Monomeric alkaloids

A few alkaloids, clearly originating from tryptophan and secologanine, cannot be accomodated in the previous types. They form the group of miscellaneous monomeric alkaloids. 

Achenbach and Schaller have reported the isolation from the root bark of T. accedens of three monomeric alkaloids in addition to several bisindole alkaloids... 

The last monomeric alkaloid, Nl-demethyl- 16-epiaccedine (24, C19H24N202, MP 170-172°C, [a]D +50°), existed as an equilibrium mixture of carbinolamine and open-chain carbonyl forms in which the latter are present in amounts of 10% in MeOH and 25% in chloroform. Hofmann degradation of 24 methiodide... 

Extensive biotransformation studies have been conducted with the As-pidosperma alkaloid vindoline, but much less work has been done with monomeric Iboga and dimeric alkaloids from this plant. The long-standing interest in this group of compounds stems from the clinical importance of the dimeric alkaloids vincristine and vinblastine, both of which have been used for more than 2 decades in the treatment of cancer. Few mammalian metabolites of dimeric Catharanthus alkaloids have been characterized. Thus the potential role of alkaloid metabolism in mechanism of action or dose-limiting toxicities remains unknown. The fact that little information existed about the metabolic fate of representative Aspidosperma and Iboga alkaloids and Vinca dimers prompted detailed microbial, mammalian enzymatic, and chemical studies with such compounds as vindoline, cleavamine, catharanthine, and their derivatives. Patterns of metabolism observed with the monomeric alkaloids would be expected to occur with the dimeric compounds. 

Vincristine (26b) and vinblastine (26a) are representative of the so-called dimeric indole alkaloids which arise in the plant by combination of non-identical monomeric alkaloids. Vincristine in particular has important clinical activity both as a single agent and in combination chemotherapies (B-77MI30614). Recently, a semi-synthetic derivative vindesine (26c) in which the C-16 methoxycarbonyl group has been converted to a primary amide... 

M. Shamma and H. Guinaudeau, Tetrahedron 40, 479S (1984). Biosynthesis of aporphinoid alkaloids. In addition to monomeric alkaloids, discusses proaporphine- and aporphine-benzyliso-quinoline dimers, dimeric oxidized aporphines, and types derived by catabolism of benzyliso-quinoline-derived dimers. 

Research on the terpenoid indole alkaloids (TIAs) is mainly primed by the pharmaceutical applications of several of the compounds. The monomeric alkaloids serpentine and ajmalicine are used as a tranquilizer and to reduce hy-... 

Five monomeric alkaloids isolated117d from the leaves of Stenosolen hetero-phyllus (Vahl) Mgf. have been identified as voacangine, voacangine hydroxy-indolenine, conoflorine, pandine, and pandoline. 

T. sultanabadense Stapf., a small plant that grows under the shade of rocks on the rocky mountain slopes of eastern Turkey, is a source of the dimeric bisbenzylisoquinoline alkaloids thalbadensine, hemandezine, and thalictine, and the monomeric alkaloids thalifoline (isoquinolone), berberine (protoberberine), and magnoflorine (aporphine). 

In another study of the leaves of the same plant, several new monomeric alkaloids were obtained (in addition to bisindoles, vide infra) including the macroline alkaloid, 19,20-dehydro-... 

Six new monomeric alkaloids were isolated from the root bark and leaves of Ervatamia hirta, of which five (105,106, 109 - 111) possess the normacusine B-afTinisine skeleton while the other (112), is the N-oxide of norfluorocurarine [91]. Compounds 105 and 106 were readily identified as the C(I6) epimers of normacusine B and affmisine, respectively, by comparison of their NMR spectral data with that of normacusine B (107) and affinisine (108). Similarly, compounds 109 and 110 were readily shown to be the O-acetyl derivative of 16-epi-affinisine and the N-oxide of affinisine, respectively. The remaining new alkaloid, dehydro- 16- pi-... 

In general, bisindole alkaloids show very characteristic ceric sulphate reactions. In contrast to the monomeric alkaloids (see refs. 18,19,153) there is often apparently no direct relationship between the colour reaction and the nature of the aromatic chromophore. 

To date, no known bisindole alkaloid has been shown to be only an artefact. In addition, no experimental evidence exists which undermines the assumption that bisindole alkaloids are actually formed from the completed monomeric partners. Support for this idea is derived from the kind of reactions apparently necessary to effect such dimerisations which are known biogenetic processes amine-aldehyde condensations, Mannich reactions, Michael additions, Friedel-Craft type condensations, Diels-Alder type processes, radical coupling etc. The observation that the skeletal distribution amongst monomeric alkaloids is reflected throughout the dimeric series lends further support. 

The third monomeric alkaloid characterized from Scaevola racemigera was scaevoline (22), which showed a molecular ion at mJz 205 and was therefore isomeric with 21 (39). Spectroscopically, the IR spectrum showed the presence of a hydroxyl group (3270 cm-1 Sh 3.80 ppm), and the pyridine a-protons were present (8.77 and 8.46 ppm), as were the carbomethoxy group (3.93 ppm) and a singlet methyl (1.62 ppm). The C-5 methylene group was missing, replaced by two olelinic protons at 7.16 and 6.65 ppm as coupled doublets (/ = 6 Hz). The structure 22 was therefore proposed for scaevoline, which was also isolated in racemic form (39). 

Alstophylline, C22H26N2O3, the tertiary base recently isolated from the bark of A. macrophylla, is a monomeric alkaloid of structure XXVIII 9). The presence in the molecule of the ]8-alkoxy-a,j8-unsaturated ketone grouping was deduced from the IR spectrum, which exhibits maxima at 1616 and 1640 cm similar to those exhibited by dimedone methyl ether (XXIX). This deduction is also consistent with the UV spectrum of alstophylline which closely resembles the summation spectrum of XXIX and 7-methoxy-9-methyl-l,2,3,4-tetrahydrocarb-azole (XXX). The NMR spectrum of alstophylline confirms this orientation of the methoxyl group. In the aromatic region (6.60-7.52 ppm) the integrated signals disclose the presence of four protons, i.e., three aromatic ones and the olefinic proton j8 to the carbonyl group. If the... 

The third new monomeric alkaloid obtained from P. caducifolia (103) was very similar in all spectral properties to pandoline (202). In particular, the UV and IR spectral data verified the nature of the aromatic nucleus, and from the PMR spectrum an ethyl side chain attached at a hydroxy substituent was evident. This could also be demonstrated by the mass spectrum, where the base peak was found at m/e 140. On this basis, the alkaloid was speculated to be the 20-isomer of pandoline. Because pandoline was more polar than the epipandoline, it was reasoned that pandoline (220) had the 20-hydroxy group in the a-position (axial) and that in 20-epipandoline (221) the hydroxy group was equatorial and j8. 

Fig. 11. Coupling of the monomeric alkaloids catharanthine and vindoline to yield dimers of the vinblastine type.

Feeding radioactive [8] as [3H-CO2CH3] and [10] as [14c-OCOCH3] into apical cutting of 3-4 month-old C. roseus plants afforded low but definite incorporations of both alkaloids into vinblastine [12] demonstrating that these monomeric alkaloids are the precursors of [12](90). Feeding both [acetyl-14C] vindoline and [OC3h3] catharanthine to 6 week-old differentiated C. roseus plants for 6 days, labelled anhydrovinblastine [11] was isolated (91). This was incorporated into vinblastine by cell-free preparations of Catharanthus roseus (92,93 ). 

FcBl of P. falciparum with an IC50 value of 2.6 aM. Tabemaemontanine acetate, a monomeric alkaloid, showed antiplasmodial activity with an IC50 value of 5.3 pM and a selectivity index (ratio of IC50 value in human MRC-5 to that in P. falciparum) >45. The isolated bisindole alkaloids were... 

In a study of the cytotoxic effects of the alkaloids of M. euchrestifolia on human cancer cell lines, it was found that while the monomeric alkaloids murrayaquinone and murrayafoline showed significant cytotoxicity against SK-MEL-5 and Colo-205 cells, the biscarbazole alkaloids, bismurrayafoline A (21) and chrestifoline A (40) by comparison, showed only marginal cytotoxicity against HOP-92, a nonsmall cell lung cancer cell line, and LOXIMVI, a melanoma cell line, whereas chrestifoline C (42), bismurrayafoline B (22), and murranimbine (48), were inactive toward all the cell lines tested (40). 

Recently however, a basic peroxidase, anhydrovinblastine synthase, which couples eatharanthine and vindoline to yield anhydrovinblastine, the putative precursor to vinblastine and vincristine, has been purified and characterized from C. roseus leaves 421,422). The enzyme showed a specifie anhydrovinblastine synthase activity of l.Snkatmg and a molecular weight of 45.40kDa. It was shown to be a high-spin ferrie heme protein belonging to the plant peroxidases superfamily (class HI peroxidases), and eytochemical studies showed that the enzyme is localized in the mesophyll vacuoles, in individual spots at the inner surface of the tonoplast. On the basis of the ability of the monomeric alkaloid substrates to reduce the C. roseus basic... 

Although alkaloids with curarizing activity usually are dimers, a monomeric alkaloid with curarizing activity, vene-curine (51), has been isolated from the curare prepared by the Hoti tribe of Venezuela (Quetin-Leclercq et al., 1989). 

Alkaloids of this type belong to a newly established subgroup of Amaryllidaceae alkaloids and own a 10b,4a-ethanoiminodibenzo[( ,iflpyrane skeleton (Table 17.9). To date, a total of five alkaloids including four monomeric alkaloids 163-166 and one dimeric alkaloid 167 have been isolated from plants of the family Amaryllidaceae [41, 44]. 

Recently a complement-modulatory activity has been reported for a series of alkaloids isolated from Cryptolepis sanguinolenta (Lindl.) Schlechter (Periplocaceae). The monomeric alkaloids cryptolepine (tested as its hydrochloride) (62), quindoline (63), and hydroxycryptolepine (64) exhibited a dose-dependent inhibitory effect on the classical pathway [38]. The activity (% inhibition) at a concentration of 1 mM... 

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