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Alkaloid - an overview | ScienceDirect Topics
Chapters and Articles You might find these chapters and articles relevant to this topic. 14.1 Introduction Alkaloids are one of the most diverse groups of secondary metabolites found in plants, marine organisms, and microorganisms. They have an array of struct
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Chapters and Articles
You might find these chapters and articles relevant to this topic.
14.1 Introduction
Alkaloids are one of the most diverse groups of secondary metabolites found in plants, marine organisms, and microorganisms. They have an array of structural types, biosynthetic pathways, and pharmacological activities. Sertuerner in 1806 laid the foundation of alkaloid chemistry with the report of the isolation of semi-purified morphine from opium. Since then, more than 20,000 alkaloids have been isolated from natural sources. “Alkaloid” simply means alkali-like; however, there are several definitions that describe the term alkaloid. The well-accepted definition is “alkaloids are naturally occurring, nitrogen-containing organic compounds with the exception of amino acids, peptides, purines and derivatives, amino sugars, and antibiotics.” The nitrogen atom remains as part of a heterocyclic ring, with some exceptions. Based on biogenesis, alkaloids are broadly classified as the true alkaloids and the pseudo-alkaloids. The majority of alkaloids are true alkaloids, which are derived from α-amino acid precursors. Other alkaloids, such as terpenes and steroids, are called pseudo-alkaloids because a relatively late amination process occurs in a transamination reaction by donating a nitrogen atom from an amino acid source.
14.1.1 Occurrence
Alkaloids have been well known for their biological activity since the beginning of human civilization. They were used to cure disease and at the tip of weapons as toxins. Alkaloids are widely distributed in higher plants such as those of the families Apocyanaceae, Ranunculaceae, Papaveraceae, Solanaceae, and Rutaceae. They are distributed in different parts of the plants, examples being nicotine in the leaves, cinchonine and quinine in bark, strychnine and nibidine in seeds, and rawelfinine and glycyrrhizin in roots. On average, the maximum amount of alkaloids are contained in leaves, followed by fruit/seeds, root, and bark. In recent years, alkaloids have also been reported in lower plants, insects, marine organisms, and microorganisms. The occurrences of such compounds are listed in Tables 14.1 and 14.2.
Table 14.1. Known Alkaloids Identified in African Plants
| Compounds and Ring Type | Plants (Family) | Pharmacological Activities |
|---|---|---|
| Acridone | ||
| Arborinine (1) | Teclea gerrardii I.Verd. (Rutaceae) [1] | Antimicrobial [2,3], anti-inflammatory, and antioxidant [4,5] |
| 1,3-Dimethoxy-N-methylacridone (2) | T. gerrardii I.Verd. (Rutaceae) [1] | Antimicrobial [1] |
| Melicopicine (3) | T. gerrardii I.Verd. (Toddaloideae: Rutaceae) [6] | Antiplasmodial [2] |
| 1,2,3-Trimethoxy-N-methylacridone (4) | T. gerrardii I.Verd. (Toddaloideae: Rutaceae) [6] | – |
| 1-Hydroxy-3-methoxy-10-methyl-9-acridone (5) | Zanthoxylum leprieurii Guill. et Perr. (Rutaceae) [4] | Cytotoxicity [4] |
| 1,3-Dihydroxy-2-methoxy-10-methyl-9-acridone (6) | Z. leprieurii Guill. et Perr. (Rutaceae) [4] | – |
| 1,2-Dihydroxy-3-methoxy-10-methyl-9-acridone (7) | Z. leprieurii Guill. et Perr. (Rutaceae) [4] | – |
| 1-Hydroxy-2,3-dimethoxy-9-acridone (8) | Z. leprieurii Guill. et Perr. (Rutaceae) [4] | – |
| Evoxanthine (9) | T. gerrardii I.Verd. (Rutaceae) [1] | – |
| Acridone precursor | ||
| Tecleanone (10) | T. gerrardii I.Verd. (Rutaceae) [1] | – |
| Belladine | ||
| Belladine (11) | Nerine filifolia Baker (Amaryllidaceae) [7] | – |
| Benzo[c]phenanthridine | ||
| Chelerythrine (12) | Zanthoxylum davyi (I.Verd.) Waterm. (Rutaceae) [8], Zanthoxylum lemairei (Rutaceae) [9] | Cytotoxicity [10,11], antiparasitic [9] |
| Dihydrochelerythrine (13) | Z. davyi (I.Verd.) Waterm. (Rutaceae) [8] | Antimicrobial [12,13], cytotoxicity [14] |
| Bocconoline (14) | Z. davyi (I.Verd.) Waterm. (Rutaceae) [8] | Antiparasitic [15] |
| 6-Methoxy-7-demethyldihydrochelerythrine (15) | Z. davyi (I.Verd.) Waterm. (Rutaceae) [8] | – |
| 6-Hydroxydihydrochelerythrine (16) | Z. davyi (I.Verd.) Waterm. (Rutaceae) [8] | – |
| Benzophenanthridine | ||
| 6-Acetonyl-N-methyl-dihydrodecarine (17) | Z. lem lemairei (Rutaceae) [9] | Antiparasitic [9] |
| Nitidine (18) | Z. lem lemairei (Rutaceae) [9] | Antiparasitic [9] |
| Carbazole | ||
| Heptaphylline (19) | Clausena anista (Willd.) (Rutaceae) [16] | Antimicrobial, cytotoxicity [17] |
| Girinimbine (20) | C. anista (Willd.) (Rutaceae) [16] | – |
| Ekeberginine (21) | C. anista (Willd.) (Rutaceae) [16] | – |
| 3-Methylcarbazole (22) | C. anista (Willd.) (Rutaceae) [16] | – |
| Cherylline | ||
| Cherylline (23) | Crinum moorei (Amaryllidaceae) [18], Crinum macowanii Baker (Amaryllidaceae) [19] | Enzyme inhibitor [20], protein affinity [21] |
| Crinine | ||
| 6-Hydroxycrinamine (24) | Crinum delagoense (Amaryllidaceae) [22] | Enzyme inhibitor [20] |
| Hamayne (25) | C. delagoense (Amaryllidaceae) [22], C. macowanii Baker (Amaryllidaceae) [19], Brunsvigia josephinæ (Red.) Ker-Gall. (Amaryllidaceae) [23] | Cytotoxicity [24], antiplasmodial [25], enzyme inhibitor [20] |
| Crinine (26) | C. moorei (Amaryllidaceae) [18], C. macowanii Baker (Amaryllidaceae) [19], C. macowanii Baker (Amaryllidaceae) [26], Boophone disticha L. Herb (Amaryllidaceae) [27], Ammocharis tinneana (Kotschy & Peyr.) Milne-Redh. & Schweick. (Amaryllidaceae) [28] | Cytotoxicity [29], enzyme inhibitor [20], protein affinity [21] |
| Powelline (27) | C. moorei (Amaryllidaceae) [18], C. macowanii Baker (Amaryllidaceae) [26], A. tinneana (Kotschy & Peyr.) Milne-Redh. & Schweick. (Amaryllidaceae) [28] | Protein affinity [21] |
| Crinamidine (28) | C. moorei (Amaryllidaceae) [18], C. macowanii Baker (Amaryllidaceae) [26] | Enzyme inhibitor [20] |
| Epibuphanisine (29) | C. moorei (Amaryllidaceae) [18]A. tinneana (Kotschy & Peyr.) Milne-Redh. & Schweick. (Amaryllidaceae) [28] | Enzyme inhibitor [20], protein affinity [21] |
| Buphanisine (30) | B. disticha L. Herb (Amaryllidaceae) [27] | Binding activity [27] |
| Epivittatine (31) | C. moorei (Amaryllidaceae) [18] | Enzyme inhibitor [20], protein affinity [21] |
| 3-O-Acetyl hamayne (32) | Crinum bulbispermum (Amaryllidaceae) [30], B. josephinæ (Red.) Ker-Gall. (Amaryllidaceae) [23] | Enzyme inhibitor [20] |
| Crinamine (33) | C. bulbispermum (Amaryllidaceae) [30], B. josephinæ (Red.) Ker-Gall. (Amaryllidaceae) [23] | Enzyme inhibitor [20] |
| Bulbispermine (34) | C. bulbispermum (Amaryllidaceae) [30], C. macowanii Baker (Amaryllidaceae) [19]. | Cytotoxicity [24,25], enzyme inhibitor [31] |
| Maritidine (35) | Cyrtanthus falcatus (Amaryllidaceae) [32] | Protein affinity [21] |
| O-Methylmaritidine (36) | C. falcatus (Amaryllidaceae) [32] | Protein affinity [21] |
| 11-O-Acetylambelline (37) | N. filifolia Baker (Amaryllidaceae) [7] | Enzyme inhibitor [33] |
| Buphanamine (38) | B. disticha L. Herb (Amaryllidaceae) [27] | Binding activity [27] |
| Distichamine (39) | B. disticha L. Herb (Amaryllidaceae) [27,34] | Antimicrobial [34], binding activity [27] |
| Buphanidrine (40) | B. disticha (L.f.) Herb (Amaryllidaceae) [35], A. tinneana (Kotschy & Peyr.) Milne-Redh. & Schweick. (Amaryllidaceae) [28], C. macowanii Baker (Amaryllidaceae), B. disticha L. Herb (Amaryllidaceae) [26,27], B. disticha (L.f.) Herb (Amaryllidaceae), [34] | Binding activity, antimicrobial [34,35] |
| Haemanthamine (41) | Cyrtanthus elatus (Jacq.) Traub (Amaryllidaceae) [36] | Antiplasmodial [37] |
| Haemanthidine (42) | C. elatus (Jacq.) Traub (Amaryllidaceae) [36] | Cytotoxicity [38] |
| 6α-Hydroxycrinamidine (43) | A. tinneana (Kotschy & Peyr.) Milne-Redh. & Schweick. (Amaryllidaceae) [28] | – |
| 6α-Hydroxyundulatine (44) | A. tinneana (Kotschy & Peyr.) Milne-Redh. & Schweick. (Amaryllidaceae) [28] | – |
| Flexinine (45) | A. tinneana (Kotschy & Peyr.) Milne-Redh. & Schweick. (Amaryllidaceae) [28] | – |
| 1,2β-Epoxyambelline (46) | A. tinneana (Kotschy & Peyr.) Milne-Redh. & Schweick. (Amaryllidaceae) [28] | – |
| 11-O-Acetyl-1,2β-epoxyambelline (47) | A. tinneana (Kotschy & Peyr.) Milne-Redh. & Schweick. (Amaryllidaceae) [28] | – |
| Criwelline (48) | C. delagoense (Amaryllidaceae) [22] | – |
| Undulatine (49) | C. moorei, N. filifolia Baker (Amaryllidaceae) [7,18] | – |
| 3-O-Acetyl-crinine or krepowine (50) | C. moorei (Amaryllidaceae), C. macowanii Baker (Amaryllidaceae) [26,18] | – |
| 1-Epideacetyl-bowdensine (51) | C. moorei (Amaryllidaceae) [18] | – |
| Ambelline (52) | N. filifolia Baker (Amaryllidaceae) [7], A. tinneana (Kotschy & Peyr.) Milne-Redh. & Schweick. (Amaryllidaceae) [28], B. josephinæ (Red.) Ker-Gall. (Amaryllidaceae) [23] | – |
| 6α-Hydroxybuphanidrine (53) | N. filifolia Baker (Amaryllidaceae) [7] | – |
| Dinitrogenous | ||
| (+)-Plicamine (54) | Cyrtanthus obliquus (L.f.) Ait (Amaryllidaceae) [39] | – |
| (−)-Secoplicamine (55) | C. obliquus (L.f.) Ait (Amaryllidaceae) [39] | – |
| Erythrinaline | ||
| (+)-11α-hydroxyerysotrine (56); (+)-erysodine (57), (+)-11α-hydroxyerysodine (58), (+)-erysotrine N-oxide (59) | Erythrina lysistemon Hutch. (Fabaceae) [40] | Antioxidant [40] |
| (+)-11α-Hydroxyerysotrine N-oxide (60), (+)-11β-methoxyerysotrine N-oxide [(+)-O-methylerythrartine N-oxide] (61), (+)-erythrabine (62), (+)-erysotramidine (63), (+)-erysotrine (64), (+)-erythristemine (65) | E. lysistemon Hutch. (Fabaceae) [40] | – |
| Furoquinoline | ||
| Evoxine (66) | T. gerrardii I.Verd. (Rutaceae) [1] | Antimicrobial [1] |
| 7-(γ,γ-Dimethylallyloxy)-γ-fagarine (67) | T. gerrardii I.Verd. (Rutaceae) [1] | Cytotoxicity [41] |
| Flindersiamine (68) | Teclea natalensis (Sond.) Engl., (Rutaceae) [42], Teclea nobilis (Rutaceae) [43] | Antibacterial [42], cytotoxicity [44,45] |
| Dictamnine (69) | T. natalensis (Sond.) Engl., (Rutaceae) [42] | Antimicrobial [3,46], cytotoxicity [47,48] |
| Kokusaginine (70) | Teclea afzelii Engl. (Rutaceae) [49,50] | Antimicrobial [49], antiplasmodial [50] |
| Nkolbisine (71) | T. afzelii Engl. (Rutaceae) [49,50] | Antimicrobial [49], antiplasmodial [50] |
| Skimmianine (72) | T. nobilis (Rutaceae) [43], T. gerrardii I.Verd. (Toddaloideae: Rutaceae) [6], Teclea simplicifolia Verdoorn (Rutaceae) [51] | Antiplasmodial [52], cytotoxicity [53] |
| Maculine (73) | T. nobilis [43], T. afzelii (Rutaceae) [50] | Antiplasmodial [50] |
| Tecleaverdoornine (74) | T. afzelii (Rutaceae) [50] | Antiplasmodial [50] |
| Montrifoline (75) | T. afzelii (Rutaceae) [50], T. nobilis (Rutaceae) [43], T. simplicifolia Verdoorn (Rutaceae) [51] | Antiplasmodial [50] |
| 4,7-Dimethoxy-8-[(3-methyl-2-butenyl)oxy]furo[2,3–b]quinoline (76) | T. natalensis (Sond.) Engl., (Rutaceae) [42] | – |
| Galanthamine | ||
| Galanthamine (77) | C. elatus (Jacq.) Traub (Amaryllidaceae) [36] | Binding activity [20] |
| Indole | ||
| Geissolosimine (78), geissospermine (79), geissoschizoline (80), geissoschizone (81), vellosiminol (82) | Geissospermum vellosii (Apocynaceae) [54] | Antiplasmodial [54] |
| Palicoside (83) | Strychnos usambarensis Gilg [55]. | Antifungal [56] |
| Akagerine (84) | S. usambarensis Gilg [55]. | – |
| Serotobenine (85) | Campylospermum flavum (Schum.) Farron. (Ochnaceae) [57]. | – |
| Indolopyridoquinazoline | ||
| l-Hydroxyrutaecarpine (86) | Vepris louisii (Rutaceae) [58] | – |
| 7,8-Dehydro-1-hydroxyrutaecarpine (87) | V. louisii (Rutaceae) [58] | – |
| Indolosesquiterpene | ||
| Greenwayo-dendrin-3-one (88), 3-O-acetyl greenwayodendrin (89), N-acetylpolyveoline (90), polyveoline (91) | Polyalthia suaveolens (Annonaceae) [59] | Antiparasitic, enzyme inhibitor [59] |
| Isoquinoline | ||
| Ancistrotectorine (92) | Ancistrocladus guineënsis Oliv. (Ancistrocladaceae) [60] | Antiparasitic [61] |
| Crotsparine (93) | Antizoma miersiana (Menispermaceae) [62], Antizoma angustifolia (Burch.) Miers ex Harv. (Menispermaceae) [63] | Antiplasmodial [64] |
| Bulbocapnine (94) | A. miersiana (Menispermaceae) [62], A. angustifolia (Burch.) Miers ex Harv. (Menispermaceae) [63] | Enzyme inhibitor [65] |
| Cycleanine (95) | A. miersiana (Menispermaceae) [62] | Cytotoxicity [66] |
| Dicentrine (96) | A. miersiana (Menispermaceae) [62] | Anthelmintic [67], antiprotozoal [68], cytotoxicity [69,70], vasodilatative [71] |
| Glaziovine or N-methylcrotsparine (97) | A. angustifolia (Burch.) Miers ex Harv. (Menispermaceae) [63] | Antiprotozoal [72], antiviral, cytotoxicity [73,74] |
| Pronuciferine (98) | A. angustifolia (Burch.) Miers ex Harv. (Menispermaceae) [63] | Cytotoxicity [74] |
| Salutaridine (99) | A. angustifolia (Burch.) Miers ex Harv. (Menispermaceae) [63] | Cytotoxicity [75] |
| Cissacapine (100) | A. miersiana (Menispermaceae), A. angustifolia (Burch.) Miers ex Harv. (Menispermaceae) [62,63] | – |
| Cycleaneonine (101); insulanoline (102) | A. miersiana (Menispermaceae) [62] | – |
| Insularine (103) | A. miersiana (Menispermaceae), A. angustifolia (Burch.) Miers ex Harv. (Menispermaceae) [62,63] | – |
| Lycorine | ||
| Lycorine (104) | C. delagoense (Amaryllidaceae) [22], C. moorei (Amaryllidaceae) [18], C. macowanii Baker (Amaryllidaceae) [19,26] | Antimicrobial [26,76,77], anti-inflammatory [78], enzyme inhibitor [20] |
| 1-O-Acetyllycorine (105) | C. moorei (Amaryllidaceae) [18] | Enzyme inhibitor [20], protein affinity [21] |
| Sternbergine (106) | B. josephinæ (Red.) Ker-Gall. (Amaryllidaceae) [23] | Antiplasmodial [25] |
| 9-O-Demethylpluviine (107) | A. tinneana (Kotschy & Peyr.) Milne-Redh. & Schweick. (Amaryllidaceae) [28] | – |
| Mesembrine | ||
| Mesembrine (108) | Sceletium tortuosum (Mesembryanthemaceae) [79] | Enzyme inhibitor, inhibitor of 5-HT reuptake [79] |
| Mesembrenone (109) | S. tortuosum (Mesembryanthemaceae) [79] | Inhibitor of 5-HT reuptake [79] |
| Mesembrenol (110) | S. tortuosum (Mesembryanthemaceae) [79] | Inhibitor of 5-HT reuptake [79] |
| Monoterpenoid indole | ||
| Δ14-Vincanol (111) | Voacanga africana Stapf. (Apocyanaceae) [80] | – |
| O-Methyl-16-epi-Δ14-vincanol (112) | V. africana Stapf. (Apocyanaceae) [80] | – |
| Δ14-Vincamone (113) | V. africana Stapf. (Apocyanaceae) [80] | – |
| N-acetylnoraporphine | ||
| N-Acetylanonaine (114) | Papaver aculeatum (Papaveraceae) [81] | PAF inhibitor [82,83] |
| Naphthylisoquinoline | ||
| Ancistrocladinium A (115), 5′-O-demethylhamatine (116), 5′-O-demethylhamatinine (117), 6-O-demethylancistroealaine A (118), 6,5′-O,O-didemethylancistroealaine A (119), 5-epi-6-O-methylancistrobertsonine A (120), 5-epi-4′-O-demethylancistrobertsonine C (121) | Ancistrocladus congolensis (Ancistrocladaceae) [84] | – |
| Antiparasitic [84] | ||
| Phenanthridone | ||
| Narciprimine (122) | Cyrtanthus contractus (Amaryllidaceae) [85] | Enzyme inhibitor [85] |
| Piperidine | ||
| γ-Coniceine (123), coniine (124), methylconiine (125), conhydrine (126) | Conium maculatum (Umbelliferae) [86,87] | – |
| Pyrrolizidine | ||
| 7-Angelylplatynecine (127) | Senecio chrysocoma (Asteraceae) [88] | – |
| 7-O-Senecioylplatynecine (128) | Solanecio mannii (Hook. f.) C. Jeffrey (Asteraceae) [89] | – |
| 7-O-Trigloylplatynecine (129) | S. mannii (Hook. f.) C. Jeffrey (Asteraceae) [89] | – |
| 9-Angelylplatynecine (130) | S. chrysocoma (Asteraceae) [88] | – |
| Acetylseneciphylline (131) | Senecio pterophorus (Asteraceae) [90] | – |
| Bulgarsenine (132), eruciflorine (133), erucifoline (134) integerrimine (135), jacobine (136), jaconine (137) | Solanecio tuberosus (Sch. Bip. ex A. Rich.) C. Jeffrey var. tuberosus (Asteraceae) [89] | – |
| Madurensine (138) | Crotalaria capensis (Fabaceae) [91] | – |
| Neoplatyphylline (139), retroisosenine (140), retrosine (141) | S. tuberosus (Sch. Bip. ex A. Rich.) C. Jeffrey var. tuberosus (Asteraceae) [89] | – |
| Sarracine (142) | S. chrysocoma (Asteraceae) [88] | – |
| Senecionine (143) | S. pterophorus (Asteraceae) [90], Solanecio angulatus (Vahl) C. Jeffrey, and S. tuberosus (Sch. Bip. ex A. Rich.) C. Jeffrey var. tuberosus (Asteraceae) [89] | – |
| Seneciphylline (144) | S. tuberosus (Sch. Bip. ex A. Rich.) C. Jeffrey var. tuberosus (Asteraceae) [89], S. pterophorus (Asteraceae) [90] | Receptor binding activity [92] |
| Spartioidine (145) | S. pterophorus (Asteraceae) [90] | – |
| Quinoline | ||
| Cyclomegistine (146) | T. gerrardii I.Verd. (Toddaloideae: Rutaceae) [6] | – |
| Edulinine (147) | T. nobilis (Rutaceae) [43], T. simplicifolia Verdoorn (Rutaceae) [51] | Anticonvulsant [93] |
| Quinolinone | ||
| 4-Methoxy-1-methyl-2(1H)-quinolinone (148) | Z. davyi (I.Verd.) Waterm. (Rutaceae) [8] | Antimicrobial [94,95] |
| Quinolizidine | ||
| 3-Hydroxylupanine (149), calpumine (150), calpurmenine (151), calpurmenine pyrrolecarboxylic acid ester (152), epilupinine (153), lupinine (154), virgiline (155), virgiline pyrrolecarboxylic acid ester (156) | Calpunia aurea subsp. aureus (Leguminosae) [96] | – |
| Quinolone | ||
| Isoplatydesmine (157) | T. nobilis (Rutaceae) [43], T. simplicifolia Verdoorn (Rutaceae) [43] | – |
| Ribalinine (158) | T. nobilis (Rutaceae), [43], T. simplicifolia Verdoorn (Rutaceae) [51] | – |
| Secobenzo[c]phenantridine | ||
| 10-O-Demethyl-17-O-methylisoarnottianamide (159) | Z. lem lemairei (Rutaceae) [9] | Antiparasitic [9] |
| 10-O-Demethyl-12-O-methyl isoarnottianamide (160) | Z. leprieurii Guill. et Perr. (Rutaceae) [4] | – |
| Tazettine | ||
| Tazettine (161) | C. falcatus (Amaryllidaceae) [32], C. obliquus (L.f.) Ait (Amaryllidaceae) [39] | Enzyme inhibitor [20], protein affinity [21] |
| Triterpenoid | ||
| Buxaminol A (162) | Buxus natalensis (Oliv.) Hutch (Buxaceae) [97] | Enzyme inhibitor [97] |
5-HT, hydroxytryptamine; PAF, platelet-activating factor.
Table 14.2. New Alkaloids Isolated in African Plants
| Compounds and Ring Type | Plants | Area of Plant Collection | Plant Part | Physical Properties |
|---|---|---|---|---|
| 2-indolinone | ||||
| Isothomandersine (163), thomandersine (164) | Thomandersia laurifolia (Acanthaceae) [98] | Cameroon | Leaves | – |
| 2-quinolinone | ||||
| N-Methylpreskimmianine (165) | V. louisii (Rutaceae) [58] | Cameroon | Stem bark | mp 88–89°C [58] |
| Veprisine or 7,8-dimethoxy-N-methylflindersine (166) | V. louisii (Rutaceae) [58] | Cameroon | Stem bark | mp 89–90°C [58] |
| 2-quinolone | ||||
| Veprisilone (167) | V. louisii (Rutaceae) [58] | Cameroon | Trunk bark | mp 135–136°C [58] |
| Acridone | ||||
| Helebelicine A or 3-hydroxy-1,4-dimethoxy-10-methyl-9-acridone (168) | Z. leprieurii Guill. et Perr. (Rutaceae) [4] | Cameroon | Fruits | mp 122–123°C [4] |
| Helebelicine B or 3-hydroxy-1,2-dimethoxy-10-methyl-9-acridone (169) | Z. leprieurii Guill. et Perr. (Rutaceae) [4] | Cameroon | Fruits | Yellow amorphous powder [4] |
| Oriciacridone A (170) | Oriciopsis glaberrima Engl. (Rutaceae) [99] | Cameroon | Stem bark | mp 249°C; [α]25D −45.7° (c 0.075, DMSO) [99] |
| Oriciacridone B (171) | O. glaberrima Engl. (Rutaceae) [99] | Cameroon | Stem bark | mp 309°C; [α]25D −85.3° (c 0.075, DMSO) [99] |
| Tegerrardin A (172) | T. gerrardii I.Verd. (Rutaceae) [1] | South Africa | Stem bark | mp 158–159°C [1] |
| Tegerrardin B (173) | T. gerrardii I.Verd. (Rutaceae) [1] | South Africa | Stem bark | Pale yellow gum [1] |
| Toddaliopsins A (174), B (175), C (176), and D (177) | Toddaliopsis bremekampii I.Verd. (Rutaceae) [100] | South Africa | Leaves | Yellow glass [100] |
| Aporphine | ||||
| 6a,7-Dehydro-1,2-dimethoxy-7-hydroxy-N-methylaporphine (178) | Enantia chlorantha (Apocyanaceae) [101] | Cameroon | Stem bark | mp 258–260°C [101] |
| 6a,7-Dehydro-1,2-dimethoxy-7-hydroxyaporphine (179) | E. chlorantha (Apocyanaceae) [101] | Cameroon | Stem bark | mp 256–257°C [101] |
| Aristolactam | ||||
| Piperumbellactams A (180), B (181), C (182), and D (183) | Piper umbellatum (Piperaceae) [102] | Cameroon | Branches | – |
| Belladine | ||||
| N-Demethylbelladine (184) | N. filifolia Baker (Amaryllidaceae) [7] | South Africa | Bulbs | – |
| Benzophenanthridine | ||||
| Buesgeniine (185) | Zanthoxylum buesgenii (Rutaceae) [103] | Cameroon | Stem bark | mp 141–142°C [103] |
| Turraeanthin B (186) | Turraenthus africanus (Meliaceae) [104] | Cameroon | Stem bark | mp 270–272°C [104] |
| Carbazole | ||||
| Atanisatin (187) | C. anista (Rutaceae) [105] | Nigeria | Stems | – |
| Clausamtin (188) | C. anista (Rutaceae) [105] | Nigeria | Roots | mp 154–156°C [105] |
| O-Demethylmurrayanine or 3-formyl-1-hydroxycarbazole (189) | C. anista (Willd.) (Rutaceae) [16] | Cameroon | Stem bark and roots | mp 74–75°C [16] |
| Crinine | ||||
| 3-[4′-(8′-Aminoethyl)phenoxy] bulbispermine (190) | C. moorei (Amaryllidaceae) [19]. | South Africa | Whole plant | [α]29D +53.3° (c 0.045, CHCl3) [18] |
| 6α-Methoxybuphanidrine (191) | N. filifolia Baker (Amaryllidaceae) [7] | South Africa | Bulbs | [α]20D +34.6° (c 0.13, CHCl3) [7] |
| Delagoenine (192) | C. delagoense (Amaryllidaceae) [22] | South Africa | Bulbs | mp 120–122°C; [α]20D +34.2° (c 0.48, MeOH) [22] |
| Delagoensine (193) | C. delagoense (Amaryllidaceae) [22] | South Africa | Bulbs | mp 132–134°C; [α]20D +28.2° (c 0.475, MeOH) [22] |
| Filifoline (194) | N. filifolia Baker (Amaryllidaceae) [7] | South Africa | Bulbs | mp 191–193°C; [α]20D +12° (c 0.85, MeOH) [7] |
| Josephinine (195) | B. josephinæ (Red.) Ker-Gall. (Amaryllidaceae) [23] | South Africa | Bulbs | mp 230–232°C; [α]22D −30.9° (c 0.5, EtOH) [23] |
| Macowine (196) | C. macowanii Baker (Amaryllidaceae) [26] | South Africa | Bulbs | mp 115–117°C; [α]20D −34° (c 0.235, CHCl3) |
| Dinitrogenous | ||||
| Obliquine (197) | C. obliquus (L.f.) Ait (Amaryllidaceae) [39] | South Africa | Bulbs | mp 136–139°C; [α]20D +20.5° (c 0.6, MeOH) [39] |
| Erythrinaline | ||||
| (+)-11β-Hydroxyerysotrine (198) | E. lysistemon Hutch. (Fabaceae) [40] | Botswana | Flowers and pods | Yellowish crystals [40] |
| (+)-11β-Hydroxyerysotrine N-oxide (199) | E. lysistemon Hutch. (Fabaceae) [40] | Botswana | Flowers and pods | [α]D +25° (c 0.04, MeOH) [40] |
| (+)-11β-Methoxyerysotramidine (200) | E. lysistemon Hutch. (Fabaceae) [40] | Botswana | Flowers | [α]D +60° (c 0.11, MeOH) [40] |
| (+)-11β-Hydroxyerysotramidine (201) | E. lysistemon Hutch. (Fabaceae) [40] | Botswana | Flowers and pods | [α]D +100° (c 0.14, MeOH) [40] |
| Furoquinoline | ||||
| Isohaplopine 3′,3′-dimethylallylether (202) | T. simplicifolia Verdoorn (Rutaceae) [51] | Ethiopia | Leaves | mp 118–119°C [51] |
| Isohaplopine or 8-hydroxy-4,7-dimethoxyfuroquinoline (230) | T. simplicifolia Verdoorn (Rutaceae) [51] | Ethiopia | Leaves | mp 121–123°C [51] |
| Nobiline (204) | T. nobilis (Rutaceae) [43] | Ethiopia | Leaves and fruits | mp 117–119°C [43] |
| Quinosuaveoline A (205) | Oricia suaveolens (Engl.) Verd. (Rutaceae) [44]. | Cameroon | Stems and leaves | Yellow amorphous powder [44] |
| Quinosuaveoline B (206) | O. suaveolens (Engl.) Verd. (Rutaceae) [44]. | Cameroon | Stems and leaves | Colorless amorphous powder [44] |
| Tecleanatalensine A (207) | T. natalensis (Sond.) Engl. (Rutaceae) [42] | South Africa | Leaves | Pale yellow gum [α]D +11° (c 0.19, CH2Cl2) [42] |
| Tecleanatalensine B (208) | T. natalensis (Sond.) Engl. (Rutaceae) [42] | South Africa | Leaves | Pale yellow gum [42] |
| Guanidine | ||||
| Millettonine (209) | Millettia laurentii (Leguminosae) [106] | Cameroon | Stem bark | mp 170°C; [α]21D +46.2° (c 0.71, MeOH) [106] |
| Millaurine A (210) | M. laurentii De Wild. (Fabaceae) [107] | Cameroon | Seeds | mp 136–137°C; [α]25D +46.7° (c 0.2, MeOH) [107] |
| Indole | ||||
| Flavumindole (211) | C. flavum (Schum.) Farron (Ochnaceae) [57] | Cameroon | Stem bark | mp 157–158°C; [α]20D +32° (c 0.05, MeOH) [57] |
| Indoloquinazoline | ||||
| Orisuaveoline A (212) | O. suaveolens (Engl.) Verd. (Rutaceae) [44] | Cameroon | Stems and leaves | Yellow amorphous powder [44] |
| Orisuaveoline B (213) | O. suaveolens (Engl.) Verd. (Rutaceae) [44] | Cameroon | Stems and leaves | Yellow amorphous powder [44] |
| Indolosesquiterpene | ||||
| Polysin (214) | P. suaveolens (Annonaceae) [59] | Cameroon | Stem bark | – |
| Isoquinoline | ||||
| Ancistroguineine A (215) | A. guineënsis Oliv. (Ancistrocladaceae) [60] | South Africa | Leaves | mp 202–204°C; [α]25D +191.4° (c 0.52, CHCl3) [60] |
| Ancistroguineine B (216) | A. guineënsis Oliv. (Ancistrocladaceae) [60] | South Africa | Leaves | [α]25D +141.2° (c 0.04, CHCl3) [60] |
| Lycorine | ||||
| 1,2-O-Diacetylzephyranthine (217) | C. elatus (Jacq.) Traub (Amaryllidaceae) [36] | South Africa | Bulbs | mp 157–159°C; [α]20D −13.5° (c 0.20, MeOH) [36] |
| Zephyranthine (218) | C. elatus (Jacq.) Traub (Amaryllidaceae) [36], A. tinneana (Kotschy & Peyr.) Milne-Redh. & Schweick. (Amaryllidaceae) [28] | South Africa | Bulbs | mp 115–118°C; [α]20D −30.6° (c 0.56, MeOH) [36] |
| Monoindole | ||||
| 12-Methoxyicajine (219) | Strychnos icaja (Loganiaceae) [77] | Cameroon | Stem bark | White amorphous powder [77] |
| 15-Hydroxyvomicine (220) | S. icaja [77] | Cameroon | Stem bark | White amorphous powder [77] |
| Phenanthridine | ||||
| Mooreine (221) | C. moorei (Amaryllidaceae) [18]. | South Africa | Whole plant | Amorphous [18] |
| Piperidine | ||||
| N-Methylpseudoconhydrine (222) | C. maculatum (Umbelliferae) [87] | South Africa | Whole plant | mp 157°C; [α]25D +25° (MeOH) [87] |
| Pyrrolizidine | ||||
| Globiferine (223) | Crotalaria globifera E. Mey. (Leguminosae) [108] | South Africa | Seeds | mp 156–129°C; [α]18D −8.6° (c 0.0232, CHCl3) [108] |
| Isorosmarinine (224) | S. pterophorus (Asteraceae) [90] | South Africa | – | mp 137–142°C [90] |
| Merenskine N-oxide (225) | Senecio latifolius DC (Asteraceae) [109] | South Africa | Whole plant | mp 146°C; [α]20D +26.1° (c 0.33, EtOH) [109] |
| Neosarracine (226) | S. chrysocoma (Asteraceae) [88] | South Africa | – | – |
| trans-Anacrotine (227) | C. capensis (Fabaceae) [91] | South Africa | Seeds | [α]22D +11° (c 1.7, CHCl3) [91] |
| Pyrrolizidine (macrocyclic diesters) | ||||
| Oxypterine (228) | Lotononis oxyptera (Fabaceae) [110] | South Africa | Leaves and seeds | mp 127–129°C; [α]22D +19.6° (c 2.6, CHCl3) [110] |
| Quinolinone | ||||
| 2,6-Dihydro-9-methoxy2,2,6-trimethyl-5H-pyrano[3,2c]quinolin-5-one (229) | Agathosma sp. (Rutaceae) [111] | South Africa | Aerial part | Yellow oil [111] |
| 4,6-Dimethyl-1-methyl-2-(1H)-quinolinone (230) | Agathosma sp. (Rutaceae) [111] | South Africa | Aerial parts | mp 143–144°C [111] |
| N-Methylswietenidine-B or 1-methyl-3,4-dimethoxy-2-quinolone (231) | C. anista (Willd.) (Rutaceae) [16] | Cameroon | Stem bark and roots | mp 237–239°C [16] |
| Quinolizidine | ||||
| 13-O-(2′-Pyrrolylcarbonyl)calpurmenine (232) | Calpurnia aurea (Ait.) Benth. subsp. sylvatica (Leguminosae) [112] | South Africa | Leaves | – |
| 3β,4α,13α-Trihydroxylupanine (233), calpaurine or 3β,4α-dihroxy 13α-O-(2′-pyrrolylcarbonyl) lupanine (234) | C. aurea subsp. aureus (Leguminosae) [96] | Ethiopia | Leaves | – |
| Calpurmenine (235) | Calpurnia aurea (Ait.) Benth. subsp. sylvatica (Leguminosae) [112] | South Africa | Leaves | – |
| Secobenzo[c]phenanthridine | ||||
| 10-O-Demethyl-12-O-methylarnottianamide (236) | Z. leprieurii Guill. et Perr. (Rutaceae) [4] | Cameroon | Roots | Brown amorphous powder [4] |
| Turraeanthin A (237) | T. africanus (Meliaceae) [104] | Cameroon | Stem bark | mp 237–239°C [104] |
| Tazettine | ||||
| 8α-Ethoxyprecriwelline (238) | C. bulbispermum (Amaryllidaceae) [30] | South Africa | Whole plant | Amorphous [α]28D +116.6° (c 0.06, CHCl3) [18] |
| N-Desmethyl 8α-ethoxy pretazettine (239) | C. bulbispermum (Amaryllidaceae) [30] | South Africa | Whole plant | Amorphous [α]28D +160.63° (c 0.09, CHCl3) [18] |
| N-Desmethyl-8β-ethoxy pretazettine (240) | C. bulbispermum (Amaryllidaceae) [30] | South Africa | Whole plant | Amorphous [α]28D +34° (c 0.14, CHCl3) [18] |
| Triterpenoid | ||||
| O(2)-Natafuranamine (241) | B. natalensis (Oliv.) Hutch (Buxaceae) [97] | South Africa | Stem bark | Yellow gum [α]20D +5.3° (c 0.75, CHCl3) [97] |
| O(10)-Natafuranamine (242) | B. natalensis (Oliv.) Hutch (Buxaceae) [97] | South Africa | Stem bark | Yellow solid [α]20D +20.7° (c 0.75, CHCl3) [97] |
| 31-Demethylbuxaminol A (243) | B. natalensis (Oliv.) Hutch (Buxaceae) [97] | South Africa | Stem bark | While amorphous powder [α]20D +59.4° (c 0.09, CHCl3) [97] |
| Cyclonataminol (244) | B. natalensis (Oliv.) Hutch (Buxaceae) [97] | South Africa | Stem bark | Yellow amorphous powder [α]20D −70° (c 0.05, CHCl3) [97] |
14.1.2 Classification and Nomenclature
Alkaloids are classified on the basis of taxonomy, pharmacology, biosynthetic path, and chemical structure. The classification based on chemical structure is popular among the readers who need to cover a broad range of compounds. Based on chemical structure, alkaloids are broadly classified into heterocyclic and nonheterocyclic alkaloids.
Heterocyclic alkaloids are those which contain a nitrogen atom in their heterocyclic ring. Based on the type of ring, they are further classified as pyrrole, pyrrolidizine, pyridine, piperidine, quinoline, isoquinoline, norlupinane, indole alkaloids, and so on (Figure 14.1).
Figure 14.1. Different classes of heterocyclic alkaloids.
Nonheterocyclic alkaloids are also sometimes called proto-alkaloids or biological amines. These are less commonly found in nature. These molecules have a nitrogen atom which is not a part of any ring system. Examples of these include ephedrine, cathinone, and colchicine (Figure 14.2).
Figure 14.2. Nonheterocyclic alkaloids.
When there was no systematic nomenclature, alkaloids were named based on different criteria such as their source or physiological response, according to their discovery and prefixes. Alkaloids named based on their sources include ephedrine and papaverine; those named according to their physiological response include morphine and emetine.
URL: https://www.sciencedirect.com/science/article/pii/B978012405927600014X
18.3.2 Alkaloids
Alkaloids are the class of phytochemicals that contains nitrogen atoms in their structure and play vital physiological roles in humans and animals [25,26]. Alkaloids are diverse, with about 3000 distinct alkaloids identified in plants, fungi, and animals [27]. Typically, alkaloids are crystalline, colorless, non-toxic, stable, and have low molecular weight, making them ideal pharmaceutical compounds. Their chemical structures range from simple and linear to complex and cyclic configurations. They are often further subdivided into three: true alkaloids (heterocyclic), protoalkaloids (non-heterocyclic), and pseudo-alkaloids, based on their biosynthetic pathway, molecular structure, and chemical precursor.
(a)True/Heterocyclic alkaloids possess highly polar, active cyclic amino acid derivatives as part of their structure. Because of the presence of intra-cyclic nitrogen atoms and enormous biological activity, these highly reactive heterocyclic alkaloids can form salts that are water-soluble in nature with organic acids such as tartaric, acetic, oxalic, lactic, malic, and citric acids. Examples of alkaloids in this group include cocaine, morphine, and quinine which are abundantly found in nature [28]. Others include nicotine, dopamine, geissospermine, piperine, berberine, and gasoline.
(b)Protoalkaloids/Non-heterocyclics alkaloids contain a nitrogen atom outside the ring rather than part of the heterocyclic system. They are often derived from amino acids or biogenic amines. Some of the examples are mescaline, colchicine, cathinone, and other proto alkaloids; they are uncommon. Mescaline is a phenylethylamine alkaloid derived from the plant Lophophora williamsii, better known as peyote [28].
(c)Pseudo-alkaloids are those alkaloids whose basic carbon skeletons are not derived from amino acids. In reality, pseudo-alkaloids are produced by amination or transamination of amino acid precursors or byproducts. Pseudo-alkaloids could be acetate and phenylalanine-derived or terpenoid, as well as steroidal alkaloids. Pseudo-alkaloids include coniine, capsaicin, ephedrine, solanidine, caffeine, theobromine, and quinidine [29]. Furthermore, another school of thought has grouped alkaloids into pyrrolidine, pyridine, quinoline, isoquinoline, indole, quinazoline, etc., based on the nature of the n-containing heterocyclic rings present in their structure [29]. Functionally, alkaloids limit the activity of the topoisomerase enzyme, thus stalling DNA replication to induce cell death [30]. Expectedly, alkaloids have been utilized in drug development for various ailments such as inflammation, bacterial infections, and cancer [31].
URL: https://www.sciencedirect.com/science/article/pii/B9780323905930000174
Alkaloids
Alkaloids are a group of highly diverse natural products that contain one or more basic nitrogen atoms in a heterocyclic ring (da Silva et al., 2007; Michael, 2008). Because of their great structural diversity, there is no uniform classification of alkaloids and no specific class of enzymes for their biosynthesis. However, according to their biogenetic origins, alkaloids can be grouped into four classes, i.e., alkaloids derived from amino acids, purine alkaloids, aminated terpenes, and polyketide alkaloids (Roberts and Wink, 1998). Although many well-known alkaloids (e.g., hypocyamine, physostigmine, cocaine, morphine, codeine, vinblastine) are produced by plants, alkaloids can also be produced by various other organisms such as fungi (Hoffmeister and Keller, 2007). Alkaloids are considered to be part of an organism’s chemical defense (Roberts and Wink, 1998). However, many alkaloids have found applications in human medicine as analgesics, antiarrhythmics, antihypertensives, antiprotozoals, antitumors, stimulants, and vasodilators (Hesse, 2002), and in agriculture as insecticides (Matolcsy et al., 2002).
The most studied fungal alkaloids are ergots in Claviceps species (Haarmann et al., 2009) and loline in Epichloë and Neotyphodium (Schardl, 2001). Like PKS and NRPS genes, the genes involved in biosynthesis of ergot and loline alkaloids are clustered in the corresponding fungal species (Haarmann et al., 2005; Spiering et al., 2005; Lorenz et al., 2009). The first enzymatic activity in ergot biosynthesis by Claviceps species is mediated by dimethylallyl tryptophan synthase (DMATS) (Gerhards et al., 2014). Genome mining of sequenced fungal genomes has discovered that many fungi including Aspergillus species contain DMATS genes (Steffan et al., 2009; Fan et al., 2014). Both the production of ergot alkaloid and the presence of its biosynthetic pathway are revealed in A. fumigatus (Narayan and Rao, 1982; Coyle and Panaccione, 2005). The similarities of corresponding genes in A. fumigatus and C. purpurea indicate that the ergot alkaloid biosynthetic pathways have a common origin in Aspergillus and Claviceps fungi (Coyle and Panaccione, 2005). NRPSs are also often involved in alkaloid biosynthesis. For example, as mentioned before, NRPS gene ftmA of A. fumigatus is involved in production of fumitremorgins alkaloids (Maiya et al., 2006).
Marine and endophytic fungi, including Aspergillus species, are currently the subject of a special focus for secondary metabolite discovery. In the last decade, a vast number of biologically active alkaloids such as amides, amines, indole derivatives, isoquinolines, pyridines, quinolones, quinazolines, and many others have been discovered in endophytic fungi, including Aspergillus (Zhang et al., 2012b). Table 22.3 presents recent findings (2010–15) in alkaloid compounds produced by a number of Aspergillus species. As seen, in addition to indole-derived ergot alkaloids, a wide range of alkaloids such as different amines and amides, acremolins, benzodiazepines, costaclavines, cyclopiazonic acid derivatives, cytochalasins, diketopiperazines, fumitremorgins, indole derivatives, isochaetominines, protuboxepins, pseurotins, protubonines, terremides, quinazolines, and waikialoids have been discovered in Aspergillus species (Table 22.3). Among these, amines and amides, as well as indole alkaloids represent some of the dominant classes of alkaloids produced by Aspergillus. Most of these compounds or their derivatives exhibited biological activities and may have found application in medicine. Therefore, discovery of the production of a diverse set of alkaloids by Aspergillus species introduces this fungus as a potent resource for alkaloid research.
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Alkaloids
Alkaloids are nitrogen containing compounds of low molecular weight, mostly derivative of amino acids. In plants, alkaloids perform a protective role against pathogens and herbivores. Various alkaloid drugs of plant origin are clinically available. These include different analgesics, anti-nociceptive, anti-inflammatory, anti-neoplastic, muscle relaxant, gout suppressant, anti-viral, cytotoxic, anti-cholinergic and anti-myasthenia gravis etc. (Seifu et al., 2012).
Berbamine, a bisbenzylisoquinoline alkaloid in medicinal plant Berberis amurensis, has shown anti-arrhythmic, anti-hypertensive and immunosuppressive activities. Moreover, massive work has been done on various forms of cancers including, breast cancer, myeloma, lymphoma and lung cancer (Cheng et al., 2009). It has been investigated for its in vitro anti-inflammatory action by hindering the gene expression of inflammatory mediators. In vivo anti-inflammatory effect has been reported on subcutaneous (SC) air pouch inflammation (Wong et al., 1992). The possible mechanism involved in regulating inflammation included reduced PGE2 and COX2 formation by macrophages; inhibition of TNF-a, IL-6 and IL-1ß release; decreased expression and release of MMP-2 & MMP-9 (Jia et al., 2017).
Berberine, another bisbenzylisoquinoline alkaloid from Berberis sp., has shown anti-cancer activity in various studies against different human cancer cell lines (Lin et al., 2008). In addition, it has been mentioned to induce apoptosis and cell cycle arrest; inhibit enzymes like DNA topoisomerase I and II, reverse transcriptase, NADH oxidase and diaminooxidase. Also, berberine presented anti-oxidant action by significantly increasing superoxide dismutase action and reducing malondialdehyde (MDA) formation and superoxide anion. Additionally, berberine has ability to hold metal ions like copper and iron, thus reducing their concentration in lipid peroxidation (Seifu et al., 2012). Furthermore, the in vitro testing on PMA-induced macrophages, using cell viability, real time PCR, western blotting and flow cytometry, resulted in suppression of mRNA expression & protein production of EMMPRIN and MMP-9, suggesting berberine role in correcting atherosclerosis plaque (Huang et al., 2011). Another study strengthens the role of berberine in decreasing expression and protein levels of MMP-1, 2 & 9 via NF-кB p65 pathway, thus playing a crucial role in the cell migration and preventing the invasion of cancer (Lin et al., 2008).
Rutaecarpine, an indolopyridoquinazoline alkaloid separated from Evodia rutaecarpa has been described to have many pharmacological actions, including anti-thrombotic, anti-cancer, anti-oxidant and cardiovascular problems. Furthermore, rutaecarpine showed not only anti-inflammatory action by reducing prostaglandin production (Woo et al., 2001) but also constrained osteoclastogenesis by affecting main signaling pathways of osteoclast differentiation. This might be due to impairment of macrophage colony stimulating factor (M-CSF) and RANKL-stimulated signaling pathways (Fukuma et al., 2018).
Cepharanthine, a bisbenzylisoquinoline alkaloid was extracted from Stephania cephalantha Hayata. Former studies displayed that cepharanthine demonstrated anti-inflammatory effect. Cepharanthine inhibited IL-6 and TNF-α formation in LPS stimulated RAW264.7 cells in vitro and LPS treated mice in vivo by obstructing MAPK & NF-κB pathway (Huang et al., 2014). Furthermore, cepharanthine suppressed TNFα induced MMP-9 formation via NF-кB inhibition in NSSV-AC cells (Azuma et al., 2002).
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Conclusion and outlooks
Alkaloids represent a significant group of secondary metabolites that have been demonstrated to exert effects in biologically important processes, including analgesic, muscle relaxant, and antioxidant activities. Alkaloids can be used for medicinal purposes and are beneficial to humanity. However, some alkaloids can also be life-threatening in some situations, and certain alkaloids have been found to cause asphyxia, paralysis, and in some cases, death.
Recently, a number of naturally occurring and synthetic indole alkaloids have been isolated or prepared and have been demonstrated to exert health benefits in subjects with respiratory diseases. Asthma, respiratory fibrosis, tuberculosis, cancer, emphysema, and other diseases may be treated with indole alkaloids. Although several in vitro and in vivo laboratory studies have demonstrated the promise of indole alkaloids, only a few clinical trials have been conducted. As a result, further clinical trials remain necessary to explore the therapeutic effects of indole alkaloids in the treatment of respiratory diseases.
The effectiveness of indole alkaloids can be calculated based on their proclivity for addressing multiple disease targets and their beneficial abilities to communicate with multiple disease targets through multimodal mechanisms of action. The most important feature of indole alkaloids is their scaffold, which transfers the action from one target to another when substituted. Therefore, developing semisynthetic indole alkaloids agents may eradicate MDR in respiratory diseases in the future.
URL: https://www.sciencedirect.com/science/article/pii/S0944711321001926
Abstract
Alkaloids are amino acid–derived basic nitrogen-containing organic compounds, mainly restricted to the plant kingdom. In plants, alkaloids are synthesized and accumulated as noxious molecules in response to environmental modulations and biotic and abiotic stresses. Human history has always been fascinated and influenced by various plant-derived alkaloids used as potions, remedies, psychoactive drugs, central nervous system stimulants, or poisons. In various cellular and animal models, plant alkaloids have displayed various pharmacological and medicinal activities such as neuroprotective, antihypertensive, cardioprotective, anticancer, antiinflammatory, vasorelaxant, antiparasitic, antibacterial, antifungal, antiprotozoal, antipyretic, abortifacient, antidiabetic, and antitussive activities. The neuroprotective ability of alkaloids has been exerted against Alzheimer disease, Parkinson disease, Huntington disease, multiple sclerosis, anxiety, depression, cognitive impairment and dementia, neurotoxicity, cerebral ischemia, drug addiction and substance abuse, psychological disorders, epilepsy, autoimmune encephalomyelitis, brain cancer, and so on. Alkaloids are known modulators of different biochemical and molecular markers regulating a number of signal transduction pathways, which are attributed to their potential as disease-modifying agents against the complex nature of neurological disorders. Bioactivity-guided isolation of many neuroprotective alkaloids has supported the age-old folkloric use of alkaloid-containing botanicals depicted in traditional literature and in many pharmacopeia. Since synergism exists among phytochemicals, the structure–activity relationship in alkaloids administered alone, or in combination with other natural or synthetic drugs or as ingredient(s) in polyherbal formulations, may elucidate the underlying mode of action of plant alkaloids. However, very few structure–activity relationship studies have been conducted in relation to the neuroprotection offered by the alkaloids. The present work describes the origin of neuroprotective plant alkaloids together with their underlying mechanism as therapeutic agents depicted in vitro, in vivo, ex vivo, or in human clinical studies. Hence the enormous structural diversity provided by the Nature and lead-identifying strategies incorporated with modern integrated approaches such as robotic separation, metabolic engineering, synthetic biology, genetic sequencing, and structure–activity studies will lead to the synthetic optimization of alkaloids as disease-modifying agents.
URL: https://www.sciencedirect.com/science/article/pii/B9780128095935000069
3.2.5 Alkaloids
Alkaloids are a group of compounds that contain mostly basic nitrogen atoms in their chemical structure. This group is largely present in the stem and root barks or rhizomes of the plants giving a bitter taste to these plant organs. These compounds are well known to possess antiparasitic (antimalarial), antimicrobial and antibacterial properties. Some of them exhibited a significant anticancer activity in preclinical and clinical trials [82,83]. Some alkaloids like vinflunine (tested on murine P388 cells) induces cell death through apoptosis leading to DNA fragmentation. This induction of apoptosis is mediated through activation of caspase-3 and/or caspace-7. In addition, this alkaloid exhibit its cytotoxic effect by stimulating c-Jun N-terminal kinase (JNK) triggered by cellular stress [82]. Two other plant alkaloids namely cryptolepine and neocryptolepine isolated from the roots of Cryptolepis sanguinolenta were investigated by Dassonneville et al. [84] for their anticancer properties. Their chemical structures are similar except the respective orientation of their indole and quinolone rings. The authors reported that the cytotoxicity of these two alkaloids acts through an apoptotic pathway by caspase-3 activation but one of them, cryptolepine, was found to be four times more toxic than its isomer proving that the positions of the indole and quinolone rings are crucial to the activity of these alkaloids. Another alkaloid, ellipticine, exhibits its anticancer activity through a covalent binding to DNA leading to its damage [85]. Finally some alkaloids are able to inhibit multidrug resistance (MDR) that is considered to be one of the major reasons of chemotherapy failure. Ivanova et al. [86] reported the effect of three alkaloids, neogermitrine, veralosinine and veramigrine, which were able to increase the intracellular concentration of the reference compound rodamine 123 by 87, 93 and 88 times respectively compared to untreated cancer cells [86]. This kind of alkaloid is relevant to resolve the problem of drug resistance and then to improve the efficacy of anticancer drugs.
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1.2.2 Alkaloids
W. Meissner created the term “alkaloids” in 1818 to describe all organic substances derived from plants that have a basic structure. Later research revealed that alkaloids include a heterocyclic ring system that contains the nitrogen atom. Primary, secondary, tertiary, and quaternary amines are all included in this definition [21]. There have been various scientific breakthroughs since then that have helped shape the characteristics that define this class of substances, which has resulted in numerous chemical structures being introduced into this class. Alkaloids have been found in plants, animals, and microbes, including humans, marine creatures, fungi, and other bacteria. Compounds possessing side chain–bearing nitrogen, nitrogen-containing functional groups, or any combination of these were also categorized as alkaloids because of their neutral nature [22].
It is possible to categorize alkaloids based on their chemical structure, biologic activity, biosynthesis mechanism, and occurrence into heterocyclic and nonheterocyclic alkaloids, as shown in Fig. 1.3.
Figure 1.3. Classification of alkaloids.
1.2.2.1 Heterocyclic alkaloids
Fig. 1.4 depicts the basic structure of the naturally occurring alkaloids. Heterocyclic alkaloids have a nitrogen atom in their structure. They are made biosynthetically from the amino acids they are named after, and they are frequently generated after a decarboxylation procedure. Based on the amino acid of origin, six primary categories of alkaloids have been identified so far. l-ornithine, l-tyrosine/l-phenylalanine, l-lysine, l-tryptophan, l-histidine, and glycine/aspartic acid are all derivatives of these amino acids [23]. Derivatives of these primary groups also play a significant role. For example, isoquinoline alkaloids, a derivative of l-tyrosine/l-phenylalanine, are a class of compounds that are among the most diversified natural compound in the world. In their skeleton, they have an isoquinoline or tetrahydroisoquinoline ring that is biogenically produced from phenylalanine and tyrosine [24]. The isoquinoline alkaloids are a diverse category of compounds that are not structurally homogenous. There are eight subgroups within this group (i.e., benzylisoquinoline, aporphine, protoberberine, protopine, benzo[c]phenanthridine, morphinan, phthalideisoquinoline, and emetine alkaloids), each with a distinct degree of oxygenation and intramolecular rearrangement, as well as a varied pattern of distribution and the occurrence of additional rings linked to the main system.
Figure 1.4. Basic structure of naturally occurring alkaloids.
When it comes to alkaloids, protoberberines represent about a quarter of all structures revealed so far, making them the most common nitrogen-containing secondary metabolites found in nature. Isoquinoline alkaloids may be found in Berberidaceae, Papaveraceae, Fumariaceae, Ranunculaceae, Menispermaceae, Rutaceae, and Annonaceae, as well as in a variety of other plant groups (in the dehydro forms). Plants of the Magnoliaceae and Convolvulaceae families are also rich in these alkaloids [25,26].
Proline and l-ornithine, two amino acids, are shown to be precursors of the alkaloids nicotine, tropane, stachydrine, necine, and pyrrolizidine. Tropane (l-ornithine derivatives), another major alkaloid, is one of the world's oldest plant medicines, with ethnopharmacologic uses including analgesia, hallucinogens, and poisons. Esters (mono-, di-, and tri), tropanes (carboxylated and benzoylated), and ornithine-derived compounds are prevalent in the Solanaceae (family of flowering plants), Convolvulaceae (bindweed or morning glory family), Brassicaceae (a large and commercially significant flowering plant family), Erythroxylaceae (a family of flowering trees and shrubs), and Euphorbiaceae (the spurge family) [27]. Due to a tropic acid residue connected to the ecgonine nucleus as an ester, some of these alkaloids have chiral structures. Racemic mixtures can arise during alkaline extraction, especially when the former exists naturally in its R form (for example, the synthesis of (+)-atropine from (−)-hyoscyamine). Tropanic, benzoic, acetic, tiglic, isobutyric, isovaleric, and anisic acids were all found in the tropane alkaloids, as were a number of other acids. Drugs like scopolamine (a tropane alkaloid) are routinely used to treat digestive and urinary system spasms. Ophthalmologic eyedrops usually contain atropine to increase pupil size, paralyze the accommodation reflex and facilitate ophthalmic examinations. To enhance their appearance, ladies have been using Atropa belladonna juice to make their pupils larger since at least the Renaissance period. However, tropane alkaloids have a long list of adverse effects and contraindications. Cardiac abnormalities, particularly irregular heartbeat, as well as euphoric and disorienting moods, depressed tendencies toward the central nervous system, and dryness of the mucous membranes are all documented side effects. Glaucoma, prostatic hyperplasia, urinary tract illness, and pregnancy should all be avoided [28,29]. The central nervous system action of tropane alkaloids makes them a popular drug of abuse. Cocaine is one of the most well-known of these substances. Cocaine can cause cardiac death at large dosages by blocking sodium channels. In the long run, chronic use might lead to depression, suicide attempts, sleeplessness, or psychomotor retardation. More than 4000 people died as a result of its misuse in 2013. Cocaine's medicinal uses are confined to anesthetic purposes in nasal and lacrimal procedures [30]. The alkaloid's ligand impact on the central nervous system's opioid receptors accounts for its dependence-inducing properties.
Similar to the tropane alkaloids, another derivative of l-ornithine is pyrrolizidine alkaloid (PA), which originate from l-ornithine or l-arginine. With a bridgehead nitrogen atom, it has two five-membered rings linked together. These compounds are commonly found in the Boraginaceae, Asteraceae, and Fabaceae group of plants and may be found in the seeds and flowers of all three of those groups. The hepatotoxicity of these alkaloids is determined by a double bond at C-1 and C-2. PAs are the eaters of necic acid and necines. Necic acids are mono- or dicarboxylic acids with branching carbon chains containing 5–10 carbon atoms. However, double esterification can sometimes occur, resulting in macrocyclic diesters with 11–14 ring systems (for instance, senkirkine) [31]. PA is found in many plant species and is estimated to be present in 3% of the world's flowering plants. These plants are commonly harmful to animals, wildlife, and people. PAs have caused significant human illness and mortality through accidental intake of PA-contaminated food sources or purposeful use of PA-containing alternative therapies. To avoid adverse effects, oral consumption of unsaturated PAs is limited to 0.35 g/day for adults for up to 14 days and 0.007 g PA/kg body weight for members of sensitive groups, such as children. The toxicity of these chemicals in animals is also substantial, prompting a careful investigation of their impact on animal grazing. Animals may develop severe liver disease, cirrhosis, or tumors as a result of a single treatment of PA-containing plants. Toxicities caused by PAs are far more poisonous to animals such as pigs and poultry than to sheep and goats [32].
Purine alkaloids are the derivatives of asparaginate and glutamate. Caffeine, theobromine, and theophylline are the three most widespread alkaloids belonging to this group. Indole alkaloids, β-carboline alkaloids, manzamines, ergot alkaloids, and quinolone are examples of l-tryptophan derivatives. Quinoline alkaloids are generally anthranilic acid derivatives (excluding the cinchona alkaloids and camptothecin, both of which are generated from tryptophan). Their occurrence was discovered in extracts from various Rutaceae, Rubiaceae, Asteraceae species, and fungal (Penicillium species) and bacterial (Pseudomonas species) species.
The extracts of Rutaceae species include furoquinoline alkaloids, which are anthranilic acid derivatives with spasmolytic and photosensitizing effects. It is the mutagenic, antiviral, antiplasmodial, and antibacterial characteristics of plant extracts that are due to dictamnine, skimmianine, or fagarine; these compounds also have anticholinesterase capabilities [33]. Another important anthranilic acid derivative is acridone alkaloid. There are just a few acridone alkaloids, but acronycine, isolated from the Australian plant Sarcomelicope simplicifolia, is the most critical example. This class of alkaloids, as well as their derivatives, are being studied extensively for the treatment of colon and lung cancers [34].
Pyridine and piperidine alkaloids are another two major types of alkaloids that are l-lysine derivatives. Piperidine alkaloids, which feature a saturated piperidine ring and are usually produced from lysine, have been found. In most cases, lysine is the site of α-side chain attachment for simple α-substituted piperidines. The Apiaceae (family of mostly aromatic flowering plants), Solanaceae (family of flowering plants, which also include herbs and trees), Chenopodiaceae (a subfamily of the flowering plant family Amaranthaceae), Fabaceae (bean family), Crassulaceae (stonecrop family or the orpine family), Lycopodiaceae (a family of vascular plants), and Asteraceae (composite family of the flowering plant order Asterales) include this type of alkaloids. Pilocarpine, whose production may involve histidine and threonine, is the most significant alkaloid from the category of histidine derivatives. Pilocarpus jaborandi, a neotropical plant in the Rutaceae family native to Brazil and which is grown there, produces it.
1.2.2.2 Nonheterocyclic alkaloids
Nonheterocyclic alkaloids make up a significant portion of the alkaloid family. Nonheterocyclic nitrogen-containing compounds are those made from amino acids or biogenic amines. Capsaicin and ephedrine are two of the most prominent members of this class. The compounds like hordenine from Hordeum distochon (Poaceae) and mescaline from Lophophora williamsi are also included in this protoalkaloid family [23].
1.2.2.3 Properties of alkaloids
For the most part, the salts of organic acids, esters, or tannins (Cinchona bark) are present in plant tissues as water-soluble salts of the alkaloids. The majority of alkaloids are found in the plant matrix as crystalline, amorphous, nonodorous, and nonvolatile compounds. It is possible to find liquid alkaloids of low molecular weight, such as arecoline and pilocarpine, and alkaloids without an oxygen atom in their structure. There are a few exceptions to this rule, including berberine and colchicine, the orange-yellow alkaloids betaine and sanguinarine, the red-colored sanguinarine, and the orange-yellow canadine. Tonic water still contains quinine as a bittering agent. Alkaloids with optically active counterclockwise isomers are more pharmacologically active than their racemic mixtures, which are less active or have dramatically differing activity, such as morphine's enantiomers.
Alkaloids, in general, dissolve in acidic water, whereas their salts dissolve in water. In other words, they are soluble in water or dilute acids but not in organic solvents. Organic solvents (chloroform, ether, methylene chloride) can dissolve alkaloids' free forms, but water cannot (exceptions include ephedrine and caffeine). Pharmaceutical companies take use of the structural variations in alkaloids' solubility to separate them from complex plant matrices and produce pharmaceutically acceptable products [32].
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14.1.2 Classification and Nomenclature
Alkaloids are classified on the basis of taxonomy, pharmacology, biosynthetic path, and chemical structure. The classification based on chemical structure is popular among the readers who need to cover a broad range of compounds. Based on chemical structure, alkaloids are broadly classified into heterocyclic and nonheterocyclic alkaloids.
Heterocyclic alkaloids are those which contain a nitrogen atom in their heterocyclic ring. Based on the type of ring, they are further classified as pyrrole, pyrrolidizine, pyridine, piperidine, quinoline, isoquinoline, norlupinane, indole alkaloids, and so on (Figure 14.1).
Figure 14.1. Different classes of heterocyclic alkaloids.
Nonheterocyclic alkaloids are also sometimes called proto-alkaloids or biological amines. These are less commonly found in nature. These molecules have a nitrogen atom which is not a part of any ring system. Examples of these include ephedrine, cathinone, and colchicine (Figure 14.2).
Figure 14.2. Nonheterocyclic alkaloids.
When there was no systematic nomenclature, alkaloids were named based on different criteria such as their source or physiological response, according to their discovery and prefixes. Alkaloids named based on their sources include ephedrine and papaverine; those named according to their physiological response include morphine and emetine.
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2.1.2 Alkaloids
Alkaloids are a type of nitrogen containing heteroaromatic compounds with large structural diversity [21–24], including quinine, rutaecarpine and ellipticine etc. (Fig. 1b) with blue-green fluorescence emission. As the main alkaloid of cinchona species (rubiaceae), quinine (em. ca. 450 nm) is the first representative drug to treat malaria and the classic precursor of all modern synthetic antimalarial quinines [25]. Camptothecin (em. ca. 420 nm) is isolated from camptotheca acuminate [26], which has been confirmed to show strong anti-tumor activity [27]. Ellipticine is a weakly basic polycyclic plant alkaloid with anti-tumor activity, which can insert into helical DNA [28]. The fluorescence of this kind of alkaloids is solvent dependent, with the increase of solvent polarity, the maximum fluorescence peak of the compounds shifts from 400 nm to 430 nm, resulting from intramolecular charge transfer effect [29]. Rutaecarpine (em. ca. 400 nm) is an indole pyridine quinazolinone alkaloid isolated from evodia rutaecarpa and its related plants [30,31]. It has been reported to show various important biological characteristics, such as anti-thrombosis, anti-cancer, anti-inflammation and analgesia, anti-obesity, etc. [32,33]. The alkaloid acronycine is originally isolated from the bark of an Australian tree called Acronychia baueri [34–36]. The above mentioned alkaloids mainly show blue emission due to limited conjugation and moderate ICT effect.
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