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Astonishing Diversity of Natural Surfactants: 6. Biologically Active Marine and Terrestrial Alkaloid Glycosides Valery M. Dembitsky* Department of Organic Chemistry and School of Pharmacy, Hebrew University, Jerusalem, Israel
ABSTRACT: This review article presents 209 alkaloid glycosides isolated and identified from plants, microorganisms, and marine invertebrates that demonstrate different biological activities. They are of great interest, especially for the medicinal and/or pharmaceutical industries. These biologically active glycosides have good potential for future chemical preparation of compounds useful as antioxidants, anticancer, antimicrobial, and antibacterial agents. These glycosidic compounds have been subdivided into several groups, including: acridone; aporphine; benzoxazinoid; ergot; indole; enediyne alkaloidal antibiotics; glycosidic lupine alkaloids; piperidine, pyridine, pyrrolidine, and pyrrolizidine alkaloid glycosides; glycosidic quinoline and isoquinoline alkaloids; steroidal glycoalkaloids; and miscellaneous alkaloid glycosides. Paper no. L9870 in Lipids 40, 1081–1105 (November 2005).
Alkaloids are alkaline compounds containing nitrogen. Many of these natural products are derived from amino acids, and an enormous number of bitter, nitrogenous compounds are included in this group. More than 18,000 different alkaloids have been discovered in representatives of over 300 plant families, microorganisms, fungi, marine invertebrates, insects, amphibians, and other organisms (2–9). Alkaloids often contain one or more rings of carbon atoms, usually with a nitrogen atom in the ring. The position of the nitrogen atom in the carbon ring varies with different alkaloids and with different plant families, microorganisms, and/or invertebrates. In fact, it is the precise position of the nitrogen atom that affects the properties of these alkaloids (2–7). Marine natural products are small- to medium-M.W. compounds produced by marine plants, invertebrates, and microorganisms that have stimulated interdisciplinary studies by chemists and biologists (10–12). Invertebrates such as sponges, soft corals, molluscs, coelenterates, and ascidians produce secondary metabolites of unusual structures; sponges and ascidians in particular produce nitrogen-containing substances, usually called “marine alkaloids.” Novel classes of marine alkaloids have been found to interact with key aspects of the cell cycle, enzymes or other targets and lead to insights into new *Address correspondence at Department of Organic Chemistry, P.O. Box 39231, Hebrew University, Jerusalem 91391, Israel. E-mail:
[email protected] For the previous article in this series, see Reference 1. Abbreviations: DIBOA, 2,4-dihydroxy-1,4-benzoxazin-3(4H)-one; SGA, steroidal glycoalkaloids; THIQM, tetrahydroisoquinolinemonoterpene. Copyright © 2005 by AOCS Press
therapeutics. The study of biologically active marine alkaloids has profoundly influenced the course of discovery in fields ranging from pharmacology to oncology (11,12). State-of-theart studies in molecular genetics, enzymology, and biochemistry address the issues of biosynthesis of marine natural products by identifying and sequencing the genes involved in transcription-translation and regulation of their cognate enzymes (5,6). The future promises heterologous expression of important marine natural products through manageable microbial fermentation (13–15). The total synthesis of terrestrial and marine natural alkaloids aims for no less than total control of bond construction and stereochemistry of complex molecules from simple starting materials. New methods for building carbon–carbon bonds and managing heteroatom reactivity lie at the cutting edge of organic synthesis (16–20). Alkaloid glycosides, a specific group of water-soluble terrestrial and marine natural compounds, can be subdivided into several groups, presented in this review, including: acridone, aporphine, benzoxazinoid, ergot, indole, quinoline, isoquinoline, piperidine, glycosidic lupine alkaloids, steroidal glycoalkaloids, and miscellaneous alkaloid glycosides. ACRIDONE ALKALOIDS Acridone alkaloids constitute a small group of natural products found exclusively in the family Rutaceae, including Citrus, Glycosmis, and Severinia species (21). They exhibit a wide range of pharmacological activities including cytotoxicity, which is presumed to be exerted by the inhibition of topoisomerase-II (22), an intracellular enzyme. These compounds, as well as their analogs and derivatives, have been tested for their antimicrobial activities and effects on mammalian cells (23). Acronycine has been tested for antitumor properties (24,25), and acronycine analogs were reported to be effective against Trichomonas vaginalis (26). Thirty acridone alkaloids were evaluated for their antiplasmodial activities in a rodent model (24). Seven of the alkaloids in the series had activities equivalent to that of chloroquine against Plasmodium yoelii. Atalaphillinine was effective as a prophylactic agent against P. berghei and P. vinckie infections in mice. Acridone alkaloids isolated from Boenninghausenia japonica (Rutaceae) showed antiproliferative activity against human gastric adenocarcinoma (MK-1), human uterine carcinoma (HeLa), and murine melanoma (B16F10) cells (27). The acridone alkaloid
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acronycine, isolated from several Sarcomelicope species (Rutaceae) exhibited promising activity against a broad spectrum of solid tumors (28). Only a few glycosides of acridone alkaloids have been isolated from the family Rutaceae. Gravacridonediol 1 and gravacridonetriol 2 were identified from a methanol extract of roots of Ruta graveolens (29,30), and gravacridonediol 1 also was found in Boenninghausenia albiflora callus tissue (31). Acridone derivatives have been identified in the extracts of the roots of Thamnosma rhodesica (Rutaceae) (32). This study was the first to report rhodesiacridone, one of these acridone derivatives. This novel compound showed activities against the intracellular form of the protozoan parasite Leishmania major, a human pathogen. Gravacridonediol 1 and 1-hydroxy-10methylacridone exhibited activities against the intracellular form of the same parasite and the fungus Cladosporium cucumerinum, respectively (32). A new compound, gravacridonol monoglucoside 3, and gravacridonediol 1 were identified from cell suspension cultures of T. montana grown in Gamborg B5 medium (32). The in vitro activities of furo[2,3b]quinoline and acridone alkaloids 4 and 5 against Plasmodium falciparum were evaluated by an isotopic semimicrotest. A pyran ring in the furoquinoline nucleus and 2-O-pyrano-glycoside substituents in the acridone nucleus improved the antimalarial activities of the compounds. These features provide a suggestion for further chemical modifications (33).
diseases, from benign syndromes to more severe illnesses. More than 500 aporphine alkaloids have been isolated from various plant families, and many of these compounds display potent cytotoxic activities, which may be exploited for the design of anticancer agents (34). Aporphine glycosides, stesakine-9-O-β-D-glucopyranoside 6 and N-methyl-asimilobine-2-O-β-D-glucopyranoside 7, were isolated from the seeds of Stephania cepharantha cultivated in Japan (35). Compound 7, previously known as floripavidine, was isolated from Papaver floribundum in 1976 by Russian scientists (36). Kamaline 8, incorporating a novel urethane moiety and a glucoside unit, was isolated from Stephania venosa grown in India (37). Tubers of the Chinese medicinal herb Aristolochia tuberosa yielded two 4,5-dioxoaporphine alkaloids, 11-hydroxy-tuberosinone-N-β-D-glucoside 9 (also known as Zhu Sha Lian glucoside; 38) and tuberosinone-N-β-D-glucoside 10 (39). Aristololactam II N-β-D-glucopyranoside 11 (or cepharanone A N-β-D-glucoside) was isolated from Aristolochia clematitis grown in Czechia (40).
BENZOXAZINOID ALKALOID GLUCOSIDES
APORPHINE ALKALOID GLYCOSIDES Aporphine alkaloids form an important group of secondary plant metabolites. They are also derived biogenetically from anthranilic acid. Some of these compounds have been used for many years in traditional medicine for the treatment of various
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Benzoxazinoid acetal glucosides [having 2-hydroxy-2H-1,4benzoxazin-3(4H)-one skeleton] are a unique class of natural products abundant in family of Gramineae, including the major agricultural crops maize, wheat, rye, and wild grasses (41). Also they are found in different species of Acanthaceae (42,43), Ranunculaceae (44), Scrophulariaceae (45), and others. Benzoxazinoids serve as important factors of host plant resistance against microbial diseases and insects and as allelochemicals and endogenous ligands. Interdisciplinary investigations by biologists, biochemists, and chemists have considered how to make agricultural use of the benzoxazinones as natural pesticides. These natural metabolites are not only constituents of a plant defense system but also part of an active allelochemical system used in the competition with other plants.
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The 2-O-β-D-glucopyranosyl-4-hydroxy-7-methoxy-(2H)1,4-benzoxazin-3(4H)-one 12 (alternative name: DIMBOA glucoside) isolated from blue light-illuminated maize (Zea mays) coleoptiles (46) plays the essential role in the phototropism of maize coleoptiles. Compounds 13–16 were obtained from monocotyledonous plants such as maize in their early growth states, which are harvested on a schedule to give optimal yield (47). These compounds have been reported to act as weight loss agents, appetite suppressants, mood enhancers, and adjunctive therapy for arthritis, sleep apnea, fibromyalgia, diabetes, and hyperglycemia. Benzoxazinoid acetal glucosides 15–19 and 7chloro-(2R)-2-O-β-D-glucopyranosyl-2H-1,4-benzoxazin3(4H)-one 21 have been isolated from the aerial parts of Acanthus ilicifolius (48). Benzoxazinoid cyclic hydroxamic acid glucosides 12–15 were identified from the genus Aphelandra (Acanthaceae), e.g., A. fuscopunctata, A. squarrosa, and A. tetragona (49). Dried seeds of Acanthus mollis contain 4% by dry weight of the 2,4-dihydroxy-1,4-benzoxazin-3(4H)-one (DIBOA) glucoside 16 (49). The results obtained showed that in all species the glucosides as well as the hydroxamic acid aglucones were present in the roots, whereas in the aerial plant parts only traces of the glucosides were detected. The phytotoxicity of DIBOA suggests that they might be involved in the allelopathic activity attributed to rye. Chinese woad, Baphicacanthus cusia (= Strobilanthes cusia, Acanthaceae), is an herbaceous plant native to northeast India, Myanmar, Thailand, and the southern part of China. Roots of B. cusia collected from Dinghushan (Guangdong, China) contain two alkaloids, 15 and 16 (50). The chlorocontaining alkaloid glucoside, 7-Cl-DIBOA-Glc 20 as well as 15 and 16 were isolated from the aerial part of Acanthus ebracteatus (51). Compounds 17 and 18 were isolated from Lamium amplexicaule, L. purpureum, and L. garganicum belonging to Lamiaceae family (52).
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ERGOT ALKALOID GLYCOSIDES Ergot alkaloids are one of the pharmacologically most important groups of indole alkaloids (53). These alkaloids are isolated from the dried sclerotium of the fungus Claviceps purpurea (Hypocreaceae) (54,55). This fungus is a parasite on rye, wheat, and other grains. Ingestion of contaminated grain, most often after the grain has been made into bread, causes ergotism, also known as the “Devil’s curse” or “St. Anthony’s fire;” this form of poisoning has been a problem for centuries (53). It is possible that ergot-infected grasses were produced in the first agricultural settlements of Mesopotamia around 9000 B.C., but ergot is thought to have first been mentioned around 600 B.C. by the Assyrians (55). The Roman historian Lucretius (98–55 B.C.) referred to ergotism as Ignis sacer, meaning Holy Fire, which was the name given to ergotism during the Middle Ages, and it was during these times that ergotism occurred frequently. Ergotism can cause convulsions, nausea, and diarrhea in mild forms, and there is some thought that an outbreak of ergotism may have been the cause of the “bewitchings” that led to the Salem witch trials in the United States in 1691. Ergotism has now been recognized as the effects of ingesting a mycotoxin, and ergotism plagues have been eliminated (56,57). However, the alkaloids derived from ergot have assumed new importance for their pharmacological properties, and ergot is produced commercially for the preparation of these alkaloids. Ergot alkaloids are used in a number of therapeutic areas including the treatment of acromegaly, blood pressure regulation, hyperprolactinemia, migraine, cerebral insufficiency, orthostatic circulatory disturbances, postpartum bleeding, Parkinsonism, uterine atonia, and others (58–62). The first glycoside of ergot alkaloids, named elymoclavine-O-β-D-fructoside 22, was isolated from a saprophytic culture of Claviceps sp. strain SD-58 by Floss et al. (63) in 1967. More recently, glycoside 22 and a new elymoclavineO-β-D-fructofuranosyl-(2→1)-O-β-D-fructofuranoside 23 were isolated from saprophytic cultures of strains Claviceps sp. SD-58 and C. purpurea 88 EP grown on a sucrose medium (64). A submerged culture of C. fusiformis supplemented with chanoclavine I produced chanocalvine I O-β-D-fructofuranoside 24 and chanoclavine 1 O-β-D-fructofuranosyl-(2 → 1)-O-β-D-fructofuranoside 25 (65). The glycosides of ergot alkaloids 24–26 obtained by enzymatic synthesis showed strong inhibitory activity on prolactin secretion (26), cytotoxic activity (27), and potent effects against the resistant tumor cell line RAJI (28) (66).
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INDOLE ALKALOID GLYCOSIDES Indole alkaloids constitute the largest group of alkaloids with double ring systems containing an indole ring. They are of interest because of their structures—often extremely complex—and their surprising physiological activities. Most contain a tryptamine unit as a readily distinguishable feature or a modified structure, and tryptamine is a precursor in the biosynthesis of many of these alkaloids. Indole alkaloids and their glycosides have been isolated from marine and terrestrial plants, algae, cyanobacteria, fungi, marine invertebrates (sponges, tunicates, bryozoans, gorgonians, sea hares), some higher animals, and a few mammals including humans. Indole alkaloids show a large spectrum of biological activities (67–69). More than 2000 indole alkaloids have been found
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from the three families of Gentianales: Loganiaceae, Apocynaceae, and Rubiaceae plants. These compounds generally possess characteristic biological activities and many of them are used for medicinal purposes and as lead compounds to develop new synthetic drugs (68,69). Approximately 100 indole bases are now known (more than 20 have been identified in the last decade) that fall into the akuammiline structural category, and the chemistry and pharmacology of these have been recently reviewed (67–69). Some simple indole glycosides have been isolated from plants. Indican 29 is one of the main secondary metabolites in Polygonum tinctorium and is used as precursor for the manufacture of indigo dye (70). It also is found in Celosia argentea from Sierra Leone (71), in Vietnamese Indigofera (Leguminosae family) (72), and other plant species (70). Biosynthesis of indican 29 and of its indoxyl derivatives was recently described (70). The two precursors of indigo in the woad plant, Isatis tinctoria, were quantified by a new spectrophotometric method involving the formation of a red adduct from indoxyl and rhodanine (73). In young leaves, approximately 24% of the dry weight the indoxyl derivatives, indoxyl-3-(5-ketogluconate): indoxyl 3-O-β-D-glucoside (indican 29) and isatan B 31, and in the ratio of approximately 3:1. Glucoindican (calanthoside A) 30 and a novel indole S,O-bisdesmoside 32 (calanthoside B) were isolated from two Oriental orchids, Calanthe discolor and C. liukiuensis, together with calaphenanthrenol, calaliukiuenoside, and the known bioactive alkaloids tryptanthrin, indirubin, and isatin (74,75). Furthermore, enzymic hydrolysis of calanthoside 32 was found to produce tryptanthrin as the main product, whereas indirubin and isatin were obtained by acid hydrolysis of calanthoside. Three new indole alkaloids, including one glycoside, named bruceolline F 33, were isolated from the root wood of Brucea mollis var. tonkinensis (76). 5-(β-D-Glucopyranosyloxy)indole-3-acetic acid 34 was isolated from quackgrass (Agropyron repens) (77). Indole-3methanol-β-D-glucoside 35 and indole-3-carboxylic acid-βD-glucoside 36 are products of indole-3-acetic acid degradation in wheat leaf segments, and were isolated from leaves of the members of the Gramineae family (78). A new metabolite of indole-3-acetic acid was extracted from corn (Zea mays) seedlings and characterized as the 7-O-β-D-glucopyranoside of 7-hydroxy-2-oxoindole-3-acetic acid 37 (79). The results and prior work demonstrated the following catabolic route for indole-3-acetic acid in Z. mays: indole-3-acetic → 2-oxoindole-3-acetic acid → 7-hydroxy-2-oxoindole-3-acetic acid → 7-hydroxy-2-oxoindole-3-acetic acid glucoside.
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rugosporus (85). Pyrroindomycins possess potent antimicrobial activities against methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococci. Pyrroindomycins 43 and 44 are the first natural products that contain the highly unsaturated pyrroloindole moiety.
Microorganisms produce some simple indole glycosides. New indole nucleosides kahakamides A 38 and B 39 were isolated from the actinomycete Nocardiopsis dassonvillei, obtained from a shallow water sediment sample collected on the island of Kauai, Hawaii (80). Compounds 38 and 39 are related to the neosidomycin 40 antibiotics, a group of rare indole-N-glycosides; and 38 exhibited antimicrobial activity toward the Gram positive bacterium Bacillus subtilis. Neosidomycin 40, a known antibiotic, was isolated in 1979 from a fermentation broth of Streptomyces hygroscopicus by Furuta et al. (81). Antiviral antibiotic SF-2140 41 was obtained from the broth of Actinomadura albolutea (Nocardiaceae), which was isolated from soil. It showed antiviral and weak antibacterial activity against Gram-negative and Gram-positive bacteria (82,83). Two novel glycoconjugates, ethyl indole-3-lactate-O-β-D-glucopyranoside 42 and pmenth-1-ene-8,9-diol-9-β-D-glucopyranoside have been detected in Riesling wine (84). Unusual pyrroindomycins A 43 and B 44 were isolated from fermentations of culture LL-42D005, a strain of Streptomyces
Rare spiro oxindole alkaloid glycosides isomitraphyllic acid(16–1)-β-D-gluco-pyranoside 45 and mitraphyllic acid-(16–1)β-D-glucopyranoside 46 were isolated from the leaves of Uncaria sinensis (86). A new glycosidic indole alkaloid, echitamidine-N-oxide 19-O-β-D-glucopyranoside 47, was isolated from the trunk bark of Alstonia scholaris collected in Timor, Indonesia (87). Lyaloside 48, a monoterpenoid glucoindole alkaloid, was isolated from the leaves of Palicourea adusta together with a mixture of its hydroxycinnamic acid derivatives, (E)-O-(6′)cinnamoyl-4″-hydroxy-3″-methoxy-lyaloside 49 and (E)-O-(6′)cinnamoyl-4″-hydroxy-3″,5″-dimethoxy-lyaloside 50; these were separated by HPLC (88). From the root-wood of Brucea mollis var. tonkinensis collected in China have been isolated bruceolline A 51, bruceolline B 53 (89), and bruceolline C 52 (90).
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leaves of Palicourea marcgravii (Rubiaceae) collected in Brazil (94), and extraction of leaves from the Australian tree Ophiorrhiza acuminata has yielded harman, lyalosidic acid, and palicoside 56 (95). Two indolic alkaloidal glucosides named naucleoside 57 and nauclecosidine 58 were isolated from the polar fraction of the stems of Nauclea officinalis (96). An unusual type of indole alkaloids, ophiorines A 59 and 60, was found in the Rubiaceous plants, Ophiorrhiza japonica and O. kuroiwai (97).
Oleander [Hunteria zeylanica (Apocynaceae)] grows in Southern China and Thailand, and its leaves are used externally for the treatment of wounds and cuts. An alkaloid extracted from the leaves of H. zeylanica inhibited a glycine-induced chloride current using a receptor expression model of Xenopus oocytes (91). New glycosidic indole alkaloids, hunterioside 54 and hunterioside B 55, were isolated from the nBuOH fraction of the ethanol extracts of the stem bark of H. zeylanica collected in south Thailand (92), and more recently hunterioside B 55 was isolated from same tree (93). An indole alkaloid glucoside named palicoside 56 was isolated from the
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Neonauclea sessilifolia (= Nauclea sericea), which belongs to the Rubiaceae, grows in Southeast Asia and contains many bioactive compounds. Three novel indole alkaloid glycosides, neonaucleosides A 61, B 62, C 63, and rhynchophine 64 were isolated from the dried roots of Neonauclea sessilifolia (98). Strictosamide 65, which has antitumor activity, was isolated from the leaves of Nauclea orientalis (99) and from leaves of Sarcocephalus latifolius (100).
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eases. The occurrence of two new gluco indole alkaloids isolated from the bark of N. diderrichii—cadambine acid 70 and 3α-5α-tetrahydro-deoxycordifoline lactam 71—has been reported (106). Plants of the pantropical genus Uncaria have found widespread use in traditional medicine. Uncaria species are climbing vines with claw-like thorns (hooks). Some indole alkaloid glycosides have been isolated from this genus, including the lyaloside 48, rhynchophine 64, strictosamide 65, 3β-dihydrocadambine 72, 3β-isodihydrocadambine 73, 3,4-dehydro-5carboxystrictosidine 74, carboxystrictosidine 75, and glabratine 76 (107,108).
A new β-carboline-type alkaloidal glycoside, glucodichotomine B 66, with antiallergic activities was isolated from a Chinese natural medicine, i.e., the roots of Stellaria dichotoma var. lanceolata (101). The plant Psychotria correae (syn. Cephaelis correae) is only described from the Cordilleras de Guanacaste and Tilarfin and from the Province of Coclé in Panama, where it grows as a small tree (102). Various Cephaelis species are used in the traditional medicine of Middle America, e.g., against dizziness, hallucination, dementia, and rubella (103). In the European Pharmacopoeia, preparations of C. ipecacuanha (=Psychotria ipecacuanha) are described as emetics and expectorants, and emetine, a major alkaloid from Ipecacuanhae radix, is used as an amoebicide (104). From extracts of the leaves and/or the roots of Psychotria correae, isodolichantoside 67, the new βcarboline-type alkaloid correantoside 68, and 10-hydroxycorreantoside 69 were isolated (105). Nauclea diderrichii, belonging to the Rubiaceae family, grows in western and central Africa. Decoctions of the bark are widely used in folk medicine for the treatment of tropical dis-
A chlorinated alkaloid-type antibiotic, rebeccamycin 77, which is produced by Streptomycetes species (109), inhibits the growth of human lung adenocarcinoma cells and produces single strand breaks in their DNA. A related antibiotic without chlorine, staurosporine 78, produced by Streptomyces staurosporeus, was reported to have antifungal, hypotensive, and
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antitumor activities (110). A novel brominated analog of rebeccamycin, 79, is produced by Saccharothrix aerocolonigenes ATCC 39243 when grown in a defined medium containing 0.05% KBr (111). Bromorebeccamycin 79 and rebeccamycin 77 have a similar potency and activity against P388 leukemia in the murine model. Rebeccamycin 77 also was isolated from the cyanobacterium Nocardia aerocoligenes (112) and is a well-known topoisomerase I inhibitor. Rebeccamycin analogs were prepared either by semisynthesis from the natural metabolite or by total synthesis. Different families of rebeccamycin analogs were obtained by modifications at the imide heterocycle, dechlorination, and substitutions on the indole moieties, modifications of the sugar residue, construction of dimers, coupling of the sugar unit to the second indole nitrogen, changing of the indolo[2,3-a]carbazole skeleton to indolo[2,3-c]carbazole, and replacement of one or both indole moieties by 7-azaindole units. The biological activities of the rebeccamycin analogs were recently reviewed (113). According to their chemical structure, the analogs can inhibit topoisomerase I and/or kinases. From the structure–activity relationships, some important rules were established. Several compounds exhibit stronger antiproliferative activities than the natural metabolite with IC50 values in the nanomolar range. Some analogs, especially those possessing azaindole moieties, are much more selective than rebeccamycin toward the tumor cell lines tested (114). A new indolo[3,2-b]quinoline alkaloid glycoside, jusbetonin 80, has been isolated from the leaves of Justicia betonica (115). This compound is the first example of a glycosylated indolo[3,2-b]quinoline alkaloid. Fifteen new N-glycosides of indolo[2,3-a]carbazoles, designated tjipanazoles A1, A2, B, C1, C2, C3, C4, D, E, F1, F2, G1, G2, I, and J, have been identified and are produced by the cyanobacterium Tolypothrix tjipanasensis (116). Tjipanazoles A1 81 and A2 82, chloro-containing alkaloids, showed high antifungal activity (116). Analogs of antifungal tjipanazoles 82–85 were obtained by semisynthesis from rebeccamycin, an antitumor antibiotic isolated from cultures of Saccharothrix aerocolonigenes (117). The antiproliferative activities of the new compounds were evaluated in vitro against nine tumor cell lines. The effect on the cell cycle of murine leukemia L1210 cells was examined, and the antimicrobial activities against two Gram-positive bacteria, a Gram-negative bacterium, and a yeast were determined. The inhibitory properties toward four kinases and toward topoisomerase I were evaluated. The most cytotoxic compound in the series was a dinitro derivative 85 characterized as a potent topoisomerase I inhibitor.
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Betalains are water-soluble nitrogen-containing pigments and include the red-violet betacyanins and the yellow betaxanthins (118). Betalains accumulate in flowers, fruits, and occasionally in vegetative tissues of plants belonging to most fami-
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lies of the Caryophyllales (119). Betalains and betacyanins show antioxidant and radical-scavenging activities (120). Betanin 86 was discovered more than 45 years ago in the root of beets (Beta vulgaris), which are native to the Mediterranean countries (121). Phyllocactin (6′-O-malonyl-betanin) 87 is a well-known pigment that is isolated from flowers and fruits of the Cactaceae family (122). Red-colored plants of the family Amaranthaceae were recognized as a rich source of diverse and unique betacyanins. Gomphrenin I 88, II 91 and 92 and other colored pigments were isolated from the Amaranthaceae family (123). Acylated betacyanins were distributed among 11 species of 6 genera, with the highest proportion occurring in Iresine herbstii (79.6%) and Gomphrena globosa (68.4%). Lampranthins I 89 and II 90 were isolated from Beta vulgaris (124) and Phytolacca americana (125). Acylated pigment 93, which seems to be the first betacyanin identified containing both an aliphatic and an aromatic (hydroxycinnamoyl) acyl residue, was found in Beta vulgaris (124). The minor pigment 2-descarboxy-betanidin 94 was found in the flowers of Carpobrotus acinaciformis (Aizoaceae) and the more complex compound 95 was isolated from Bougainvillea glabra (126). Fuller information on the chemistry of betalains and the betacyanin types of glycosidic alkaloids can be foundind in a recent review by Strack and coworkers (127).
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ENEDIYNE ALKALOIDAL ANTIBIOTICS The enediyne family of alkaloidal antibiotics is characterized structurally by an enediyne core unit consisting of two acetylenic groups conjugated to a double bond or incipient double bond within a 9- or 10-membered ring (128–130). These newly discovered enediyne alkaloidal antibiotics combined unprecedented molecular structures with striking biological activities. A remarkable mechanism of action recently was proposed for these molecules to account for their phenomenal biological profiles (128–130). A few glycosides of the enediyne nitrogenous antibiotics also have been discovered. Three new compounds of the enediyne antitumor antibiotics, shishijimicins A 96, B, and C, have been isolated from the marine ascidian Didemnum proliferum (131). They encompass a novel sugar component, which is a conjugation product of a hexose and a β-carboline, attached to the calicheamicinone aglycon. Shishijimicins showed extremely potent cytotoxicity against HeLa cells, with IC50 values of 1.8–6.9 pM. Kedarcidin 97, one of the most complex and reactive of the natural enediyne antitumor agents, was isolated from the culture broth of a novel actinomycete strain L585–6 (ATCC 53650) (132). In vivo studies showed this natural metabolite to be extremely active against P388 leukemia and B16 melanoma. Cytotoxicity assays on the HCT116 colon carcinoma cell line result in an IC50 value of 1 nM. In vitro experiments with ΦX174, pM2 DNA, and 32P-end-labeled restriction fragments demonstrate that this chromophore binds and cleaves duplex DNA with remarkable sequence selectivity, producing single-strand breaks (133). Lipids, Vol. 40, no. 11 (2005)
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GLYCOSIDIC LUPINE ALKALOIDS
The chlorinated enediyne nitrogenous compound C-1027, 98, a potent antitumor agent with a previously undescribed molecular architecture and mode of action, has been isolated from Streptomyces globisporus (134). Antibiotic C-1027, a macromolecular peptide with high cytotoxicity to cultured cancer cells, was conjugated to monoclonal antibody 3A5 and its Fab (immunoglobulin) fragment separately using SPDP (N-succinimidyl 3-[2-pyridyldithio]-propionamido), widely used in immunochemistry, as the linker agent. McAb 3A5, identified as IgG1, was directed against human hepatoma BEL-7402 cells (135). The nonchlorinated analog of C-1027, 99, also was isolated from S. globisporus (136). Maduropeptin 100, a complex of new macromolecular antitumor antibiotics, is a metabolite of Actinomadura madurae H710–49. The active components, maduropeptins A1, A2, and B, are acidic chromopeptides with M.W. of around 22,500 and are composed of 14 types of amino acids and an unstable chromophore. The antibiotics are active in vitro against Gram-positive bacteria and are highly cytotoxic to tumor cells. They produced significant prolongation of survival time of mice implanted with P388 leukemia and B16 melanoma (137).
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Lupines are widely distributed across the western United States and Canada and there are many species. Most are perennial and produce a hard seed that is viable for many years. Over 100 different alkaloids have been identified in these plants, each with differing biological activities. The types and concentrations of these alkaloids vary between the species and between collections of the same species. Lupines with high alkaloid content are termed “alkaloid-rich” or “bitter” lupines; this terminology includes the majority of the western range lupines. “Alkaloidpoor” or “sweet” lupines are used for animal and human feed (138). The majority of the more than 20 alkaloids isolated from Lupinus are quinolizidine alkaloids, with some piperidine and other components known lupanine and lupinine. The teratogenic alkaloid anagyrine is highest in the seeds, pods, and young leaves. The quinolizidine alkaloids implicated in lupine poisoning are found mostly in the seeds and pods. Large quantities of the plant material must be ingested in a short time to cause death. The alkaloids remain after drying, so that hay containing sufficient quantities of lupine can be toxic. General symptoms of lupine poisoning include dizziness and incoordination. Lupine seeds can be made edible by soaking and boiling the seeds in several changes of water (139). Several species of lupine (Lupinus spp.) are poisonous to livestock, producing death in sheep and “crooked calf disease” in cattle (140). Quinolizidine and indolizidine alkaloids and their analogs
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have been isolated from microbial, plant and animal sources, including ants, amphibians and beetles (141). A few glycosidic lupine alkaloids have been isolated from some plant species. The (−)-(trans-4′-α-L-rhamnosyloxycinnamoyl)epilupinine 101 and its 3′-methoxy derivative 102 were isolated from the aerial parts of Lupinus varius (142). Glycosidic alkaloids 102 and 104 were isolated from the aerial parts of L. hirsutus (143); 103 and 105 were isolated from L. luteus (144).
PIPERIDINE, PYRIDINE, PYRROLIDINE, AND PYRROLIZIDINE ALKALOID GLYCOSIDES Both pyridine and piperidine alkaloids are six-membered Nheterocycles, the former being unsaturated and the latter saturated. These groups of compounds have been known for a long time (145). The best-known piperidine alkaloid, coniine, is a poison derived from the poison hemlock, Conium maculatum. Socrates is reputed to have been killed with a poison hemlock extract. Other well-known piperidine alkaloids include cocaine, strychnine, and atropine. Cocaine was first isolated from the plant Erythroxylon coca by the German chemist Friedrich Gaedcke in 1855 and named “erythroxyline.” The poisonous alkaloid strychnine was the first alkaloid to be identified in
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plants of the genus Strychnos (family Loganiaceae). Cocaine is an example of a tropane type of pyrrolidine alkaloid in which the N-heterocycle is derived from L-ornithine, an amino acid derived from glutamate. Strychnine was first discovered by French chemist Joseph-Bienaime Caenoiu and Pierre-Joseph Pelletier in 1818. Atropine, commonly known as Deadly Nightshade, was isolated from belladonna (Atropa belladonna) in 1831, and the use of a water-soluble salt (atropine methonitrate) was introduced into ophthalmology in 1902. A large number of piperidine-based alkaloids occur in neotropical poison frogs (Dendrobatidae), mainly as trace compounds (146). The well-known pyridine alkaloid, nicotine, and the piperidine-pyridine alkaloid, anabasine (or neonicotine), are both found in plants from the genus Nicotiana, which includes cultivated, wild, and tree tobacco (147,148). Nicotine was isolated from leaves of tobacco (N. tabacum) in 1828, and anabasine was isolated from and N. glauca in 1929 (148). Pyrrolidine alkaloids have been found in many species of the three major plant families Boraginaceae, Compositae, and Fabaceae, and are produced as well by some fungi and microorganisms. Hygrine and cuscohygrine are well-known simple pyrrolidine alkaloids isolated from natural sources (147). Alkaloids mimicking sugars in size and shape are now believed to be widespread in plants and microorganisms. Iminosugars are monosaccharide analogs in which the ring oxygen has been replaced by an imino group. Such iminosugars inhibit the glycosidases involved in a wide range of important biological processes because of their structural resemblance to the sugar moiety of the natural substrate and the presence of the nitrogen atom mimicking the positive charge of the glycosyl cation intermediate in the enzyme-catalyzed glycoside hydrolysis. These iminosugars and their derivatives are arousing considerable attention as potential therapeutic agents and show antiviral, anticancer, antidiabetic, nematicidal, and other activities (149). The taxonomic distribution of iminosugars in plants and their biological activities has recently been reviewed (150). Three simple iminosugars, 4-O-β-D-mannoside 106, 4-O-βD-mannobioside 107, and 4-O-D-glucopyranosyl-1-deoxynojirimycin 108, have been isolated from the bulbs of Scilla sibirica (151). Elongation of the β-mannopyranosyl chain of 106 to give 107 enhanced the inhibitory activity of α-L-fucosidase, βglucosidase, and β-galactosidase. A novel piperidine-type alkaloid, 2-β-D-glucopyranosyl-2undecyl-3,5-dihydroxy-6-carboxypiperidine 109, was isolated from Cyclamen coum (152), and secoiridoid glucoside LA-9 110 was found in an extract from fruits of Ligustrum vulgare (153). The 3-hydroxy-5-(hydroxymethyl)-4-(methoxymethyl)-2methylpyridine glucoside 111 was isolated from seeds of Albizzia lucida (154). Caerulomycin D 112, a new metabolite from Streptomyces caeruleus, possessed a novel ring system (155). Antitumor agents BE-14324 113 and BE-14324A 114 were isolated from Streptomyces spp. or their mutants (156). IC50 values of 114 on proliferation of mouse leukemia cell P388 (P388/S), its vincristine-resistant mutant P388/V, and adriamycin-resistant mutant P388/A were 1.0, 0.7, and 1.0 µg/mL, respectively.
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pyrrolidine alkaloid 1,4-dideoxy-1,4-imino-D-arabinitol 120 has been identified in the leaves of bluebells (Hyacinthoides nonscripta) (160). The new glycoside named pisatoside 121 was isolated from Pisum sativum (161). A novel acaricide, gualamycin 122, was isolated from the culture broth of Streptomyces sp. NK11687 (162).
The pyrrolidine alkaloids broussonetine A 115, Q 116, B 117, K 118, and L 119 were isolated from the branches of Broussonetia kazinoki Sieb (Moraceae) (157–159). ICompound 116 inhibited β-glucosidase, β-galactosidase, and βmannosidase (157), whereas compounds 118 and 119 inhibited β-glucosidase, β-galactosidase, β-mannosidase (158); and 115 and 117 showed a strong inhibition of β-galactosidase and α-mannosidase (159). The glycosidase-inhibiting
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A few pyrrolizidine alkaloid glycosides have been isolated from plant species. The highly oxygenated pyrrolizidine casuarine, its 6-O-α-D-glucopyranoside 123, and 1-epi-australine 2-O-β-D-glucopyranoside 124 were isolated from pods of the Australian Alexa leiopetala (Leguminosae) (163); and a glucosidic alkaloid malaxin 125 was isolated from orchid Malaxis congesta (164).
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GLYCOSIDIC QUINOLINE AND ISOQUINOLINE ALKALOIDS
A few tropane alkaloid glycosides from natural sources have been discovered. They have the 8-azabicyclo[3,2,1]octane nucleus, and their analogs are important for medical treatment (165). Some of the most potent tropane alkaloids are atropine, hyoscyamine, and scopolamine (166–168). These alkaloids affect the central nervous system, including nerve cells of the brain and spinal cord that control many direct body functions and the behavior of humans (169,170). Tropane alkaloids are found in many other poisonous plants of the nightshade family (Solanaceae), including henbane (Hyoscyamus niger), pituri (Duboisia hopwoodii), deadly datura (Datura and Brugmansia spp.), mandrake (Mandragora officinarum), and “beautiful lady” (Atropa belladonna), all of which were used extensively in folk medicines (170). The occurrence and distribution of tropane and biogenetically related pyrrolidine alkaloids in 18 Merremia species of paleo-, neo-, and pantropical occurrence have been studied, and two tropane alkaloid glycosides 126 and 127 have been isolated (166). Calystegine B1 128 was isolated from Nicandra physalodes fruits (Solanaceae) (171) and from Hyoscyamus niger (172).
Quinoline (or benzo[b]pyridine) is a two-ring aromatic compound structurally analogous to naphthalene but having a nitrogen atom in place of a carbon atom adjacent to the ring fusion. Quinoline (cinchona) alkaloids are named from the quinoline found in the cinchona plant (Cinchona ledgeriana) and belong to the quinoline alkaloids developed in the nucleus from L-tryptophan. Quinoline alkaloids are widely used in the pharmaceutical and chemical industry (173,174). Furthermore quinine is also an important bitter agent in the beverage (soft drink) industry. Quinine has been a valuable antimalarial agent and muscle relaxant compound for more than 100 years; its isomer quinidine has been used as a cardiac depressant (antiarrhythmic agent) (175,176). Quinine is an optical isomer of quinidine. Quinoline and isoquinoline alkaloids represent one of the two largest groups of alkaloids (the other being indole alkaloids and their derivatives) and have been found in species of cyanobacteria, fungi, marine invertebrates, and amphibians (11,177–179). The lipid extract of the marine cyanobacterium Lyngbya majuscula collected from Curaçao afforded two quinoline alkaloids in low yield, and one of them was glycoside 129 (180). Two new glycosidic quinoline alkaloids, 130 and 131, were isolated from the 1-butanol extract of the aerial parts of Echinops gmelinii (Compositae) (181). The aerial part of Haplophyllum perforatum yielded a new glycoalkaloid, haplosinine 132 as well as 133 and 131 (182). The anticancer alkaloid glycosides camptothecin 20-O-βglucoside 134 and deoxypumilioside 135 have been isolated
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from Mostuea brunonis (183). The L-(+)-N-methylcoclaurine D-xyloside (latericine) 136 was isolated from the flowering plant Papaver californicum (184), and the similar alkaloid veronamine 137 was obtained from Thalictrum fendleri (185).
Alangiside 138 and O-methyl-alangiside 143 were isolated from Alangium lamarckii (186); demethylisoalangiside 139 and 2,11-bisglucoside 140 were obtained from the dried roots of Cephaelis acuminata (187). The 6-141 and 3′-O-β-D-glucopyranosyl-alangiside 142 were isolated from dried fruits of A. lamarckii (188). The acylated tetrahydroisoquinoline-monoterpene glucosides, 2′-O-trans-feruloyl-demethyl-alangiside 144 and their analogs 145, 146, and 147 were isolated from the fruits of A. lamarckii (189).
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Five tetrahydroisoquinolinemonoterpene (THIQM) glycosides—6′′-O-α-D-gluco-pyranosyl-ipecoside 148, (4R)-4-hydroxyipecoside 150, (4R)-151, and (4S)-4-hydroxy-6,7-di-Omethyl-ipecosides 152 and 153—were isolated from Cephaelis acuminata (187), and 148 was isolated from Alangium lamarckii (190). Two new glucosides, 154 and 155, which possess structures different from any other known THIQM glucosides, were isolated from the fruits of A. lamarckii (191). Four new N-acylated THIQM glucosides, trans-cephaloside 156, cis-
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cephaloside 157, 6-O-methyl-trans-cephaloside 158. and 6-Omethyl-cis-cephaloside 159, were isolated from the roots of Cephaelis ipecacuanha (192). Dauricoside 160, a new glycosidal alkaloid, was isolated from the rhizomes of Menispermum dauricum (193). Isolated compound 160 inhibited bloodplatelet aggregation induced by ADP. Ipecac grows in the rain forests of Brazil and other parts of South and Central America. It is also cultivated to a small degree in India and Southeast Asia. Ipecac roots are used medicinally, and ipecac’s major constituents are the alkaloids emetine and cephaline (194). The alkaloids have several important actions, including activation of brain centers that can induce vomiting, inhibition of the sympathetic nervous system, and inhibition of protein synthesis (195,196). Ipecac syrup is commonly used as a remedy for poisoning, to be taken following ingestion of toxic but noncaustic substances. Unusual ipecac alkaloids 161–163 were identified from extract of the dried roots of Cephaelis acuminata (197).
STEROIDAL GLYCOALKALOIDS Steroidal glycoalkaloids (SGA) have been found in several vegetables: potatoes (Solanum tuberosum), tomatoes (Lycopersicon esculentum), sugar beets (Beta vulgaris) and fruits: apples (genus Malus), cherries (genus Prunus) and red bell peppers (Capsicum annuum), but mainly in the plants of the Nightshade family, particularly the potato—an everyday food for many people for more than 2000 years (198–202). Potatoes are an essential component of the diet of many humans and animals and are thus a potential source of food poisoning (199,202). The steroidal alkaloids are teratogenic, embryotoxic, and genotoxic (200,203,204) compounds with potent permeabilizing properties toward mitochondrial membranes. Glycoalkaloids are plant steroids with a carbohydrate side chain attached to the 3-OH position, e.g., α-solanine and α-
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chaconine from potatoes, α-tomatine and dehydrotomatine from tomatoes (199,200,209). Recent research has found that SGA are responsible for increasing the risk of brain, breast, lung and thyroid cancer (198,205–208). Glycoalkalois are toxic to humans; the lethal dose is 3–6 mg per kg of body mass. Structures of potato glycoalkaloids of α-solanine 164-167, and of α-chaconine 168-171 were identified from the Solanum tuberosum species (199,200,209). Structures of tomato glycoalkaloids 172-175 isolated from Lycopersicon esculentum species (199,200,209) also have been determined.
Some new glycoalkaloids have been isolated from different plant species and their structures elucidated by physical and chemical methods. The glycoalkaloid α-solasonine 176, extracted from Australian Solanum sodomaeum, showed antineoplastic activity against Sarcoma 180 in mice (ED50 was 9 mg/kg) (210). Bioassay-guided fractionation of the methanol extract of the root bark of S. arundo led to the isolation of a steroidal glycoalkaloid, designated arudonine, 177 (211). This steroidal glycoalkaloid inhibited the growth of lettuce seedlings (Lactuca sativa). Glycoalkaloid 178 was extracted from the leaves of S. lyratum and the seeds of Medicago hispida and Agrostemma githago collected in Anhui Province of China (212). The unusual glycoalkaloid 179 has been isolated from the rhizomes of Veratrum album (Liliaceae) (213). Major novel steroidal alkaloid glycosides, named esculeoside A 180 and esculeoside B 181, were first isolated from the pink color-type and the red color-type, respectively, of the ripe tomato fruits of Lycopersicon esculentum (213). The steroidal alkaloid glycosides, lycoperoside A 182, B 183, C 184, and D 185 were isolated from tomato fruits (L. esculentum) (214). Lipids, Vol. 40, no. 11 (2005)
Various chemical constituents isolated from different Solanum species include alkaloids, phenolics, flavonoids, sterols, saponins, and their glycosides were reviewed (215). Notable biological activities reported from the various species are the antioxidant activity of S. tuberosum and S. lyratum, antifertility activity of S. xanthocarpum, antiulcerogenic activity of S. nigrum, antineoplastic activity of S. nigrum, S. dulcamara, S. capsicastrum, S. trilobatum, S. lyratum and S. indicum, and the hepatoprotective activity of S. lyratum, S. capsicastrum, S. nigrum, S. indicum, and S. incanum.
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192 and vicine 193. These glycosides hamper the development of fava beans as a worldwide food and feed crop because they cause a disease called favism in people who have an inherited absence of the enzyme glucose-6-phosphate dehydrogenase in their red blood cells (217,218). Two monoterpene alkaloid glucosides loxylostosidine A 194 and B 195 were isolated from Lonicera xylosteum [European fly honeysuckle; Caprifoliaceae (219)]. Xylostosidine 196 has a similar structure and also was isolated from this plant species (220). American dwarf honeysuckle (L. xylosteum) was found in the states of Connecticut, Massachusetts, Michigan, Missouri, North Carolina, New Jersey, New York, and Vermont in the United States; the presence of alkaloids in North American L. xylosteum has not been investigated. The alkaloid isorheagenine glycoside 197 was isolated from Papaver rhoeas (221).
MISCELLANEOUS ALKALOID GLYCOSIDES Fenazines 186-191 are a rare class of glycosidic alkaloids produced by a filamentous bacterium (isolate CNB-253, an unknown Streptomyces sp.) that was isolated from the shallow sediments in Bodega Bay (California) (216). Isolated compounds showed antibacterial activity. Fava beans, Vicia faba, are a common human food in the Mediterranean regions of Europe. Their potential as a protein supplement for livestock is being explored in the United States and Canada. Fava beans contain the toxic glycosides covicine
Three new alkaloids, daphcalycinosidines A 198, B 199, and C 200 and daphcalycic acid have been isolated from the seeds of Daphniphyllum calycinum (222,223).
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Neosurugatoxin 201, which contains two sugars (myoinositol and xylopyranose) and bromine in its chemical structure, was isolated from toxic Japanese ivory shell, Babylonia japonica (224). Compound 201 was unstable in alkaline solution, and at 1 × 10−9 g/mL 201 inhibited the contractile response in isolated guinea pig ileum induced by 3 × 10−5 g nicotine/mL. Compound 201 also evoked mydriasis in mice at a minimum dose of 3 mg/g. The structurally related compounds prosurugatoxins 202 and surugatoxin 203 are also produced by Japanese ivory shell, and poisoning cases have been reported in Niigata, Fukui, and Shizuoka prefectures.
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The methanolic extract of the stem bark of Schumanniophyton magnificum and schumanniofoside 204, a chromone alkaloidal glycoside isolated from it, reduced the lethal effect of black cobra (Naja melanoleuca) venom in mice. This effect is greatest when the venom is mixed and incubated with the extract of schumanniofoside. It is thought that the mode of action is by oxidative inactivation of the venom (225). In 1907, Bourquelot and Herissey (226) discovered bakankosine 205 in seeds of the Madagascarean tropical woody plant Strychnos vacacua (family Loganiaceae, order Gentianales). More recently, the structure of bakankosine 205 was confirmed by synthesis (227). Hypodermic injections of 0.28 g of this glycoside per kg animal were not toxic to guinea pigs. Veratramine 3-glucoside 206 and isorubijervosine 207 have been isolated from Veratrum eschscholtzii (228), and 207 was
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isolated from V. lobelianum from Uzbekistan (229). The blue pigment trichotomine and the glycoside derivatives trichotomine G1 208, and N,N′-diglucopyranosyltrichotomine 209 were isolated from Clerodendron trichotomum fruits (230).
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in seed-bearing plants and in berries, bark, leaves, fruits, and roots. Many alkaloids of medical importance occur in the invertebrate and plant kingdoms, and some have been synthesized. Alkaloids include the nightshade poisons, codeine, cocaine, curare, hemlock, nicotine, strychnine—a large range of dangerous chemicals. Green potato skin is full of them, and tomatoes were considered extremely poisonous in the 19th century by Europeans because of their relationship with the nightshade family until shown otherwise. Native Americans knew otherwise, of course. Alkaloids are often potent as medicines because of their high interactivity with the human body chemistry. They have a long history as local medicines known to the native peopleIt is only fairly recently that, with the ability to detail the chemistry of these substances, the pharmaceutical industry has been examining the many plants, and indeed some invertebrates, amphibian, and animals, for their alkaloids. The discovery of new sources of known biologically active alkaloids and of new alkaloids as well as their glycosides in new and already examined sources together with new structural and synthetic studies calls for periodic reviews of these important compounds. REFERENCES
SUMMARY Alkaloids are a class of compounds that typically contain nitrogen and have complex ring structures. They occur in nature
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Lipids, Vol. 40, no. 11 (2005)
