptoms are C.N.S. disturbances, alopecia, and leukopenia. C.N.S. disturbances are manifested by various symptoms such as paresthesias, neuritis, paresis, and muscular atrophy, accompanied by quenched reflexes. Even behaviour may be affected after a long period of treatment. But why do all these side-effects happen, when Vinca alkaloids are unable to pass the blood-brain barrier The only explanation we have at hand is that they are possibly caused by metabolites or breakdown products of the normal biochemical pathways, which are disturbed by the alkaloids. 

From Vinca minor Meisel and Dopke (15) obtained a small quantity of an anilinoacrylate alkaloid having a molecular weight of 366 and major ions at m/e 214 and 154. A broad band at 1696-1684 cm-1 was interpreted as being due to a y-lactam functionality, and this was supported by the mass spectrum which showed an ion at m/e 241, thought to be due to... 

Mokry and Kompis reported in 1963 the isolation of the minor alkaloid, vincaminoridine, from Vinca minor 93), and subsequently described the structure 94). 

Ajmalicine (139a) and 3-isoajmalicine (140a) were both converted to oxindole alkaloids, mitraphylline (167) and isomitraphylline (168) in Mitragyna parvifolia (Roxb.) Korth. (Rubiaceae)(S4). Feeding experiments on Vinca minor Linn. (Apocynaceae) had shown that vincamine (169) is biosynthesized via geissoschizine, stemmadenine, secodine, and tabersonine (85). Apparicine (170), which lacks one carbon atom of the tryptamine side chain, appears to be derived in Aspidosperma pyricollum Miiell. Arg. (Apocynaceae) from stemmadenine (86). 

Vincamine (40) is derived from Vinca minor. The in vitro propagation of this plant has been studied (709). Axillary shoot proliferation was best with media containing BAP and NAA. As part of a program for the industrial production of this alkaloid plant cell cultures have been studied as a possible source (710). Petiard and co-workers (711,712) reported the initiation of cell cultures of V. minor based on TLC analysis small amounts of... 

Strictosidine (104) is produced by the plant Rhazya stricta. A crude enzyme preparation from the plant was used to produce labelled strictosidine this, when incubated with Catharanthus enzyme, again gave the three alkaloids (105), (106), and (107). ° Cell-free preparations of cell-suspension cultures of Amsonia tabernaemontana, Rhazya orientalis, and Vinca minor were also observed to convert (102) plus (103) into strictosidine (104) with fair efficiency the formation of vincoside (109) was never observed. ... 

---