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CHAPTER 5
ALKALOIDS ISOLATED FROM SOUTH AFRICAN MENISPERMACEAE
5.1 Introduction
The history of alkaloid chemistry, in structural terms, began in 1804, when Sertürner (the Paderborn apothecary) discovered the so-called principium somniferum in opium (Trommsdorf 1805*), which he reported the following year in the Journal der Pharmacie (Sertürner 1805*). The attention of scientists, however, was aroused only twelve years later by a publication appearing in the Annalen der Physik (Sertürner 1817*; Schmitz 1983*). There, Sertürner named his principium somniferum for the first time "morphium" (after Morpheus, the son or servant of sleep and creater of dream states in Ovid; altered to "morphinium" by the French physicist Gay- Lussac).
Often, a very great deal of time would pass between the isolation of an alkaloid and the determination of both its structure and absolute configuration. In the case of strychnine 138, years passed by and for morphine 150 years (Hesse 2002). Today, it is usual to determine the structure of a substance in the year of its isolation, especially when it seems to possess pharmacological properties as promising as those of strychnine and morphine.
There are three main types of alkaloids: i) True alkaloids have a heterocyclic ring with nitrogen and are derived from amino acids. ii) Proto alkaloids do not have a heterocyclic ring with nitrogen, but are also derived from amino acids. iii) Pseudo alkaloids have a heterocyclic ring with nitrogen, but are not derived from amino acids (they can be derived from terpenoids or purines).
In true alkaloids the basic units of biogenesis are amino acids. The non-nitrogen containing rings or side chains are derived from terpene units and/or acetate, while methionine is responsible for the addition of methyl groups to nitrogen atoms. Alkaloids are basic and form water-soluble salts. Most alkaloids are well-defined crystalline substances that react with acids to form salts. In plants they may exist in the free state, as salts or as N-oxides. The criteria currently used for 243 alkaloid classification are biogenesis, structural relationship, biological origin and spectroscopic/spectrometric properties (chromophores in UV spectroscopy, ring systems in mass spectrometry) (Hesse 2002). Based on amino acid precursor, alkaloids can be further subdivided. The principal precursors are ornithine, lysine, nicotinic acid, tyrosine, tryptophan, anthranilic acid and histidine. Ornithine gives rise to pyrrolidine and trypane alkaloids, lysine to piperidine, quinolizidine and indolizidine alkaloids and nicotinic acid to pyridine alkaloids. Tyrosine produces phenylethylamines, tetrahydroisoquinoline, benzyltetrahydroisoquinoline, phenethylisoquinoline, terpenoid tetrahydroisoquinoline and Amaryllidaceae alkaloids. Tryptophan gives rise to β-carboline, terpenoid indole, quinoline, pyrroloindole and ergot alkaloids. Anthranilic acid acts as a precursor to quinazoline, quinoline and acridine alkaloids, while histidine gives imidazole derivates (Dewick 2002).
5.1.1 Known alkaloids of the Menispermaceae
Up to the end of 1996, 1 858 alkaloids were described from 244 plants of the family Menispermaceae, with 813 citations (Barbosa-Filho et al. 2000).
(S)-Norcoclaurine, a benzyltetrahydroisoquinoline, was identified as a very important intermediate in the formation of almost all the alkaloids present in plants of this family (Barbosa- Filho et al. 2000). The biosynthetic pathway for the formation of (S)-norcoclaurine is as follows: Phosphoenolpyruvic acid reacts with erythrose-4-phosphate to form shikimic acid, which reacts with phosphoenolpyruvic acid, followed by a series of steps to form phenylpyruvic acid which, after reductive amination, is transformed into phenylalanine. This amino acid may then undergo decarboxylation to form phenylethylamine or deamination to form phenylacetaldehyde. These two compounds may react to form (S)-norcoclaurine (Figure 5.1).
244
O O OH PO O OH PEP OH 1 H Phosphoenolpyruvic acid NH2 HO OH + OH OH Phenylalanine PO Shikimic acid O OH HO HO Erythrose-4-phosphate NH2 HO NH HO 2, 1 Dopamine 5 O H
OH HO H NH2 , 3 4 HO HO
S L-Tyrosine ( )-Norcoclaurine HO
4-Hydroxyphenylacetaldehyde
Figure 5.1. Biosynthetic pathway for the formation of (S)-norcoclaurine. The enzymes involved in the process are: 1, Phenolase; 2, L-Tyrosine decarboxylase; 3, L-Tyrosine transaminase; 4, p- Hydroxyphenylpyruvate decarboxylase; 5, (S)-Norcoclaurine synthase.
245
Barbosa-Filho et al. (2000) created a biosynthetic map for the alkaloids identified in the Menispermaceae. The purpose was to show a probable biosynthetic relationship between the different classes of alkaloids isolated from this family (Figure 5.2)
Bisbenzylisoquinoline (604)
Phenanthrene (2)
Proaporphine Aporphine (303) Stephaoxocane (5) (30) Aristolochic acid (4) Tropoloneisoquinoline (9) Azafluoranthene (11)
Isooxoaporphine (9)
Hirsutine (5)
Cohirsine (4) BIQ Protoberberine (275) (59) Benzazepine (2)
Morphinan (63) Hasubanane (78)
Acutunine (9) Eribidine (7) Erythrina (28)
Pavine (4)
Isoquinoline alkaloids (5) Phenethylcinnamide alkaloids (5) Others (4)
Figure 5.2. Probable biosynthetic relationships between the different classes of alkaloids isolated from plants of the family Menispermaceae. The numbers in brackets are the numbers of alkaloids isolated in each class. (BIQ = Benzylisoquinline alkaloids)
246
5.1.2 Classification of the alkaloids of the Menispermaceae
The family Menispermaceae yielded 22 different types of alkaloids (Barbosa-Filho et al. 2000). To be considered as a separate type, there must be at least two different alkaloids with the same basic skeleton. In the case where only one alkaloid has been identified, these were classified as "Others" (Barbosa-Filho et al. 2000).
I - Benzylisoquinoline alkaloids
6 N 7 2 8 1 N
12 11
1-Benzylisoquinoline alkaloids 1-Benzyltetrahyroisoquinoline alkaloids Abuta, Burasaia, Caryomene, Cissampelos, Stephania Cocculus, Cyclea, Pachygone, Parabaena, Sarcopetalum, Sciadotenia, Stephania, Tiliacora, Tinospora
More than 100 alkaloids in the subtype 1-benzyltetrahydroisoquinoline are distributed throughout the families Annonaceae, Berberidaceae, Hernandiaceae, Lauraceae, Magnoliaceae, Menispermaceae, Papaveraceae, Ranunculaceae and Rhamnaceae. Alkaloids of this subtype represent 4% of the total number of alkaloids isolated from the family Menispermaceae. The genera in which they are most commonly found are Stephania (18) and Tiliacora (8). In the subtype 1-benzylisoquinoline only one alkaloid (papaverine) was identified in Stephania gracilenta (Khosa et al. 1987*). The most frequently cited alkaloid of this class (I) is coclaurine in the genera Abuta (1), Caryomene (1), Cocculus (4), Cyclea (2), Pachygone (1), Sarcopetalum (1), Sciadotenia (1) and Stephania (2). Other important alkaloids are reticuline (5 citations) and oblongine (4 citations).
247
II - Bisbenzylisoquinoline alkaloids This class of alkaloid is divided into several subtypes according to the number of bonds between the two monomers, the type of bond(s) and their relative position to each other.
(a) One bond Diphenylether tail to tail Diphenyl ether head to tail
NH NH O NH
O NH
Abuta, Albertisia, Caryomene, Menispermum, Cyclea Sciadotenia
(b) Two bonds Diphenyl ether head to head Diphenyl ether head to head Diphenyl ether tail to tail Phenyl-Phenyl tail to tail
O O HN NH HN NH
O
Abuta, Albertisia, Anisocycla, Arcangelisia, Caryomene, Cissampelos, Cocculus, Curarea, Tiliacora Cyclea, Limacia, Limaciopsis, Pycnarrhena, Sciadotenia, Sinomenium, Spirospermum, Stephania, Strychnopsis, Tiliacora
248
Diphenyl ether head to tail Phenylbenzyl ether head to tail Diphenyl ether tail to head Diphenyl ether tail to head
H2C O NH O NH
NH O NH
Chondodendron, Cissampelos, Curarea, Cyclea, Epinetrum, Limaciopsis, Sciadotenia, Cissampelos, Cyclea Sinomenium, Stephania, Synclisia
(c) Three Bonds Diphenyl ether head to head Diphenyl ether head to head Phenyl ether tail to tail Phenyl-phenyl tail to tail
O O
HN NH HN NH O O
O
Albertisia, Anisocycla, Cocculus, Pachygone, Pachygone, Tiliacora Stephania, Synclisia, Triclisia
249
Diphenyl ether head to tail Phenyl ether head to tail Phenyl ether tail to head Phenyl and benzylphenyl ether tail to head
O O HN HN O O NH NH O
OCH2
Cyclea Cissampelos, Cyclea
This type of alkaloid, together with the aporphines and protoberberines are considered good chemical markers of the family Menispermaceae. These alkaloids are also present in the families of Annonaceae, Berberidaceae, Lauraceae and Ranunculaceae and represent 40% of the total number of alkaloids isolated from plants of the Menispermaceae family. It is frequently found in Stephania (171), Cyclea (87) and Cocculus (63).
III - Proaporphine alkaloids
NH Abuta, Anamirta, Caryomene, Cocculus, Diploclisia, Legnephora, Limacia, Menispermum, Pachygone, Sarcopetalum, O Sciadotenia, Stephania
Proaporphines represent 2% of the total alkaloids isolated from Menispermaceae, predominantly in the genera Stephania (14), Caryomene (4), Cocculus (2) and Legnephora (2).
250
IV - Aporphine alkaloids Anamirta, Anisocycla, Chasmanthera, Cissampelos, Cocculus, Coscinium, Cyclea, Dioscoreophyllum, Diploclisia, Fibraurea, NH Heptacyclum, Kolobopetalum, Legnephora, Menispermum, Pachygone, Penianthus, Pycnarrhena, Rhigiocarya, Sinomenium,
Stephania, Strychnopsis, Tiliacora, Tinomiscium, Tinospora, Triclisia
More than 500 compounds are distributed between the families Annonaceae, Hernandiaceae, Lauraceae, Magnoliaceae, Menispermaceae, Monimiaceae, Ranunculaceae and others. It is the second most abundant type of alkaloid in the family Menispermaceae, with 303 compounds (20 %). The genus Stephania is the richest one, with a total of 188 isolated alkaloids and Cocculus second with only 12 alkaloids.
V - Tropoloneisoquinoline alkaloids
N
Abuta, Cissampelos
O
This type of alkaloid has been found only in the family Menispermaceae from the genera Abuta and Cissampelos.
251
VI - Azafluoranthene alkaloids
N Abuta, Cissampelos, Telitoxicum, Triclisia
This type of alkaloid belongs exclusively to the family Menispermaceae. Only six compounds were identified from the genera Abuta, Cissampelos, Telitoxicum and Triclisia.
VII - Phenanthrene alkaloids N
Anisocycla, Stephania
A very rare type of alkaloid, less than 20 were isolated in the families Annonaceae, Aristolochiaceae, Lauraceae, Menispermaceae, Monimiaceae and Ranunculaceae. In the Menispermaceae only the alkaloid stephenanthrine was isolated from the genera Stephania and Anisocycla.
VIII - Aristolochic acid-derived alkaloid
COOH O
NO2 NH
Cocculus Stephania 252
It is known as a chemical marker for the family Aristolochiaceae, from which 70 different compounds have been isolated, but occurs also in Annonaceae, Menispermaceae, Monimiaceae, Lauraceae and Ranunculaceae. In the Menispermaceae only three compounds were isolated from the genera Cocculus and Stephania.
IX - Isooxaporphine alkaloids
N
O Menispermum, Sinomenium
The first example of this type of alkaloid was isolated in 1982 from Menispermum dauricum and was named menisporhine (Kunimoto & Satoh 1982*). Later others were isolated from various other members of the family Menispermaceae.
X - Protoberberine alkaloids Abuta, Anamirta, Anisocycla, Arcangelisia, Burasaia, Chasmanthera, Cocculus, Coscinum, N Dioscoreophyllum, Fibraurea, Heptacyclum, Jateorhiza, Legnephora, Menispermum, Parabaena, Penianthus, Rhigiocarya, Sinomenium, Sphenocentrum, Stephania,
Tinospora, Triclisia
This alkaloid group has 275 citations among the alkaloids of the family Menispermaceae and the genera richest in this type were Stephania (112), Tinospora (26) and Fibraurea (21).
253
XI - Hirsutine alkaloids
N Cocculus
Only five alkaloids of this type have been isolated all from Cocculus hirsutus (Barbosa-Filho et al. 2000).
XII - Cohirsine alkaloids O
N Cocculus
In the same way as hirsutine alkaloids, all five alkaloids from this class have been isolated from Cocculus hirsutus (Ahmad & Iqbal 1993; Ahmad et al. 1987).
XIII - Benzazepine alkaloids
O N
Abuta
The alkaloids of this type have a similar carbon skeleton similar to the benzodiazepine drugs, known as minor tranquillisers. Only three compounds from this class were isolated: puntarenine 254 from Berberis empetrifolia; saulatine and dihydrosaulatine both from Abuta bullata (Barbosa- Filho et al. 2000).
XIV - Morphinane alkaloids Morphinan-6-one Morphinan-7-one
NH NH 6 7 O O
Cocculus, Menispermum, Sinomenium, Antizoma, Chasmanthera, Cocculus, Stephania Kolobopetalum, Rhigiocarya, Sinomenium, Stephania Morphinan-8-one Dehydromorphinane
NH NH 8 O
Stephania, Triclisia Cocculus, Sinomenium, Stephania
Morphinane type alkaloids occurred in 4% of the samples tested in the family Menispermaceae. They differ from those present in the family Papaveraceae in not having the ether bridge between the carbons C-4 and C-5. In this group four different sub-groups can be assigned: a) morphinan- 6-one alkaloids isolated from Cocculus, Menispermum, Sinomenium and Stephania b) morphinane-7-one alkaloids isolated from Antizoma, Chasmanthera, Cocculus, Kolobopetalum, Rhigiocarya, Sinomenium and Stephania c) morphinane 8-one alkaloids isolated from Stephania and Triclisia and d) dehydromorphinane alkaloids isolated from Cocculus, Sinomenium and Stephania. 255
XV - Hasubanane alkaloids
N Stephania
O
All the alkaloids isolated from this class were from the genus Stephania. This group can be subdivided into four different sub-groups: a) hasubanan-6-one b) hasubanan-8-one c) 8,10- epoxyhasubanane and d) dehydrohasubanane.
XVI - Acutumine alkaloids
O N Limacia, Menispermum, Sinomenium
O
All five alkaloids isolated were from the genera Limacia, Menispermum and Sinomenium (all Menispermaceae).
XVII - Eribidine alkaloids
N Cocculus, Hyperbaena, Stephania
A rare class of alkaloids, only 12 different compounds were isolated from the genera Cocculus, Hyperbaena and Stephania in the family Menispermaceae. 256
XVIII - Erythrine alkaloids
N Cocculus, Hyperbaena, Pachygone
The name derives from Erythrina, one of the genera of the family Fabaceae/Leguminosae, from which many alkaloids and the first of this type were isolated. From Menispermaceae were isolated 28 alkaloids, distributed between the genera Cocculus (25), Hyperbaena (2) and Pachygone (1).
XIX - Pavine alkaloids
NMe Chasmanthera, Cyclea
About 50 different alkaloids are well distributed in the families Berberidaceae, Lauraceae, Papaveraceae and Ranunculaceae. Only three alkaloids were isolated in the family Menispermaceae from the genera Chasmanthera and Cyclea in the family Menispermaceae.
XX - Isoquinoline alkaloids Tetrahydroisoquinoline Tetrahydroisoquinolone
NH NH
O
Menispermum Abuta, Menispermum, Stephania Families like Cactaceae, Chenopodiaceae and Fabaceae/Leguminosae are known to produce simple isoquinoline alkaloids. In the Menispermaceae they are very rare. Only three compounds of this type were isolated from the genera Abuta, Menispermum and Stephania. 257
XXI - Phenethylcinnamide alkaloids
H H N N
O O
Penianthus, Sinomenium, Tinospora Tinospora
These types of alkaloids are abundant in the families Fumariaceae, Lauraceae, Magnoliaceae, Papaveraceae and Rutaceae. Only two alkaloids in this class were isolated in the family Menispermaceae from the genera Penianthus, Sinomenium and Tinospora in die family Menispermaceae.
XXII - Stephaoxocane alkaloids
N
O Cissampelos, Stephania
OH
A relatively new class of alkaloid, only five examples are described in the literature, all of them from the Menispermaceae, within the genera Cissampelos (Da-Cunha et al. 1998) and Stephania (Toda et al. 1996*).
258
XXIII - Alkaloids with miscellaneous structures
These five alkaloids were isolated only once from plants of the family Menispermaceae.
OCH3 H3CO
N N H3C OH HO CH3 H H
H CO OCH3 3 OH O a) Thalicarpine was isolated from Cocculus larifolius (Bhakuni & Jain 1982*), also from plants in the families Ranunculaceae and Hernandiaceae.
H3CO
N CH3 H3CO H O OH H3CO C O b) Cohirstine (=cohristitine) was isolated from Cocculus hirsutus (Ahmad & Iqbal, 1992a*, 1993*).
NHCO2Me
H
H
OH c) Gusalung C was isolated from Arcangelisia gusalung (Zhang et al. 1995*). 259
OCH3
H3CO
O H3CO N
d) Kokusaginine was isolated from Tinospora malabarica (Bowen & Motawe 1985*) and previously from the family Rutaceae (Buckingham 1993f*).
OCH3
N O H3C N O H O
OH
e) Neotrilobine was isolated from the roots of Cocculus trilobus (Chen et al. 1994*).
5.2 Alkaloids identified in the genera of the South African Menispermaceae
Genus Albertisia The genus Albertisia is the most homogeneous group inside the family, producing only bisbenzylisoquinoline type of alkaloids (Barbosa-Filho et al. 2000).
5.2.1 Extraction and isolation of alkaloids from Albertisia delagoensis
Albertisia delagoensis was collected in March 2001, at Tembe Elephant Park (KwaZulu-Natal, SA) and a voucher specimen (Van Wyk & De Wet, 4075) was deposited in the herbarium of the University of Zululand (ZULU).
Extraction of leaves Air-dried, ground leaves (580 g) were extracted as described under General Experimental Techniques to yield 7.20 g of a crude alkaloid extract. The following alkaloids were identified by 260
HPLC using reference standards isolated from rhizomes: O-methylcocsoline (1), cocsuline (2) and cocsoline (3).
Figure 5.3. TLC plate showing purified alkaloids from Albertisia delagoensis leaves. B = O-Methylcocsoline (1); D = Cocsuline (2) and E = Cocsoline (3) (letters refer to fractions eluted from column chromatography).
Extraction of rhizome
Air-dried, ground rhizome (723 g) was extracted as described under General Experimental Techniques to yield 3.63 g of a crude alkaloid extract. Column chromatography of 3 g of alkaloid extract yielded O-methylcocsoline (1) (167 mg); cocsuline (2) (366 mg) and cocsoline (3) (684 mg) (Figure 5.4).
Figure 5.4. TLC plate showing purified alkaloids from Albertisia delagoensis rhizomes. D = O-Methylcocsoline (1); E = Cocsuline (2) and F = Cocsoline (3).
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5.2.1.1 O-Methylcocsoline (1)
C35H34O5N2
OCH3 O N N H3C H H O H
O
H3CO
Class of compound: Bisbenzyltetrahydroisoquinoline
1 H NMR: δH 7.49 (1H, dd, J 8.4 and 1.8 Hz, H-14’), 7.20 (1H, dd, J 8.4 and 2.4 Hz, H-13’), 7.08 (1H, dd, J 8.1 and 2.1 Hz, H-10’), 6.95 (1H, J 8.1 and 1.8 Hz, H-14), 6.87 (1H, d, J 8.1 Hz, H-13), 6.82 (dd, J 8.1 and 2.4 Hz, H-11’) 6.61 (1H, s, H-5), 6.58 (1H, d, J 1.8 Hz, H-10), 6.31 (s, H-5’ ) 6.20 (1H, s, H-8 ) 3.92 ( 3H, s, OMe), 3.83 (3H, s, OMe), 2.48 (3H, s, NMe).
13 C NMR: δC 154.6 (C-12’), 149.7 (C-11), 147.5 (C-12), 145.9 (C-6’), 140.0 (C-6 or 7), 139.4 (C-7’ or 8’), 138.9 (C-9’), 134.2 (C-6 or 7), 133.4 (C-9), 131.4 (C-14’), 130.7 (C-4a), 129.3 (C-4’a), 128.8 (C-10’), 127.3 (C-8a), 122.3 (C-11’), 122.2 (C-14), 121.1 (C-13’), 120.6 (C-8’a), 117.7 (C-10), 116.1 (C-5), 113.1 (C-8), 112.5 (C-13), 106.8 (C-5’), 60.4 (C-1’), 59.6 (C-1), 56.3 (OMe), 156.2 (OMe), 44.7 (C-3’), 42.2 (C-α’), 42.1 (C-3, NMe), 41.5 (C-d’), 28.0 (C-4), 24.0 (C-4’).
HPLC: Retention time of 31.85 minutes.
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Also isolated from: Menispermaceae: Albertisia papuana Becc. (Lebouef et al. 1982a*; Lavault et al. 1987*); Pachygone loyaltiensis Diels (Lebouef et al. 1987*).
5.2.1.2 Cocsuline (2)
C35H34 N2O5
CH3O O N N O H CH3 H H
O
OCH3
Class of compound: Bisbenzyltetrahydroisoquinoline
1 H NMR: δH 7.56 (1H, dd, J 8.4 and 2.1 Hz, H-14’), 7.14 (2H, dd, J 8.7 and 2.7 Hz, H-10’, 13’), 6.93 (1H, dd, J 8.4 and 2.7 Hz, H-11’), 6.87 (1H, d, J 8.1 Hz, H-13), 6.78 (1H, dd, J 8 and 2.1 Hz, H-14), 6.59 (1H, s, H-5), 6.50 (1H, d, J 2.1 Hz, H-10), 6.30 (1H, s, H-5’), 6.11 (1H, s, H-8), 3.84 (3H, s, OMe), 2.56 (3H, s, N’Me), 2.38 (3H, s, NMe).
13 C NMR: δC 153.78 (C-12’), 148.0 (C-12), 145.9 (C-6’), 143.7 (C-11), 140.1, 139.5, 139.3, 139.2 (C-6 or 7,7’, 8’, 9’), 134.9 (C-6 or 7), 134.2 (C-9), 131.2 (C-10’), 129.9 (C- 4a or 8a), 129.4 (C-4’a or 8’a), 128.5 (C-14’), 127.2 (C-4a or 8a), 122.4 (C-14), 122.3 (C-13’), 121.3 (C-11’), 120.2 (C-4’a or 8’a), 116.6 (C-10), 115.7 (C-13), 115.6 (C-5), 113.9 (C-8), 106.5 (C-5’), 67.4 (C-1), 60.5 (C-1), 56.2 (OMe), 50.5 (C-3), 45.0 (C-3’), 45.0 (C-3’), 42.5 (N-Me), 42.0 (N’-Me), 41.8, 40.9 (C-α, α), 27.6 (C-4), 23.4 (C-4’).
HPLC: Retention time of 30.97 minutes. 263
Also isolated from: Euphorbiaceae: Andrachne cordifolia Müell. Arg., O.F. (Khan et al. 1983). Menispermaceae: Cocculus pendulus (Forsk.) Diels (Bhakuni et al. 1970; Bhakuni & Joshi 1975; Gupta 1978*; Ikram et al. 1982*; Hussain et al. 1984; Jain et al. 1991; Suleiman et al. 1993; Al-Khalil et al. 1993*); Triclisia patens Oliver (Tackie et al. 1974; Partridge et al. 1988*); Triclisia gilletii (De Wild.) Staner (Tackie et al. 1974; Buckingham 1993*); Triclisia dictyophylla Diels (Spiff et al. 1981); Cocculus leaeba DC. (C. pendulus) (Ikram et al. 1982*); Synclisia scabrida Miers (Ohiri et al. 1981*; 1983); Albertisa papuana Becc. (Lebouef et al. 1982a* Lavault et al. 1987*) Albertisia laurifolia Yamamoto (Xue et al. 1985*); Pachygone dasycarpa Kurz (Guinaudeau et al. 1997).
5.2.1.3 Cocsoline (3)
C34H32 N2O5
CH3O O N N O H CH3 H H
O OH
Class of compound: Bisbenzyltetrahydroisoquinoline
264
1 H NMR: δH 7.47 (1H, br. d. J 7.2 Hz, H-14’), 7.12 (1H, dd, J 8.4 and 2.4 Hz. H-13’), 7.06 (1H, br. d. J 6.6, H-10’), 6.85-6.74 (3H, M, H-11’, 13, 14), 6.58 (5H-5), 6.51 (br,s,H-10), 6.30 (1H, s, H-5’), 6.14 (1H, s, H-8), 3.83 (3H, s, OMe), 2.46 (3H, s, N’Me).
13 C NMR: δC 154.8 (C-12’), 147.9 (C-12), 145.9 (C-6’), 144.6 (C-11), 139.6 (C-6 or 7), 139.1 (C-7’, 8’), 138.9 (C-9’), 135.4 (C-6 or 7), 132.8 (C-9), 131.4 (C-14), 130.9 (C-4a), 129.2 (C-4’a), 128.8 (C-10’), 127.1 (C-8a), 122.8 (C-11’), 122.0 (C-14), 120.8 (C-13), 120.4 (C-8’a), 117.6 (C-10), 116.6 (C-5), 116.1 (C-13), 112.8 (C- 8), 106.7 (C-5’), 60.4 (C-1’), 59.7 (C-1), 56.2 (OMe), 44.6 (C-3’), 42.5 (C-α), 41.9 (C-3, NMe), 41.4 (C-α’), 28.3 (C-4, 23.8 (C-4’).
MS: m/e 548 (62), 349 (28), 335 (100), 321 (27), 305 (13), 168 (74).
HPLC: Retention time of 29.32 minutes.
Also isolated from: Menispermaceae: Cocculus pendulus Diels (Bhakuni & Joshi 1975; Ikram et al. 1982*; Hussain et al. 1984; Fazal & Khan 1984; Jain et al. 1991); Synclisia scabrida Miers (Ohiri et al. 1981*; 1983); Cocculus leaeba DC. (Ikram et al. 1982*); Cocculus hirsutus Diels (El-Shabrawy et al. 1982*; El-Shabrawy 1985); Albertisia papuana Becc. (Lebouef et al. 1982a*; Lavault et al. 1987*); Albertisia laurifolia Yamamoto (Xue et al. 1985*); Anisocycla cymosa Troupin (Kanyinda et al. 1989). 265
Genus Antizoma The genus Antizoma yielded only one phytochemical citation, sinoacutine (better known as salutaridine), a morphinane alkaloid (Dekker et al. 1988).
5.2.2 Extraction and isolation of alkaloids from Antizoma angustifolia
Antizoma angustifolia was collected in February 2001, at Pienaars River (Pretoria, Gauteng, SA) and a voucher specimen (Van Wyk & De Wet, 4059) was deposited in the herbarium of the University of Zululand (ZULU).
Extraction of leaves Air-dried, ground leaves (860 g) were extracted as described under General Experimental Techniques to yield 4.13 g of a crude alkaloid extract. Column chromatography of 1 g of alkaloid extract yielded glaziovine (4) (6 mg) and crotsparine (5) (1.2 mg) (Figure 5.5).
Figure 5.5. TLC plate showing purified alkaloids from Antizoma angustifolia leaves. AB = glaziovine (4) and C = Crotsparine (5).
Extraction of stem and rhizome Air-dried, ground stem and rhizome (1.24 kg) were extracted as described under General Experimental Techniques to yield 1.72 g of a crude alkaloid extract. Column chromatography of 1 g of alkaloid extract yielded glaziovine (4) (11 mg) and crotsparine (5) (52 mg) (Figure 5.6).
266
Figure 5.6. TLC plate showing purified alkaloids from Antizoma angustifolia rhizomes. D = glaziovine (4) and G = Crotsparine (5)
5.2.2.1 Glaziovine (4)
C18H19NO3
CH3O
N HO CH3 H
O
Class of compound: Proaporphine
1 H NMR: δH 6.96 (1H, dd, J 9.9 and 3.0 Hz, H-8), 6.81 (1H, J 9.9 and 2.7 Hz, H-12), 6.54 (1H, s, H-3), 6.34 (1H, dd, J 9.9 and 1.8 Hz, H-9), 6.26 (1H, dd, J 9.9 and 1.8 Hz,
H-11), 3.78 (3H, s, OCH3), 3.42 (1H, dd, J 10.5 and 6 Hz, H-6a), 3.09 (1H, dd, J
12.0 and 6.0, H-5eq), 2.91 (1H, ddd, J 16.8, 11.4 and 6.6 Hz, H-4ax), 2.73 (1H, dd,
J 16.8 and 4.5 Hz, H-4eq), 2.46 (1H, td, J 11.7 and 5.4, H-5ax), 2.34 (3H, s, N-
CH3), 2.42 (1H, dd, J 12.0 and 6.3 Hz, H-7), 2.19 (1H, dd, J 11.7 and 10.8, H-7).
267
13 C NMR: δC 186.4 (C-10), 153.4 (C-12), 149.7 (C-8), 147.4 (C-2), 140.9 (C-1), 134.5 (C- 7c), 128.7 (C-9), 127.5 (C-11), 124.0 (C-7b), 122.9 (C-3a), 109.8 (C-3), 65.7 (C-
6a), 56.5 (2-OCH3), 55.0 (C-5), 50.7 (C-7a), 47.1 (C-7), 43.5 (N-Me), 27.1 (C-4). MS: m/e (%) 297 (M+, 100), 97 (23), 85 (23), 83 (33), 81 (37), 73 (21), 71 (45), 70 (23), 69 (81), 67 (23), 60 (23), 57 (90), 55 (78), 45 (30), 43 (100), 41 (79).
HPLC: Retention time of 16.94 minutes.
First isolated from leaves of Ocotea glaziovii Mez, Lauraceae (Gilbert et al. 1964).
Also isolated from: Annonaceae: Annona purpurea Moc. & Sessé ex Dunal. (Sonnet & Jacobson 1971); aerial part of Desmos tiebaghiensis (Däniker) R.E. Fr. (Leboefuf et al. 1982); bark and leaves of Guatteria sagotiana R.E. Fr. (Rasamizafy et al. 1986); Neostenanthera gabonensis (Engl. & Diels) Exell (Renner & Achenbach 1988); stem bark of Annona cherimolia Mill. (Siméon et al. 1990). Berberidaceae: Berberis brandisiana Ahrendt (Hussain et al. 1986). Euphorbiaceae: Croton sparsiflorus Morong (Bhakuni et al. 1970; Bhakuni & Jain 1981). Fumariaceae: Corydalis claviculata (L.) DC. (Allais & Guinaudeau 1990). Lauraceae: Leaves of Ocotea brachybotra (Meiss.) Mez (Vecchietti et al. 1977*); Litsea cubeba (Lour.) Pers. (Sun et al. 1996); roots of Nectandra salicifolia (H.B.K.) Nees (Böhlke et al. 1996). Menispermaceae: Pachygone ovata (Poir.) Hook. f ex Thomson (Dasgupta et al. 1979); Stephania venosa (Blume) Spreng. (Charles et al. 1987); Stephania cephalantha Hayata (Nawai et al. 1999). 268
Papaveraceae: Papaver caucasicum M. Bieb., P. persicum Lindl., P. triniaefolium Boiss, P. fugax Poir and P. polychaetum Schott & Kotschy ex Boiss. (Pfeifer & Kuhu 1968a, b); Meconopsis cambrica (L.) Vig. (Hemingway & Phillipson 1975).
5.2.2.2 Crotsparine (5)
C17H17NO3
CH3O
N HO H H
O Class of compound: Proaporphine
1 H NMR: δH 6.96 (1H, dd, J 9.9 and 2.7 Hz, H-8), 6.84 (1H, dd, J 9.9 and 3.0 Hz, H-12), 6.56 (1H, s, H-3), 6.36 (1H, dd, J 9.9 and 1.8 Hz, H-9), 6.26 (1H, dd, J 9.9 and
1.8 Hz, H-11), 4.25 (1H, dd, J 10.2 and 6.0 Hz, H-6a), 3.80 (3H, s, OCH3), 3.42
(1H, ddd, J 12.9, 6.3 and 1.8 Hz, H-5eq), 3.12 (1H, ddd, J 12.9, 10.8 and 6.3 Hz,
H-5ax), 2.69 (2H, m, H-4), 2.36 (1H, dd, J 12.0 and 6.6 Hz, H-7), 2.16 (1H, dd, J 12.0 and 10.8 Hz, H-7).
13 C NMR: δC 186.1 (C-10), 153.2 (C-12), 149.4 (C-8), 147.2 (C-2), 140.7 (C-1), 135.7 (C- 7c), 128.7 (C-9), 127.5 (C-11), 123.7 (C-7b), 123.4 (C-3a), 110.2 (C-3), 57.9 (C- 6a), 56.6 (2-OMe), 50.8 (C-7a), 48.2 (C-7), 45.2 (C-5), 26.1 (C-4).
MS: m/e (%) 284 (19), 283 (M+, 100), 169 (27), 97 (26), 85 (55), 83 (84), 81 (31), 71 (37), 69 (100), 57 (65), 55 (48), 47 (23), 43 (65), 41 (46).
HPLC: Retention time of 13.34 minutes.
269
First isolated from the whole plant of Croton sparsiflorus Morong (Syn C. bonplandium Bail), Euphorbiaceae (Bhakuni & Dhar 1968, 1969*; Bhakuni et al. 1970; Bhakuni & Jain 1981).
Also isolated from: Annonaceae: Annona purpurea Moc. & Sesse ex Dunal (Sonnet & Jacobson 1971); leaves of Alphonsea sclerocarpa Thwaites. (Tadić et al. 1987); Desmos tiebaghiensis (Däniker) R.E. Fr. (Leboeuf et al. 1982); leaves of Guatteria sagotiana R.E. Fr. (Rasamizafy et al. 1986); Neostenanthera gabonensis (Engl. & Diels) Exell (Renner & Achenbach 1988); seeds of Monodora brevipes Benth. (Etse et al. 1989); stem of Uvaria klaineana Engl. & Diels (Akendengue et al. 2002). Berberidaceae: Berberis brandisiana Ahrendt (Hussain et al. 1986). Euphorbiaceae: Croton ruizianus Müell. Arg. (Del Castillo Cotillo et al. 1996). Fumariaceae: Corydalis claviculata DC. (Allais & Guinaudeu 1990). Lauraceae: stem bark of Nectandra salicifolia (Böhlke et al. 1996). Menispermaceae: Pachygone ovata (Poir.) Miers ex Hook. f. & Thomson (Dasgupta et al. 1979); Stephania cephalantha Hayata (Nawai et al. 1999). Papaveraceae: Papaver caucasicum M. Bief., P. persicum Lindl., P. triniaefolium Boiss., P. fugax Poir and P. polychaetum Schott & Kotschy ex Boiss (Pfeifer & Kuhn 1968a, b); Meconopsis cambrica (L.) Vig. (Hemigway & Phillipson 1975; Hemingway et al. 1981).
270
5.2.3 Extraction and isolation of alkaloids from Antizoma miersiana
Antizoma miersiana was collected in February 2001 at Botterkloof Pass (Clanwilliam, Western Cape Province, SA) and a voucher specimen (Van Wyk & De Wet, 4067) was deposited in the herbarium of the University of Zululand (ZULU).
Extraction of leaves Air-dried, ground leaves (377 g) were extracted as described under General Experimental Techniques to yield 25.21 g of a crude alkaloid extract. Column chromatography of 2 g of alkaloid extract yielded crotsparine (5) (205 mg) (5.2.2.2) and bulbocapnine (6) (16 mg) (Figure 5.7).
Figure 5.7. TLC plate showing purified alkaloids from Aantizoma miersiana leaves. B = Bulbocapnine (6) and E = Crotsparine (5).
Extraction of rhizome Air-dried, ground rhizome (641 g) was extracted as described under General Experimental Techniques to yield 13.1 g of a crude alkaloid extract. Column chromatography of 0.7 g of alkaloid extract yielded cissacapine (7) (222 mg), cycleanine (8) (3 mg), cycleaneonine (9) (6 mg), insulanoline (10) (12 mg) and insularine (11) (77 mg) Figure 5.8. 271
Figure 5.8. TLC plate showing purified alkaloids from Antizoma miersiana rhizomes. B = Cycleaneonine (9), C = Cycleanine (8), D = Insularine (11), E = Cissacapine (7), F = insulanoline (10) (not spotted on plate) and G = unidentified because of its impurity.
5.2.3.1 Bulbocapnine (6)
C19H19NO4
O
N O CH3 HO
CH3O
Class of compound: Aporphine
1 H NMR: δH 7.00 (1H, s, OH), 6.81 (2H, s, H-8,9), 6.62 (1H, s, H-3), 6.08 (1H, d, J 1.2 Hz,
OCH2O), 5.93 (1H, d, J 1.2 Hz, OCH2O), 3.89 (3H, s, OCH3), 3.16-2.90 (4H, m,
H-4, 5, 6a, 7), 2.63 (1H, dd, J 16.2 and 3.6 Hz, H-4), 2.52 (3H, s, N-CH3), 2.52- 2.40 (2H, m, H-5, 7).
13 C NMR: δC 148.2 (C-10) 145.9 (C-2), 142.8 (C-11), 140.4 (C-1), 129.6 (C-7a), 128 (C- 11a), 127.3 (C-3a), 119.2 (C-8), 118.4 (C-11a), 114.2 (C-11b), 110.8 (C-9), 107.6 272
(C-3), 100.2 (OCH2O), 62.7 (62.7 (C-6a), 56.1 (OMe), 53.0 (C-5), 44.0 (N-CH3), 35.4 (C-7), 29.4 (C-4).
MS: m/e (%) 325 (M+, 100), 324 (60), 310 (86), 282 (25), 280 (26), 97 (21), 85 (56), 83 (91), 81 (23), 72 (52), 71 (32), 69 (62), 60 (21), 59 (89), 57 (54), 55 (56), 47 (23), 44 (27), 43 (69), 42 (27), 41 (54).
HPLC: Retention time of 22.14 minutes.
Also isolated from: Lauraceae: Laurus nobilis L. (Tomita et al. 1963*); Cassytha americana Nees [C. filiformis L.] (Cava et al. 1968); Lindera strychnifolia Villar and L. umbellata Thunb. (Tomita et al. 1969*). Menispermaceae: Cissampelos pareira L. (Ahmad et al. 1992). Papaveraceae: Corydalis sp. (Gadamer & Kuntze 1911*; Manske 1954*; Preininger et al. 1976*; Margvelashvili et al. 1976*; Margvelashvili 1978*; Verzar & Minh Hoang 1978*; Slavík & Slavíkova 1979*; Kiryakov et al. 1979*; Khusainova & Sadykov 1981*; Kiryakov et al. 1982*); Corydalis cava Schweigg. & Kort. (Spaeth et al. 1928*; Verzar et al. 1984*; Gasic et al. 1985*; Petri et al. 1986*); Dicentra sp. (Manske 1954); Corydalis marschalliana Pers. (Kiryakov et al. 1974*); Glaucium sp. (Lalezari et al. 1976*; Shafiee et al. 1977a*, b; Shafiee & Lajevardi 1978; Shafiee et al. 1979); Corydalis solida Sw. (Kiryakov et al. 1982*; Gasic et al. 1991*); Corydalis bulbosa (L.) DC. (Kiryakov & Iskrenova 1984*); Glaucium corniculatum (L.) Rudolph ssp. refractum (Shafiee et al. 1985); Corydalis integra Barb. & Major (Allais et al. 1988*); Hypecoum imberbe Sibth. & Sm. (Pabuççuoglu et al. 1989); Corydalis intermedia (L.) Mérat (Slavík & Slavíková 1989*); Corydalis caucasica (M. Bieb.) DC. (Sener 1989*; 273
Denisenko et al. 1991); Corydalis hsiaowutaishanensis Wang (Zhou et al. 1991*); Corydalis rutaefolia DC. ssp. erdelii (Sener et al. 1991*); Corydalis solida SW. ssp. brachyloba Boiss. (Sener & Temizer 1991*).
5.2.3.2 Cissacapine (7)
C38H38N2O6
H3CO
N O CH3 O H
O H H3C O N
OCH3
Class of compound: Bisbenzyltetrahydroisoquinoline
1 H NMR: δH 7.03 dd (1H, dd, J 8.1, 1.8 Hz, H-13), 6.55 (1H, d, J 8.1 Hz, H-14), 6.44 (1H, s, H-5), 5.77 (1H, d, J 1.8 Hz, H-10), 4.80 d (1H, d, J 14.1 Hz, H-15b), 4.47 (1H, d, J 14.1, H-15a) 4.15 (1H, dd, J 12.0, 2.7 Hz, H-1), 3.82 (3H, s, 6-OMe), 3.42-3.30, 3.10 (1H, ddd, J 12.3, 3.3 Hz, H-α), 2.55 (3H, s, N-Me).
13 C NMR: δC 150.2 (C-12), 149.7 (C-6), 146.9 (C-8), 139.6 (C-7), 131.5 (C-9), 129.8 (C-4a), 129.0 (C-14), 126.1 (C-10), 123.8 (C-11), 121.4 (C-8a), 121.4 (C-13), 107.1 (C- 5), 75.9 (C-15), 59.1 (C-1), 56.1 (6-OMe), 45.3 (C-3), 42.9 (N-Me), 40.5 (C-α), 24.9 (C-4). MS: m/e (%) 619 (43), 618 (M+, 100), 169 (34), 97 (36), 85 (34), 84 (24), 83 (52), 81 (41), 71 (43), 70 (22), 69 (100), 67 (25), 57 (86), 56 (28), 55 (80), 45 (28), 43 (24), 43 (98), 41 (68).
HPLC: Retention time of 28.60 minutes. 274
First isolated from Cissampelos capensis (L.f.) Diels, Menispermaceae (Van Heerden et al., unpublished results) Literature: None
5.2.3.3 Cycleanine (8)
C38H42N2O6
CH3O
N CH3O CH3 O
O
CH3 OCH3 N
OCH3
Class of compound: Bisbenzyltetrahydroisoquinoline 1 H NMR: δH 7.02 (2H, dd, J 8.4, 2.7 Hz, H-14, 14’), 6.58 (1H, J 8.4, 2.7 Hz, H-13, 13’), 6.55 (2H, s, H-5, 5’), 6.26 (2H, dd, J 8.4, 2.7 Hz, H-10, 10’), 5.80 (2H, dd, J 8.4, 2.7 Hz, H-11, 11’), 4.25 (2H, d, J 9.9 Hz, H-1, 1’), 3.79 (6H, 2 x OMe), 3.38 (6H, 2 x OMe), 2.51 (2 x NMe).
275
HPLC: Retention time of 26.34 minutes.
First isolated from Cissampelos insularis Makino (Kondo et al. 1937*).
Also isolated from: Annonaceae: Cleistopholis staudtii Engl & Diels (Waterman & Mohammed 1984*); Isolona hexaloba (Pierre) Engl. & Diels (Hocquemiller et al. 1984*; Fournet et al. 1998). Menispermaceae: Root of Cissampelos insularis Makino [Paracyclea insularis (Makino) Kudo & Yamamoto] (Kondo et al. 1937*); tuber of Stephania cephalantha Hayata (Kondo et al. 1937*, 1938*; Tomita & Kishikita 1944*; Tomita & Kozuda 1966*; Kunimoto et al. 1981*; Zhu et al. 1983*; Kimura et al. 1986a*; Sugimoto et al. 1988; Sugimoto & Yamada 1989; Kinoshita et al. 1992; Deng et al. 1992; Kashiwaba et al. 1994*; Kashiwaba et al. 1997); Stephania capitata Spreng (Tomita & Shirai 1942*); stem and bark of Chondodendron tomentosum Ruiz & Pav. (Dutcher 1946; Bick & Clezy 1960*); Root of Cyclea insularis (Makino) W.Y. Lien (Kikuchi & Bessho 1958*); tuber and above ground parts of Stephania rotunda Lour. [S. glabra (Roxb.) Miers] (Shchelchkova et al. 1965*); root of Epinetrum cordifolium Mangenot & Miège and E. mangenotii Guill. & Debray (Debray et al. 1966); stem, root and rhizome of Paracyclea ochiaiana (Yamamoto) Kudo & Yamamoto (Tomita et al. 1967*) leave and root of Epinetrum villosum (Excell) Troupin (Bouquet & Cave 1971*); roots of Cissampelos pareira (Roychowdhurry 1972*; Dwuma-Badu et al. 1975; Dou et al. 1987*); Limaciopsis loangensis Engl. (Cavé et al. 1979*); roots of Synclisia scabrida Miers (Scheinmann et al. 1980; Ohiri et al. 1981*, 1983); whole plant of Stephania elegans Hooks. f & Thomson (Singh et al. 1981); Cyclea tonkinensis Gagnep. (Chou et al. 1981*); Cyclea hypoglauca Diels (Zhou et al. 1982*); 276 rhizome of Stephania glabra (Roxv.) Miers (Bhakuni & Gupta 1982; Bhakuni et al. 1983; Martinez et al. 1998); root of Stephania epigeaeaH.S. Lo (Huang & Chen 1979*; Yang & Luo 1980*; Chen et al. 1985*; Kimura et al. 1986b*) tuber of Stephania pierrei Diels (Kimura et al. 1986b*; Tantisewie et al. 1989); Stephania tetrandra S. Moore (Zhu et al. 1983*; Ogino et al. 1988); Cyclea sutchuenensis Gagnep. (Lai et al. 1993a); root of Anisocycla jollyana (Pierre) Diels (Kanyinda et al. 1997).
Umbelliferae/Apiaceae: root of Heracleum wallichii DC. (Gupta et al. 1976*).
5.2.3.4 Cycleaneonine (9)
C38H42N2O6
CH3O
N O CH3 OH
O
CH3 OCH3 N
OCH3
Class of compound: Bisbenzyltetrahydroisoquinoline
1 H NMR: δH 7.13 (2H, d, J 8.0 Hz, H-10’, 14’), 7.01 (2H, d, J 8.0 Hz, H-11’, 13’), 6.80 (2H, d, J 8.6, H-10, 14), 6.61 (2H, d, J 8.6 Hz, H-11, 13), 6.51 (1H, s, H-5’), 6.10 (1H,
s, H-5), 5.13 (1H, d, J 12.0, OCH2), 5.01 (1H, br. s, OH), 4.97 (1H, d, J 12.0,
OCH2), 3.84 (3H, s, 6’-OMe), 3.83 (3H, s, 6-OMe), 3.66 (3H, s, 7’-OMe), 2.33 (3H, s, N-Me), 2.15 (3H, s, N’-Me).
MS: m/e 622 (20, M+), 312 (71), 311 (100)
277
First isolated from root of Cyclea racemosa Oliver, Menispermaceae (Dreyfuss et al. 1987*; Lai et al. 1988).
Also isolated from: Menispermaceae: stem of Cyclea racemosa Oliver and root of C. sutchuenensis Gagnep. (Wang et al. 1993a, b).
5.2.3.5 Insulanoline (10)
C37H38N2O6
CH3O
N O CH3 O H
H O H3COH N
OCH3
Class of compound: Bisbenzyltetrahydroisoquinoline
1 H NMR: δH 7.16 (1H, dd, J 8.4 Hz, H-10’), 6.88 (2H, m, H-11’, 14), 6.47 (1H, s, H-5 or 5’), 6.44 (1H, s, H-5 or 5’), 6.19 (1H, d, J 8.4 Hz, H-13), 6.12 (1H, d, J 1.8 Hz, H- 10), 6.05 (1H, dd, J 8.4 and 2.1 Hz, H-14’), 5.53 (1H, dd, J 8.4 and 2.1 Hz, H- 13’), 4.95 (1H, d, J 14.4 Hz, H-15), 4.76 (1H, d, J 14.1 Hz, H-15), 4.36 (1H, dd, J 12.0 and 2.7 Hz, H-1 or H-1’), 4.21 (1H, d, J 9.9 Hz, H-1 or 1’), 3.83 (OMe), 3.79 (OMe), 2.57 (NMe), 2.33 (NMe).
MS: m/e (%) 607 (42), 606 (M+, 100), 169 (75), 149 (35), 147 (36), 97 (32), 85 (25), 83 (33), 71 (41), 70 (30), 69 (100), 57 (69), 56 (24), 55 (47), 44 (47), 43 (78), 42 (24), 41 (50).
278
HPLC: Retention time of 27.78 minutes.
Isolated from: Menispermaceae: rhizome of Cyclea insularis (Makino) W.Y. Lien (Kikuchi & Bessho 1958); root of Cyclea hypoglauca Diels (Fang et al. 1985*; Unadkat et al. 1986*); root of Cyclea sutchuenensis Gagnep. (Lai et al. 1993; Sheng et al. 1993*; Wang et al. 1993b).
5.2.3.6 Insularine (11)
C38H40N206
CH3O
N O CH3 O H
H O H3C OCH3 N
OCH3 Class of compound: Bisbenzyltetrahydroisoquinoline
1 H NMR: δH 7.10 (1H, dd J 8.4 and 2.4 Hz, H-10’), 6.85 (1H, dd, J 8.4 and 2.1 Hz, H-14), 6.79 (1H, dd, J 8.1 and 2.7 Hz, H-11’), 6.51 (1H, s, H-5), 6.46 (1H, s, H-5’), 6.16 279
(1H, d, J 8.4 Hz, H-13), 6.14 (1H, d, J 2.1 Hz, H-10), 6.02 (1H, dd, J 8.4 and 2.1 Hz, H-14’) 5.53 (1H, dd, J 8.4 and 2.7 Hz, H-13’), 4.94 (1H, d, J 14.7 Hz, H-15), 4.75 (1H, d, J 14.1 Hz, H-15), 4.33 (1H, dd, J 11.7 and 2.7 Hz, H-1), 4.14 (1H, d, J 9.3 Hz, H-1’), 3.83 (3H, s, 7’-OMe), 3.78 (3H, s, 6-OMe), 3.31 (3H, s, 7-OMe), 2.54 (3H, s, NMe), 2.49 (3H, s, NMe).
13 C NMR: δC 154.7 (C-12’), 152.3 (C-6), 151.4 (C-12), 150.4 (C-6’), 147.8 (C-8’), 143.8 (C- 8), 140.3 (C-7’), 139.0 (C-7), 131.6 (C-9’), 130.7 (C-9), 130.5 (C-4a), 129.7 (C- 4a’), 129.7 (C-14), 129.7 (C-10’), 127.7 (C-14’), 127.3 (C-10), 124.8 (C-8a), 124.6 (C-11), 122.8 (C-8a’), 120.4 (C-13), 117.7 (C-11’), 113.1 (C-13’), 109.2 (C-5), 108.1 (C-5’), 75.9 (C-15), 66.3 (7-OMe), 59.9 (C-1’), 58.6 (C-1), 56.6 (6’- OMe), 56.4 (6-OMe), 45.5 (C-3), 45.2 (C-3’), 43.3 (N’-Me), 42.8 (N-Me), 42.1 (C-α), 36.8 (C-α’), 24.7 (C-4), 23.1 (C-4’).
MS: m/e (%) 621 (44), 620 (M+, 100), 169 (58), 147 (29), 97 (31), 83 (33), 81 (25), 71 (30), 69 (100), 57 (59), 55 (51), 45 (20), 43 (68), 41 (43).
HPLC: Retention time of 29.95 minutes.
First isolated form Cissampelos insularis Makino, Menispermaceae (Kondo & Yano 1927*).
Also isolated from: Menispermaceae: Cissampelos insularis Makino [Paracyclea insularis (Makino) Kudo & Yamamoto] (Kondo et al. 1937*); Cyclea insularis (Tomita & Uyeo 1943; Tomita & Kikuchi 1957; Kikuchi & Bessho 1958*); Stephania japonica Miers (Satomi 1955); stem root and 280 rhizome of Paracyclea ochiaiana (Tomita et al. 1967*); root of Cissampelos pareira L. (Dwuma-Badu et al. 1975); root of Cyclea hypoglauca Diels (Fang et al. 1985*); root of Cyclea sutchuenensis Gagnep. (Lai et al. 1993b; Sheng et al. 1993*).
Genus Cissampelos
The genus Cissampelos was revised by Rhodes in 1975 and consists of 19 species, of which eight were studied phytochemically (Thornber 1970; Barbosa-Filho et al. 2000): 1: C. insularis, from which were isolated an aporphine (magnoflorin), a protoberberine (cyclanoline) and five bisbenzyltetrahydroisoquinoline alkaloids (cycleanine, norcycleanine, isochondodendrine, insularine and insulanoline). 2: C. ochiaiana from which were isolated four bisbenzylisotetrahydroquinoline alkaloids (insularine, 1-curine, isochondodendrine, cycleanine). 3: C. mucronata from which only one alkaloid, d-isochondodendrine (bisbenzyltetrahydroisoquinoline) was isolated. 4: C. fasciculata from which were isolated an aporphine (corydine) and a bisbenzyltetrahydroisoquinoline (cissampetine). 5: C. ovalifolia from which was isolated four bisbenzyltetrahydroisoquinoline alkaloids (warifteine, dihydrowarifteine, methylwarifteine and dimethylwarifteine). 6: C. sympodialis from which were isolated a morphinane (milonine) and a bisbenzyltetrahydroisoquinoline (warifteine). 7: C. glaberrima from which were isolated a stephanooxocane alkaloid (eletefine), three aporphine alkaloids (cissaglaberrimine, oxobuxifolin and magnoflorine). 8: C. pareira the most studied species in this genus, from which was obtained 26 alkaloids: aporhine (6), bisbenzyltetrahydroisoquinoline (10), tropoloneisoquinoline (5), azafluoranthene (2), protoberberine (2) and benzyltetrahydroisoquinoline alkaloid (1).
5.2.4 Extraction and isolation of alkaloids from Cissampelos capensis
Cissampelos capensis (inland form) was collected in March 2000 at Ladismith (Western Cape Province, SA) and a voucher specimen (De Wet, 10) was deposited in the herbarium of the University of Zulualand (ZULU). Extraction of leaves Air-dried, ground leaves (24 g) were extracted as described under General Experimental Techniques to yield 0.15 g of a crude alkaloid extract. Column chromatography 0.14 g of 281 alkaloid extract yielded dicentrine (12) (8 mg), glaziovine (4) (30 mg), lauroscholtzine (13) (7 mg) and pronuciferine (14) (2.5 mg) (Figure 5.9).
Figure 5.9. TLC plate showing purified alkaloids from Cissampelos capensis (inland form) leaves. A = Dicentrine (12), D = Glaziovine (4), E = Lauroscholtzine (13).
Extraction of rhizome Air-dried, ground rhizome (149 g) was extracted as described under General Experimental Techniques to yield 5.1 g of a crude alkaloid extract. No alkaloids were identified from the 2 g alkaloid extract used in column chromatography (Figure 5.10).
Figure 5.10. TLC plate showing alkaloids from Cissampelos capensis (inland form) rhizomes. No alkaloids were identified from these samples.
282
Cissampelos capensis (coastal form) was collected in March 2000 at Still Bay and Mossel Bay (Western Cape Province, SA) and voucher specimens (De Wet 3 and 4 respectively) were deposited in the herbarium of the University of Zululand (ZULU).
Extraction of leaves Air-dried, ground leaves (17 g) from Mossel Bay were extracted as described under General Experimental Techniques to yield 0.4 g of a crude alkaloid extract. Column chromatography of 0.4 g of alkaloid extract yield: bulbocapnine (6) (30 mg) (§ 5.2.3.1) and salutaridine (15) (53 mg) (Figure 5.11).
Figure 5.11. TLC plate showing purified alkaloids from Cissampelos capensis (coastal form) leaves. B = Bulbocapnine (6) and C = Salutaridine (15).
Extraction of rhizome Air-dried, ground rhizome (57 g) from Still Bay were extracted as described under General Experimental Techniques to yield 0.4 g of a crude alkaloid extract. Column chromatography of 0.3 g alkaloid extract yielded cycleanine (8) (31 mg) (§ 5.2.3.3) (Figure 5.12). 283
Figure 5.12. TLC plate showing purified alkaloids from Cissampelos capensis (coastal form) rhizomes. A = Cycleanine (8), B and E are mixtures of two alkaloids.
5.2.4.1 Dicentrine (12)
C20H21NO4 O
N O CH3
CH3O OCH 3 Class of compound: Aporphine
1 H NMR: δH 7.65 (1H, s, H-11), 6.76 (1H, s, H-8), 6.49 (1H, s, H-3), 6.05 (1H, d, J 1.5 Hz,
OCHO), 5.91 (1H, d, J 1.5 Hz, OCH2O), 3.90 (3H, s, OCH3), 3.89 (3H, s, OCH3),
3.09 (4H, m), 2.62 (3H, m), 2.53 (3H, s, N-CH3).
13 C NMR: δC 148.1 (C-9), 147.6 (C-10), 146.5 (C-2), 141.7 (C-1), 128.2 (C-7a), 126.5 (C- 3a), 126.2 (C-1b), 123.4 (C-11a), 116.5 (C-1a), 111.2 (C-11), 110.4 (C-8), 106.7
(C-3), 100.6 (OCH2O), 62.4 (C-6a), 56.1 (OMe), 55.9 (OMe), 53.6 (C-5), 43.9 (N-Me), 34.2 (C-7), 29.2 (C-4). MS: m/e (%) 39 (M+, 2), 178 (24), 97 (23), 85 (22), 83 (33), 81 (37), 71 (38), 70 (21), 69 (93), 67 (24), 60 (24), 59 (44), 57 (84), 56 (28), 55 (80), 45 (33), 44 (30), 43 (100), 41 (97). 284
HPLC: Retention time of 24.89 minutes.
Also isolated from: Annonaceae: Duguetia sp. (Casagrande & Ferrari 1970); Polyalthia cauliflora Hook f. & Thomson (Jossang et al. 1984); Guatteria scandens Ducke (Hocquemiller et al. 1983); Dasymaschalon sootepense Craib (Sinz et al. 1998). Hernandiaceae: stem of Illigera luzonensis Merr. (Wang & Cheng 1968; Chen et al. 1997); Hernandia jamaicensis Britton & Harris (Cava & Venkateswarlu 1971); Illigera pentaphylla Welw. (Ross et al. 1985); Hernandia voyroni Jumella (Rasoanaivo et al. 1998). Lauraceae: Laurus nobilis L. (Tomita et al. 1963*); Cassytha melantha R. Br. (Johns et al. 1966*); Cassytha americana Nees (Cava et al. 1968); Lindera oldhami Hemsl. (Lu et al. 1972*, 1977); Ocotea macropoda (Kunth) Mez (Venkateswarlu 1972*); Litsea sp. (Patnaik & Gopinath 1975*); Ocotea brachybotra (Meiss.) Mez. (Vecchietti et al. 1977*); Ocoteae minarum Mart. ex Nees (Vecchietti et al. 1979); leaves of Litsea salicifolia Hook. f. (Rastogi & Borthakur 1980); Litsea deccanensis Gamble (Gupta & Bhakuni 1989*); root of Lindera megaphylla Hemsl. (Chen et al. 1991; Chou et al. 1994; Chen et al. 1995; Tsai et al. 1996; Huang et al. 1998); Ocotea velloziana (Meisn.) Mez (Garcez et al. 1995); Actinodaphne sesquipedalis Hook. f. & Thomson (Din et al. 1994); Ocotea leucoxylon (Sw.) Laness. (Zhou et al. 2000); Cassytha filiformis L. (Stevigny et al. 2002). Menispermaceae: Cocculus laurifolius DC. (Tomita & Kusuda 1953*); Stephania dinklagei Diels (Quevauviller & Sarrazin 1967; Camacho et al. 2000); root of Cissampelos pareira L. (Dwuma-Badu et al. 1975); Stephania sp. (Chen et al. 1982*); Stephania mashanica H.S. Lo & B.N. Wang (Wang & Wei 1983*); Stephania dicentrinifera H.S. Lo & M. Yang (Min & Zheng 1984*); Stephania epigeae H.S. Lo (Chen et al. 1987*); Stephania disciflora Hand.-Mazz. (Tian 285
& Wu 1988*); Stephania zippeliana Miq. (Charles et al. 1989*); Cyclea laxiflora (Lajis et al. 1991*); Stephania sp. (Ruan et al. 1991*); Stephania brachyandra Diels (Peng et al. 1992*); Stephania dentifolia H.S. Lo & M. Yang (Chen & Fang 1992*); tuber of Stephania pierrei Diels (Likhitwitayawuid et al. 1993); Stephania abysinica Walp. (Kande et al. 1994); seed of Stephania cephalantha Hayata (Kashiwaba et al. 2000). Magnoliaceae: Liriodendron tulipifera L. (Chen et al. 1976; Rzedowski et al. 1985); Aromadendron elegans Blume (Goh & Jantan 1992; Jantan et al. 2001); leaves of Magnolia coco (Lour.) DC. (Yu et al. 1998); Papaveraceae: Dicentra eximia (Ker-Gawl.) Torr. (Manske 1933*); Dicentra formosa Walp. (Manske 1934*); Dicentra oregana Eastw. (Manske 1934*); Glaucium contortuplicatum Boiss. (Tin-Wa et al. 1976); aerial part and root of Glaucium flavum Crantz (Lalezari et al. 1976*; Shafiee et al. 1977b); Glaucium vitellinum Boiss. & Buhse (Shafiee et al. 1977; Shafiee et al. 1979); Glaucium oxylobum Boiss. & Buhse (Shafiee et al. 1977); Papaver sp. (Shafiee & Lajevardi 1978, Shafiee et al. 1979); Glaucium corniculatum (L.) Rudolph (Ghanbarpour et al. 1978; Shafiee et al. 1985); Corydalis cava (L.) Schweigg. & Kort. (Slavik & Slavikova 1979*); Corydalis solida Sw., (Kiryakov et al. 1982*); Dicentra spectabilis (L.) Lem. (Ma et al. 2000); aerial parts of Glaucium oxylobum Boiss & Buhse (Morteza-Semnani et al. 2003).
5.2.4.2 Luaroscholtzine (13)
C20H23NO4
CH3O
N CH3O CH3
CH3O OH
Class of compound: Aporphine 1 H NMR: δH 7.90 (1H, s), 6.77 (1H, s), 6.63 (1H, s), 3.92 (3H, s, OMe), 3.89 (3H, s, OMe), 3.58 (3H, s, OMe), 2.52 (3H, s, NMe).
MS: m/e (%) 341 (M+, 23), 340 (25), 335 (20), 168 (82), 147 (44), 119 (22), 97 (30), 83 (22), 71 (25), 69 (100), 57 (50), 55 (40), 44 (53), 43 (55), 41 (44). 286
HPLC: Retention time of 20.95 minutes.
Also isolated from: Annonaceae: Enantia sp. (Jossang et al. 1977*); Guatteria scandens Ducke (Hocquemiller et al. 1983); leaves of Guatteria goudotiana Triana & Planch. (Castedo et al. 1984*, 1991); aerial parts of Desmos tiebaghiensis (Däniker) R.E. Fr. (Leboeuf et al. 1982); Xylopia sp. (Leboeuf et al. 1982); stem of Annona cherimola Miller (Chen et al. 1997); leaves of Orophea hexandra Blume (Sinz et al. 1999); leaves of Dasymaschalon sootepense Craib. (Sinz et al. 1998); stem of Anomianthus dulcis (Dunal) J. Sincl. (Sinz et al. 1998); leaves of Annona purpurea Moc. & Sessé ex Dunal (Fu et al. 1986a*, b*; Chang et al. 1998). Hernandiaceae: Hernandia sp. (Cava et al. 1966); Hernandia jamaicensis Britton & Harris (Cava & Venkateswarlu 1971); Hernandia nymphaeifolia (Presl.) Kubitzki (Yakushijn et al. 1980; Chen et al. 2001); Hernandia sp. (Lavault et al. 1980*, 1982b*); Hernandia voyroni Jumelle (Rasoanaivo et al. 1998). Lauraceae: Litsea citrata Blume (Spaeth & Suominen 1933); Neolitsea sericea Koidz. (Nakasato et al. 1966*); Litsea cubeba Pers. (Lu & Lin 1967; Wu et al. 1991; Lee et al. 1992*; Sun et al. 1997); Cassytha racemosa Nees (Johns et al. 1967*); Neolitsea pubescens (Teschn.) Merr. (Johns et al. 1969*); Ocotea macropoda Mez (Cava & Venkateswarlu 1971); Actinodaphne obovata Blume (Uprety et al. 1972); Litsea sebifera Pers. (Uprety et al. 1972); Cryptocarya odorata Guillaum (Bick et al. 1972*); Litsea glutenosa (Lour.) C.B. Rob. var. glabraria (Juss.) V. Mudgal & K.K. Khanna (Tewari et al. 1972); Cryptocarya longifolia Kosterm. (Bick et al. 1981*); Litsea sp. (Lebeuf et al. 1979*, Castedo et al. 1980*); Lindera sp. 287
(Kozuka et al. 1984); Lindera glauca Blume, L. erythrocarpa Makino and L. citriodora Hemsl. (Kozuka et al. 1984); Litsea gardneri Meisn. and Actinodaphne speciosa Nees (Bandara et al. 1989); leaves of Dehaasia triandra Merr. (Lu et al. 1989; Lee et al. 1996; Sun et al. 1997); Lindera pipericarpa Boerl. (Lajis et al. 1992*); Neolitsea konishii (Hayata) Kanehira & Sasaki (Lee & Yang 1992*); stem bark of Nectandra salicifolia Nees (Böhlke et al. 1996); aerial parts of Lindera glauca Blume (Chang 2001). Mangnoliaceae: Liriodendron sp. (Chen et al. 1974*); Liriodendron tulipifera L. (Chen et al. 1976; Ziyaev et al. 1986*; Huang Hsu & Chen 1991*). Menispermaceae: Stephania sp. (Chen et al. 1982*). Monimiaceae: Peumus boldus Molina (Ruegger 1959*; Genest & Hughes 1968; Vanhaelen 1973; Urzúa & Acuña 1983*; Pietta et al. 1988); Palmeria fengeriana Perkins (Johns et al. 1967*); Palmeria species (Johns et al. 1970*; Loder et al. 1970); Nemuaron vieillardi Baill. (Bick et al. 1973*); Monimia sp. (Leboeuf et al. 1980*; Forgacs et al. 1981*); Monimia rotundifolia Thou. (Leboeuf et al. 1980*); Hedycarya badaunii Baill. (El-Tohami et al. 1983*); Glossocalyx brevipes Benth. (Montgomery et al. 1985); Siparuna pauciflora (Beurl.) DC. (Lopez et al. 1988*); Siparuna tonduziana Perkins (López et al. 1990); Siparuna griseo- flavescens Perkins (López et al. 1993); Siparuna apiosyce (Mart.) DC. (Leitäo et al. 2000). Papaveraceae: shoot of Eschsholzia californica Cham. (Manske & Shin 1965, Döpke & Fritsch 1970*; Parfeinikov & Murav’eva 1983*; Slavík & Slavíkova 1986*; Guédon et al. 1990*; Fabre et al. 2000); Glaucium corniculatum (L.) Rudolph (Ghanbarpour et al. 1978; Shafiee et al. 1985); Glaucium sp. (Shafiee & Lajevardi 1978); Glaucium vitellinum Boiss. & Buhse (Shafiee et al. 1979); Papaver sp. (Sariyar & Öztekin 1981*); Papaver apokrinomenon Fedde (Öztekin et al. 1984, 1985*; Sariyar 2002); Papaver strictum Boiss. & Balansa (Öztekin et al. 1985*; Sariyar 2002); Eschscholtzia species (Slavik & Slavikova 1986*); tuber and aerial part of Corydalis turtschaninovii Bess. (Fu et al. 1986a*, b*; Liang & Tu 1986); Eschscholtzia douglasii (Hook & Arn) Walp. (Slavík & Slavíkova 1986*); Eschscholtzia glauca Greene (Slavík & Slavíkova 1986*); Sarcocapnos crassifolia DC. subsp. speciosa (Desf.) DC. (Castedo et al. 1988); Platycapnos spicatus (L.) Bernh. (Blanco et al. 1990, 1993); Corydalis caucasica DC. (Denisenko et al. 1991). Ranunculaceae: Thalictrum sp. (Wu et al. 1977); Delphinium sp. (Salimov et al. 1978*); Thalictrum dioicum L. (Shamma & Rothenberg 1978*); root of Thalictrum revolutum DC. (Wu et al. 1980); Thalictrum isopyroides C.A. Mey. (Al-Khalil & Schiff 1986); Thalictrum hazaricum R.A. Qureshi & M.N. Chaudhri (Herath et al. 1987). 288
Rhamnaceae: Phylica rogersii Pillans (Arndt & Baarschers 1964); Colubrina faralaotra (H. Perreir) R. Capuron (Guinaudeae et al. 1975).
5.2.4.3 Pronuciferine (14)
C19H21NO3
CH3O
N CH3O CH3
O
Class of compound: Proaporphine
1 H NMR: δH 7.02 (1H, dd, J 10.2 and 2.7 Hz, H-8), 6.86 (1H, dd, J 9.9 and 2.7 Hz, H-12), 6.61 (1H, s, H-3), 6.38 (1H, dd, J 9.9 and 2.0 Hz, H-11), 6.27 (1H, dd, J 10.2 and 2.1 Hz, H-9), 3.78 (3H, s, 2-OMe), 3.57 (3H, s, 1-OMe), 2.34 (3H, s, NMe).
13 C NMR: δC 186.1 (C-10), 153.5 (C-12), 153.3 (C-1 or 2), 150.0 (C-8), 134.3 (C-3a), 132.7 (C-7c), 128.2 (C-9), 127.7 (C-7b), 127.4 (C-11), 111.7 (C-3), 65.7 (C-6a), 61.1 (OMe), 56.3 (OMe), 54.9 (C-5), 51.2 (C-7a), 47.5 (C-7), 43.6 (N-Me), 27.5 (C-4).
MS: m/e (%) 312 (22), 311 (M+, 16), 335 (20), 310 (20), 169 (77), 147 (41), 119 (23), 97 (26), 83 (24), 71 (24), 69 (100), 59 (28), 57 (40), 55 (37), 44 (51), 43 (53), 42 (23), 41 (34).
HPLC: Retention time of 18.88 minutes.
289
Pronuciferine
Also isolated from: Annonaceae: Xylopia buxifolia Baill. and X. danguyella Ghesq. ex Cavaco & Keraudr. (Hocquemiller et al. 1981); Anomianthus dulcis (Dunal) J. Sincl. (Sinz et al. 1998); Orophea hexandra Blume (Sinz et al. 1999). Euphorbiaceae: Croton linearis Jacq. (Haynes 1966); Croton sparsiflorus Morong (Bhakuni et al. 1970). Lauraceae: Ocotea glaziovii Mez (Casagrande & Ferrari 1975); Cryptocarya chinensis Hemsl. (Lee & Chen 1993). Menispermaceae: Sinomenium acutum (Thunb.)Rehder & Wilson (Sasaki & Onji 1968); Stephania sasakii Hayata ex Yamamoto (Kunitomo et al. 1969); Stephania glabra (Roxb.) Miers (= S. rotunda Lour.), (Cava et al. 1964*,1968; Thornber 1970; Bhakuni & Gupta 1982); Cocculus laurifolius DC., Menispermaceae (Bhakuni & Jain 1981); Stephania sutchuenensis H.S. Lo. (Wang et al. 1995); seeds of Stephania cephalantha Hayata (Kashiwaba et al. 2000). Monimiaceae: Glossocalyx brevipes Benth. (Montgomery et al. 1985). Nymphaeaceae: Nelumbo nucifera Gaertn. (Bernauer 1964; Tomita et al. 1965; Kunitomo et al. 1970; Wang et al. 1991); leaves of Nelumbo nucifera (Kunitomo et al. 1973). Papaveraceae: Papaver oreophilum Rupr. (Pfeifer & Mann 1968); Papaver caucasicum M. Bieb., P. persicum Lindl., P. triniaefolium Boiss., P. fugax Poir. and P. polychaetum Schott & Kotschy ex Boiss. (Pfeifer & Kuhn 1968a, b); Meconopsis cambrica (Hemingway & Phillipson 1975; Hemingway et al. 1981); Papaver lacerum Popov (Sariyar & Phillipson 1981; Sariyar 2002); Ranunculaceae: Thalictrum pedunculatum Edgew. (Hussain et al. 1989).
290
5.2.4.4 Salutaridine (15)
C19H21NO4
CH3O
HO
N CH3
CH3O
O Class of compound: Morphinane
1 H NMR: δH 7.51 (1H, s, H-5), 6.71 (1H, d, J 8.1 Hz, H-2), 6.62 (1H, br, d, J 8.4 Hz, H-1),
6.29 (1H, s, H-8), 3.85 (3H, s, OCH3), 3.72 (3H, s, OCH3), 3.65 (1H, d, J 4.8 Hz, H-9), 3.29 (1H, d, J 17.7 Hz, H-10α), 2.94 (1H, ddd, J 17.7, 5.7 and 1.2 Hz, H- 10β), 2.57 (1H, ddd, J 12.6, 4.8 and 1.8 Hz, H-14), 2.43 (1H, td, J 12. and 3.3 Hz, H-14), 2.41 (3H, s, NMe), 2.33 (1H, ddd, J 12.6, 3.0 and 1.8 Hz, H-15), 1.73 (1H, td, J 12.0 and 4.5 Hz, H-15).
13 C NMR: δC 181.3 (C-7), 161.5 (C-14), 150.8 (C-6), 145.2 (C-3), 143.2 (C-4), 129.6 (C- 11), 123.8 (C-12), 122.1 (C-8), 120.3 (C-5), 118.7 (C-1), 109.4 (C-2), 61.0 (C-9), 56.3 (OMe), 54.8 (OMe), 47.0 (C-16), 43.7 (C-13), 41.7 (NMe), 37.7 (C-15), 32.6 (C-10).
MS: m/e (%) 328 (22), 327 (M+, 100), 327 (83), 312 (44), 299 (73), 285 (25), 284 (100), 268 (27), 256 (23), 242 (30), 226 (23), 169 (61), 147 (28), 97 (24), 85 (32), 83 (59), 70 (21), 69 (64), 57 (30), 55 (33), 44 (59), 43 (37), 42 (54), 41 (26).
HPLC: Retention time of 18.14 minutes. 291
Isolated from: Annonaceae: Desmos tiebaghiensis (Daniker) R.E. Fr. (Leboeuf et al. 1982); Guatteria melosma Diels and Cleistopholis patens Engl. & Diels (Abd-El Atti et al. 1982); Rollinia mucosa (Jacq.) Baill. (Caetano & Dadoun 1987); Cardiopetalum calophyllum Schltdl. (Seguineau et al. 1991); Guatteria goudotiana Triana & Planch. (Castedo et al. 1991); Artabotrys uncinatus (Lam.) Merr. (Hsieh et al. 2001). Asclepiadaceae: Pergularia pallida (Roxb.) Wight & Arn. (Khare et al. 1984). Berberidaceae: Nandina domestica Thunb. (Kunitomo et al. 1974a, b); Berberis ilicifolia Forst. (Fajardo et al. 1996). Euphorbiaceae: leaves and twigs of Croton salutaris Casar (Barnes 1964*; Barnes & Soeiro 1981); Croton balsamifer Jacq. Von Barbados (Chambers et al. 1966*); stem and leaves of Croton plumieri Urb. (Stuart & Woo-Ming 1969); Croton flavens L. (Stuart & Chambers 1967; Eisenreich et al. 2003); leaves of Croton lechleri Müll. Arg. (Carlin et al. 1996); Croton chilensis Müll. Arg. (Hoeneisen et al. 1997); leaves and stem of Croton hemiargyreus Müll. Arg. (Amaral & Barnes 1998). Hernandiaceae: Hernandia voyroni Jumelle (Rasoanoivo et al. 1998). Lauraceae: Cassytha pubescens R. Br. (Johns et al. 1966*); Ocotea brachybotra Mez (Vecchietti et al. 1976; Vecchietti et al. 1977*); Ocotea acutangula Mez (Vecchietti et al. 1981); Neolitsea konishii (Hayata) Kanehira & Sasaki (Lee & Yang 1992*); Litsea acuminata (Blume) Kurata (Lee & Tseng 1994); Litsea garciae S. Vidal and Neolitsea villosa (Blume) Merr. (Lee et al. 1995). Papaveraceae: Papaver caucasicum M. Bieb., P. persicum Lindl., P. triniaefolium Boiss., P. fugax Poir. and P. polychaetum Schott & Kotschy ex Boiss. (Pfeifer & Kuhu 1968a, b); Papaver orientale L. (Delenk-Heydenreich & Pfeifer 1969); Papaver bracteatum Lindl., P. fugax Poir. 292 and P. triniaefolium Boiss. (Preiniger & Santavy 1970); Corydalis incisa (Thunb.) Pers. (Kametani et al. 1971); aerial parts and root of Glaucium flavum Crantz. (Lalezari et al. 1976*; Batya et al. 1988); Corydalis koidzumiana Ohwi (Tani et al. 1974); dry latex of Papaver pseudo- orientale (Fedde) Medvedev (Shafiee et al. 1975; Sariyar & Phillipson 1977; Sariyar & Shamma 1988); roots and capsules of Papaver bracteatum, P. orientale and P. pseudo-orientale (Shafiee et al. 1975; Milo et al. 1988; Sariyar 2002); Meconopsis cambrica Vig. (Hemingway & Phillipson 1975); Glaucium contortuplicatum Boiss. (Tin-Wa et al. 1976); Corydalis ochotensis Turcz. var. raddeana NAK. (Kametani et al. 1977); Papaver somniferum L. (Vincent & Engelke 1979; Wieczorek et al. 1986; Pyysalo & Widen 1988; Gerardy & Zenk 1992; De-Eknamkul & Zenk 1992; Gerardy & Zenk 1993); Glaucium vitellinum Boiss. & Buhse (Shafiee et al. 1979); Papaver species (Preininger 1984; Sariyar & Shamma 1986); Papaver bracteatum Lindl (Slavik & Slavikova 1985); leaves of Papaver acrochaetum Bornm., P. caucasicum Bieb., P. cylindricum Cullen, P. gracile Boiss., P. persicum Lindl., P. somniferum L. (Wieczorek et al. 1986); Fumaria densiflora DC. (Taborska et al. 1986); Sarcocapnos crassifolia DC. subsp. speciosa (Boiss.) Rouy (Castedo et al. 1988); Corydalis claviculata (L.) DC. (Allais & Guinaudeau 1990); Platycapnos saxicola Willk (Suau et al. 1991); Sarcocapnos saetabensis Mateo & Figuerola Lamata (Blanco et al. 1991); Papaver alkaloids (Gurkan & Tuzun 1995); Glaucium fimbrilligerum Boiss. (Shafiee et al. 1998). Menispermaceae: Cocculus carolinus (L.) DC. (Slatkin et al. 1972*); Antizoma angustifolia (Burch.) Miers ex Harv. (Dekker et al. 1988); Stephania yunnanensis H.S. Lo (Chen et al. 1989); tuber of Stephania pierrei Diels (Likhitwitayawuid et al. 1993); Spirospermum penduliflorum DC. and Strychnopsis thouarsii Baill. (Rasoanaivo et al. 1995); Stephania cephalantha Hayata (Kashiwaba et al. 1996; Kashiwaba et al. 1997; Nawai et al. 1999). Ranunculaceae: Thalictrum dioicum L. (Shamma & Salgar 1973; Ong & Beliveau 1976; Shamma & Rothenberg 1978*).
5.2.5 Extraction and isolation of alkaloids from Cissampelos hirta.
Cissampelos hirta was collected in October 1999 at Mabibi and Monzi (KwaZulu-Natal, SA) and voucher specimens (De Wet 12 and 19, respectively) were deposited in the herbarium of the University of Zululand (ZULU). 293
Extraction of leaves Air-dried, ground leaves (36 g) from Mabibi were extracted as described under General Techniques to yield 0.045 g of a crude alkaloid extract. Column chromatography of 0.045 g alkaloid extract yielded reticuline (16) (17 mg) (Figure 5.13).
Figure 5.13. TLC plate showing purified alkaloids from Cissampelos hirta leaves. D = Dicentrine (12), F = Salutaridine (15) and G = Reticuline (16).
Extraction of rhizome Air-dried, ground rhizome (40 g) from Monzi was extracted as described under General Experimental Techniques to yield 0.96 g of a crude alkaloid extract. Column chromatography of 0.96 g alkaloid extract yielded 12-O-methylcurine (17) (32 mg) and dicentrine (12) (145 mg) (Figure 5.14).
294
Figure 5.14. TLC plate showing purified alkaloids from Cissampelos hirta rhizomes. B = Dicentrine (12) and D = 12-O-Methylcurine (17).
5.2.5.1 Reticuline (16)
C19H23NO4
CH3O
N HO CH3 OH
OCH3
Class of compound: Benzyltetrahydroisoquinoline
1 H NMR: δH 7.61 (1H, d, J 2.1 Hz, H-10), 6.71 (1H, d, J 8.1, Hz, H-13), 6.56 (1H, dd, J 8.1 and 1.8 Hz, H-14), 6.51 (1H, s, H-5 or 8), 6.37 (1H, s, H-5 or 8), 3.83 (3H, s,
OCH3), 3.82 (3H, s, OCH3), 3.65 (1H, t, J 6.0 Hz, H-1), 3.15 (1H, m, H-3), 3.00 (1H, dd, J 14.0 and 6.0 Hz, H-α), 2.80 (3H, m), 2.56 (1H, m), 2.43 (3H, s, NMe).
295
13 C NMR: δC 145.2 145.0, 144.9, 143.2 (C-6, 7, 11, 12), 133.1, 130.2, 125.2 (C-4a, 8a, 9), 120.8 (C-6’), 115.5, 113.6, 110.5, 110.4 (C-5, 8, 1’, 5’), 64.5 (C-1), 55.9 (OMe), 55.8 (OMe), 46.8 (C-3), 42.5 (N-Me), 41.0 (C-α), 25.0 (C-4).
MS: m/e (%) 192 [100, M+-137 (4-methoxy-3-hydroxybenzyl)], 177 (17), 137 (8).
HPLC: Retention time of 19.26 minutes.
First isolated from Annona reticulata L., Annonaceae (Gopinath et al. 1959).
Also isolated from: Annonaceae: stem bark of Oxandra major R.E. Fr. (Arango et al. 1987); leaves of Guatteria goudotiana Triana & Planch. (Castedo et al. 1991); bark of Annona salzmanni DC. (Paulo et al. 1992); Artabotrys monteiroae Baker ex Monteiro (Kato et al. 1993*); Annona squamosa L. (Wu et al. 1994); Cananga odorata Hook. f. & Thomson (Hsieh et al. 1999*); root bark of Annona muricata L. (Lannuzel et al. 2002). Basidiomycetes: fungus Laurobasidium lauri (Geyler) Jülich. (Martin et al. 1988). Hernandiaceae: stem bark of Hernandia nymphaeifolia (Presl) Kubitzki (Chen et al. 1997; Chen et al. 2000). Lauraceae: root bark of Sassafras albidum Nees (Chowdhury et al. 1976); wood of Phoebe pittieri Mez (Castro et al. 1985); Ocotea duckei Vattimo-Gil (Morais et al. 1998); stem bark of Neolitsea acuminatissima (Hayata) Kanehira & Sasaki (Chang et al. 2002). 296
Menispermaceae: leaves of Pachygone ovata Miers ex Hook. f. & Thomson (Dasgupta et al. 1979); tuber of Stephania pierrei Diels (Likhiwitayawuid et al. 1993); Stephania cephalantha Hayata (Nawai et al. 1999). Monimiaceae: Peumus boldus Molina (Hughes et al. 1968); bark of Laurelia philippiana Looser (Urzúa & Cassels 1982); leaves of Siparuna apiosyce DC. (Leitäo et al. 2000). Papaveraceae: Papaver somniferum L. (Brochman-Hanssen & Nielsen 1965); Romneya coulteri Harvey (Stermitz & Teng 1967); aerial part of Argemone mexicana L. (Chicalote) (Chang et al. 2003). Ranunculaceae: root of Thalictrum minus L. (Liao et al. 1978); aerial parts of Isopyrum thalictroides L. (Istatkova & Philipov 2000).
5.2.5.2 12-O-Methylcurine (17)
C37H40O6N2
MeO
N O CH3 OMe CH2
12'
CH2 O OH MeN
OMe
Class of compound: Bisbenzyltetrahydroisoquinoline
1 H NMR: δH 7.12 (1H, dd, J 8.4 and 2.1 Hz, H-14), 6.99 (1H, br. d, J 7.5 Hz, H-14’), 6.83 (1H, br. d, J 7.0 Hz, H-10’), 6.77 (1H, d, J 8.4 Hz, H-13), 6.65 (1H, s, H-5), 6.63 (1H, br. d, J 8.0 Hz, H-13’), 6.52 (1H, s, H-), 6.50 (1H, d, J 2.1 Hz, H-10), 6.40 (1H, br. d, J 8.0 Hz, H-11’), 5.52 (1H, s, H-), 3.88 (3H, s, OMe), 3.85 (2H, s, OMe), 3.68 (3H, s, OMe), 2.47 (s, NMe), 2.27 (s, NMe).
MS: m/e (%) 608 (37, M+), 312 (100), 298 (71), 296 (56). 297
HPLC: Retention time of 28.84 minutes.
Also isolated from: Annonaceae: Guatteria megalophylla Diels (Galeffi et al. 1975). Menispermaceae: Chondrodendron platiphyllym (A. St.-Hill) Miers (Guedes et al. 2002)
5.2.6 Extraction and isolation of alkaloids from Cissampelos mucronata
Cissampelos mucronata was collected in October 1999 at Coastal Cashew Farm and Owen Sithole Agriculture College (KwaZulu-Natal, SA) and voucher specimens (De Wet 33 and 34, respectively) were deposited in the herbarium of the University of Zululand (ZULU).
Extraction of leaves The combined air-dried, ground leaves (97 g) from both Coastal Cashew Farm and Owen Sithole Agriculture College were extracted as described under General Experimental Techniques to yield 0.15 g of a crude alkaloid extract. Column chromatography of 0.15 g alkaloid extract yielded dicentrine (12) (5 mg) (§ 5.2.4.1) and reticuline (16) (43 mg) (§ 5.2.5.1) (Figure 5.15).
298
Figure 5.15. TLC plate showing purified alkaloids from Cissampelos mucronata leaves. B = Dicentrine (12), F = Reticuline (16) and E = unidentified (not pure).
Extraction of rhizome Air-dried, ground rhizome (96 g) from Coastal Cashew Farm was extracted as described under General Experimental Techniques to yield 0.42 g of a crude alkaloid extract. Column chromatography of 0.42 g alkaloid extract yielded: dicentrine (12) (132 mg) (§ 5.2.4.1) and lauroscholtzine (13) (9 mg) (§ 5.2.4.2) (Figure 5.16).
Figure 5.16. TLC plate showing purified alkaloids from Cissampelos mucronata rhizomes. A = Dicentrine (12) and B = Lauroscholtzine (13).
Also identified from C. mucronata: • d-Isochondodendrine – Ferreira et al. (1965) 299
5.2.7 Extraction and isolation of alkaloids from Cissampelos torulosa
Cissampelos torulosa was collected in March 2001 at Sodwana Bay (KwaZulu-Natal, SA) and a voucher specimen (De Wet, 95) was deposited in the herbarium of the University of Zululand (ZULU).
Extraction of leaves Air-dried, ground leaves (333 g) were extracted as described under General Experimental Techniques to yield 0.47 g of a crude alkaloid extract. The following alkaloids were identified by HPLC: bulbocapnine (6) (§ 5.2.3.1), dicentrine (12) (§ 5.2.4.1), lauroscholtzine (13) (§ 5.2.4.2), pronuciferine (14) (§ 5.2.4.3), cissacapine (7) (§ 5.2.3.2), cycleanine (8) (§ 5.2.3.3), insulanoline (10) (§ 5.2.3.5), reticuline (16) (§ 5.2.5.1) and salutaridine (15) (§ 5.2.4.4).
Figure 5.17. TLC plate showing purified alkaloids from Cissampelos torulosa leaves. None of the above alkaloids were isolated in sufficient quantities or were clean enough to be identified by NMR. A = Dioctyl phthalate (impurity form solvents used).
Extraction of stem Air-dried, ground stem (164 g) was extracted as described under General Experimental Techniques to yield 0.17 g of a crude alkaloid extract. The following alkaloids were identified by HPLC: bulbocapnine (6) (§ 5.2.3.1), dicentrine (12) (§ 5.2.4.1), reticuline (16) (§ 5.2.5.1), cissacapine (7) (§ 5.2.3.2), cycleanine (8) (§ 5.2.3.3) and salutaridine (15) (§ 5.2.4.4).
300
Figure 5.18. TLC plate shows purified alkaloids from Cissampelos torulosa stems. None of the above alkaloids were isolated in sufficient quantities or were clean enough to be identified by NMR.
Genus Cocculus The genus Cocculus shows one of the greatest diversities in alkaloid types among the genera in the family Menispermaceae. Some one hundred and thirty-five alkaloids of thirteen different classes have been isolated, including the following: benzyltetrahydroisoquinoline, bisbenzyltetrahydroisoquinoline, proaporhine, aporhine, aristolochic acid derived alkaloids, protoberberine, hirsutine, cohirsine, morphinan, eribidine, erythrina, pavine and other alkaloids. Bisbenzyltetrahydroisoquinoline alkaloids represent the main type of alkaloids isolated from Cocculus, with erythrina alkaloids the second most common type. The very rare hirsutine and cohirsitine type of alkaloids were all found in C. hirsutus.
5.2.8 Extraction and isolation of alkaloids from Cocculus hirsutus
Cocculus hirsutus was collected in February 2001, at Letsitele (Limpopo Province, SA) and a voucher specimen (Van Wyk & De Wet, 4062) was deposited in the herbarium of the University of Zululand (ZULU).
Extraction of leaves Air-dried, ground leaves (776 g) were extracted as described under General Experimental Techniques to yield 0.1 g of a crude alkaloid extract (Figure 5.19). 301
Figure 5.19. TLC plate showing alkaloids from Cocculus hirsutus leaves, but none was identified, because of low quantity or impurity of these isolated alkaloids.
Extraction of stem Air-dried, ground stem (1.535 kg) was extracted as described under General Experimental Techniques to yield 1.4 g of crude alkaloid extract (Figure 5.20).
Figure 5.20. TLC plate showing alkaloids from Cocculus hirsutus stems. None was identified.
Extraction of rhizome Air-dried, ground rhizome (867 g) was extracted as described under General Experimental Techniques to yield 0.47 g of a crude alkaloid extract (Figure 5.21).
302
Figure 5.21. TLC plate showing alkaloids from Cocculus hirsutus rhizomes. None was identified.
No alkaloids were isolated from the above crude alkaloid extracts. The following alkaloids from this species were reported in the literature:
Aporphine alkaloids • Magnoflorine (Tripathi et al. 1976*; Shabrawy 1985*)
Benzyltetrahydroisoquinoline alkaloids • d,1-Coclaurine ( Rao & Row 1961*) • Coclaurine (Tripathi et al. 1976*)
Bisbenzyltetrahydroisoquinoline alkaloids • d-Trilobine (Rao & Row 1961*; Inubushi & Nomura 1962*) • Isotrilobine – stem and root (Tripathi et al. 1976*; Shabrawy 1985;* Ahmad & Rashid 1986; Ahmad & Iqbal 1993) • Daphnoline (Tripathi et al. 1976*) • Trilobine – stem and root (Tripathi et al. 1976*; Shabrawy 1985*, Ahmad & Rashid 1986, Ahamad & Iqbal 1993) • Cocsoline (El-Shabrawy et al. 1982*, 1984; Shabrawy 1985*) • Cocsoline-N-2-Oxide (El-Shabrawy et al. 1984) • 12-O-Demethyltrilobine (Shabrawy 1985*) • N,O-Dimethylcocsoline (Buckingham 1993a*) 303
Cohirsine alkaloids • Cohirsine (Ahmad et al. 1987; Ahamad & Iqbal 1993) • Cohirsinine (Ahmad et al. 1991; Ahamad & Iqbal 1993) • Shaheenine (Rasheed et al. 1991, Ahamad & Iqbal 1993) • Cohirsitinine (Ahmad & Iqbal 1992, 1993)
Hirsutine alkaloids • Jamtine (Ahmad et al. 1987, Ahmad & Iqbal 1993) • Jamtine-N-Oxide (Ahmad et al. 1987) • Hirsutine (Rasheed et al. 1991) • Haiderine (Ahmad & Iqbal 1993*) • Jamtinine (Ahmad & Iqbal 1993)
Miscellaneous alkaloids • Cohirsitine = Cohrisitine (Ahmad & Iqbal 1992)
Genus Stephania
Chemically, Stephania is the most studied genus in this family (Barbosa-Filho et al. 2000). Barbosa-Filho et al. (2000) made the following observation about this genus: a) Of the twenty-two types of alkaloids found in this family, thirteen are present in the genus Stephania. b) The alkaloids of the aporhine (188), bisbenzyltetrahydroisoquinoline (171) and protoberberine (112) types are the most common, accounting for a total of 471 alkaloids. c) All of the seventy-eight hasubanane alkaloids described in the literature were isolated from fifteen species of this genus. d) The forty-three morphinan alkaloids were isolated from seventeen species and the fourteen proaporphines were isolated from eleven species. e) The ten benzyltetrahydroisoquinoline alkaloids in the genus were isolated from five species. f) In Hutchinson's work (1973*) it was suggested that the families Menispermaceae and Aristolochiaceae share several common features in terms of the morphology of the stem. The isolation of three aristolochic acid-type alkaloids from Stephania and one from Cocculus 304
species, alkaloids that were considered exclusive to the Aristolochiaceae, has established some chemotaxonomic relations between the two families. g) On the basis of the chemical data available, there is almost no difference between Stephania japonica Miers and S. japonica Miers var. australis. h) Four species of Stephania occur in Thailand: S. erecta Craib., S. pierrei Diels, S. suberosa Forman and S. venosa Spreng. Some controversy exists in relation to the morphological aspects of S. erecta and S. pierrei (Diels 1910*; Forman 1962*; Pongboorod 1979*). However, analysing the data from the literature (Pongboorod 1979*; Prawat et al. 1982*, 1984*) related to the chemical studies of the two plants it is possible to see that the compounds isolated from S. erecta were fourteen bisbenzyltetrahydroisoquinoline akaloids. On the other hand, from S. pierrei forty-nine alkaloids were isolated including benzyltetrahydroisoquinoline (5), bisbenzyltetrahydroisoquinoline (22), protoberberine (7), aporphine (12), morphinan (2) and hasubanane (1). These chemical differences seem to be sufficient to conclude that the two plants should be considered distinct species.
5.2.9 Extraction and isolation of alkaloids from Stephania abyssinica
Stephania abyssinica was collected in February 2001, at Ebernezer Dam (Limpopo Province) and a voucher specimen (Van Wyk & De Wet, 4061) was deposited in the herbarium of the University of Zululand (ZULU).
Extraction of leaves Air-dried, ground leaves (242 g) were extracted as described under General Experimental Techniques to yield 0.63 g of a crude alkaloid extract (Figure 5.22).
305
Figure 5.22. TLC plate showing alkaloids from Stephania abyssinica leaves. None were identified, because of its complexity and the detailed literature reports availbable.
Extraction of rhizome
Air-dried, grounded rhizome (803 g) was extracted as described under General Experimental
Techniques to yield 2.1 g of a crude alkaloid extract (Figure 5.23).
Figure 5.23. TLC plate shows alkaloids from Stephania abyssinica rhizomes. None were identified.
No alkaloids were isolated from the above crude alkaloid extracts. The following alkaloids from this species were reported in the literature: 306
Aporhine alkaloids • Xylopine (Kupchan et al. 1967) • Corydine (Kande et al. 1994) • Crebanine (Kande et al. 1994) • Dicentrine (Kande et al. 1994) • Dicentrinone (Kande et al. 1994) • N-methyllaurothetanine (Kande et al. 1994) • Roemerine (Kande et al. 1994) • Stephalagine (Kande et al. 1994) • Stephanine (Kande et al. 1994)
Hasubanane alkaloids • Neostefanien (Provisional name) (De Waal & Weideman 1962) • Metaphine (De Waal et al. 1966) • Oxoxylopine (Kupchan et al. 1970; Suffness 1970*) • Stephavanine (Kupchan et al. 1970; Suffness 1970*; Dagne et al. 1993) • Prostephabyssine (Buckingham 1993b*) • Stephabyssine (Buckingham 1993c*) • Stephaboline (Buckingham 1993c*) • 6-Dihydroepistephamiersine-6-acetate (Van Wyk 1975) • 4’-O-Methylstephavanine (Dagne et al. 1993) • N,O,O,-Trimethylstephavanine (Buckingham 1993d*)
Genus Tiliacora
From the genus Tiliacora only four of the twenty-two species were previously chemically studied and yielded forty-eight different alkaloids, including bisbenzyltetrahydroisoquinoline (38), benzyltetrahydroisoquinoline (8) and aporphine (2) types (Barbosa-Filho et al. 2000).
307
5.2.10 Extraction and isolation of alkaloids from Tiliacora funifera
Tiliacora funifera was collected at Stentor Farm (Baberton, Mpumalanga, SA) in February 2001 and a voucher specimen (Van Wyk & De Wet, 4063) was deposited in the herbarium of the University of Zululand (ZULU).
Extraction of leaves Air-dried, ground leaves (545 g) were extracted as described under General Experimental Techniques to yield 0.41 g of a crude alkaloid extract (Figure 5.24).
Figure 5.24. TLC plate showing purified alkaloids from Tiliacora funifera leaves.
Extraction of rhizome Air-dried, ground rhizome (891 g) was extracted as described under General Experimental Techniques to yield 1.86 g of a crude alkaloid extract (Figure 5.25).
308
Figure 5.25. TLC plate showing purified alkaloids from Tiliacora funifera rhizomes.
No alkaloids were isolated from the above crude alkaloid extracts. The following alkaloids from this species were reported in the literature:
Benzyltetrahydroisoquinoline alkaloids • Oblongine (Ateya & Schiff 1979*; Tackie et al. 1980)
Bisbenzyltetrahydroisoquinoline alkaloids • Funiferine - root (Tackie & Thomas 1965, 1968; Tackie et al. 1973; Knapp et al. 1980) • Nortiliacorinine-A - root (Tackie & Thomas 1968; Tackie et al. 1973) • Tiliacorine - root (Tackie & Thomas 1968; Buckingham 1993e*) • Isotetrandrine - leaf (Ayim et al. 1977) • Nortiliacorine A - root (Tackie et al. 1973; Buckingham 1993e*) • Thalrugosine - leaf (Ayim et al. 1977; Ateya & Schiff 1979*) • Tiliafunimine - leaf (Tackie et al. 1973; Ateya & Schiff 1979*; Ayim et al. 1977) • Isotetrandrine (Ateya & Schiff 1979*; Ayim et al. 1977) • Funiferine-N-oxide - root (Dwuma-Badu et al. 1977; Knapp et al. 1980) • Funiferine dimethiodide (Dwuma-Badu et al. 1977; Tackie et al. 1980)
309
Genus Tinospora
Fifteen species from the genus Tinospora were chemically studied and yielded fifteen different alkaloids, with the following distribution: benzyltetrahydroisoquinoline, aporphine, protoberberine and phenethylcinnamide alkaloids, and kokusagenine which is the only furoquinoline alkaloid isolated from the family Menispermaceae and is classified as "others" (Barbosa-Filho et al. 2000).
5.2.11 Extraction and isolation of alkaloids from Tinospora caffra
Tinospora caffra was collected in March 2001, at Pongola Dam (Kwa-Zulu-Natal, SA) and a voucher specimen (Van Wyk & De Wet, 4074) was deposited in the herbarium of the University of Zululand (ZULU).
Extraction of leaves Air-dried, ground leaves (420 g) were extracted as described under General Experimental Techniques to yield 0.19 g of a crude alkaloid extract (Figure 5.26).
Figure 5.26. TLC plate showing alkaloids from Tinospora caffra leaves. None were identified, because of lack of sufficient material and the small yields obtained.
Extraction of stem Air-dried, ground stem (874 g) was extracted as described under General Experimental Techniques to yield 0.43 g of a crude alkaloid extract (Figure 5.27). 310
Figure 5.27. TLC plate showing alkaloids from Tinospora caffra stems. None were identified, because of lack of sufficient material and the small yields obtained.
No alkaloids were isolated from the above crude alkaloid extracts.
5.2.12 Extraction and isolation of alkaloids from Tinospora fragosa
Tinospora fragosa was collected in February 2001, at Sefateng (Limpopo Province) and a voucher specimen (Van Wyk & De Wet, 4060) was deposited in the herbarium of the University of Zululand (ZULU).
Extraction of leaves Air-dried, ground leaves (324 g) were extracted as described under General Experimental Techniques to yield 1.58 g of a crude alkaloid extract (Figure 5.28).
311
Figure 5.28. TLC plate showing alkaloids from Tinospora fragosa leaves. None were identified, because of the impurity of the alkaloid fractions.
Extraction of stem Air-dried, grounded stem (791 g) was extracted as described under General Experimental Techniques to yield 10.78 g of a crude alkaloid extract (Figure 5.29)
.
Figure 5.29. TLC plate shows alkaloids from Tinospora fragosa stems. None were identified, because of the low yields of alkaloids obtained.
No alkaloids were isolated from the above crude alkaloid extracts. 312
Nothing was published on the alkaloids of the above two Tinospora species and the third South Africa species, T. tenera. Alkaloids reported from other species in the genus Tinospora are:
Aporphine alkaloids: • Magnoflorine: Tinospora cordifolia Miers (Pachaly & Schneider 1981*) T. capillipes Gagnep. (Chang et al. 1983*, 1984*) T. malabarica Miers (El-Fishawy et al. 1989*) • Menisperine: T. capillipes (Chang et al. 1983*, 1984*) • N-Acetylanonaine T. crispa (L.) Hook. f. & Thomson (Pachaly et al. 1992*) • N-Formylanonaine T. malabarica (Atta-ur-Rahman & Ahmad 1987*) T. crispa (Pachaly et al. 1992*) • N-Formylnornuciferine (Tinocrispicine) T. crispa (Pachaly et al. 1992*)
Benzyltetrahydroisoquinoline alkaloids: • Tembetarine T. cordifolia (Pachaly & Schneider 1981*) T. baenzigeri Forman (Bisset & Nwaiwu, 1983) T. crispa (Bisset & Nwaiwu 1983) T. glabra (Burm. f.) Merr. (Bisset & Nwaiwu 1983) T. merriliana Diels (Bisset & Nwaiwu 1983) T. smilacina Benth. (Bisset & Nwaiwu 1983)
Phenethylcinamide alkaloids • N-cis-Feruloyltyramine T. tuberculata Beumée (Fukuda et al. 1983*, 1985*) • N-trans-Feruloyltyramine T. tuberculata (Fukuda et al. 1983*, 1985*)
313
Protoberberine alkaloids • Berberine T. baenzigeri (Bisset & Nwaiwu 1983) T. crispa (Bisset & Nwaiwu 1983) T. glabra (Bisset & Nwaiwu 1983) T. merriliana (Bisset & Nwaiwu 1983) T. smilacina (Bisset & Nwaiwu 1983) • Columbamine T. capillipes (Chang et al. 1983*, 1984*) • Dehydrodiscretamine T. capillipes (Chang et al. 1983*, 1984*) • Jatrorrhizine T. baenzigeri (Bisset & Nwaiwu 1983) T. capillipes (Chang et al. 1983*, 1984*) T. cordifolia (Bisset & Nwaiwu 1983) T. crispa (Bisset & Nwaiwu 1983) T. glabra (Bisset & Nwaiwu 1983) T. merriliana (Bisset & Nwaiwu 1983) • Palmatine T. dentata (Dwuma-Badu et al. 1977) T. baenzigeri (Bisset & Nwaiwu 1983) T. capillipes (Chang et al. 1983*, 1984*) T. cordifolia (Bisset & Nwaiwu 1983) T. glabra (Bisset & Nwaiwu 1983) T. merriliana (Bisset & Nwaiwu 1983) T. sagittata Gagnep. (Bisset & Nwaiwu 1983) T. sinensis (Lour.) Merr. (Bisset & Nwaiwu 1983) T. smilacina ((Bisset & Nwaiwu 1983) T. malabarica (Atta-ur-Rahman et al. 1992) • Stepharanine T. capillipes (Chang et al. 1983*, 1984*)
314
Miscellaneous alkaloids • Kokusagine T. malabarica (Bowen & Motawe 1985*; Bhattacharya et al. 1991*)
5.3 Summary of the isolated alkaloids *Rt = retention time in minutes for HPLC Aporphine Plant species Plant part
O
N O CH3 A. miersiana Leaves HO C. capensis Leaves
CH3O
Bulbocapnine (§ 5.2.3.1) *Rt = 22.14
O Leaves N C. capensis O CH 3 C. hirta Leaves + Rhizomes C. mucronata Leaves + Rhizomes
CH3O OCH 3 Dicentrine (§ 5.2.4.1) Rt = 24.89
315
CH3O C. capensis Leaves N C. mucronata Rhizomes CH3O CH3
CH3O
OCH3
Lauroscholtzine (§ 5.2.4.2) Rt = 20.95
Proaporphine Plant species Plant part
CH3O
N HO H A.angustifolia Leaves + Rhizomes H A. miersiana Leaves
O Crotsparine (§ 5.2.2.2) Rt = 13.34
CH3O
N A.angustifolia Leaves + Rhizomes HO CH3 H C. capensis Leaves
O
Glaziovine (§ 5.2.2.1) Rt = 16.94 316
CH3O
N CH3O CH3 C. capensis Leaves H
O Pronuciferine (§ 5.2.4.3) Rt = 18.88
Benzyltetrahydroisoquinoline Plant species Plant part
CH3O
N C. mucronata Leaves HO CH 3 C. hirta Leaves OH
OCH3 Reticuline (§ 5.2.5.1) Rt = 19.26
Bisbenzyltetrahydroisoquinoline Plant species Plant part
MeO
N O CH3 OMe CH2 C. hirta Rhizomes ' 12
CH2 O OH MeN
OMe
12-O-Methylcurine (§ 5.2.5.2) Rt = 28.84 317
H3CO
N O CH3 O H A. miersiana Rhizomes
O H H3C O N
OCH3 Cissacapine (§ 5.2.3.2) Rt = 28.60
CH3O
N O CH3 OH A. miersiana Rhizomes
O
CH3 OCH3 N
OCH3
Cyleaneonine (§ 5.2.3.4) 318
CH3O
N CH3O CH3 O A. miersiana Rhizomes C. capensis Rhizomes
O
CH3 OCH3 N
OCH3
Cyleanine (§ 5.2.3.3) Rt = 26.34
CH3O
N O CH3 H O A. miersiana Rhizomes
H O H3COH N
OCH3
Insulanoline (§ 5.2.3.5) Rt = 27.78 319
CH3O
N
O CH3 O H A. miersiana Rhizomes
H O H3C OCH3 N
OCH3
Insularine (§ 5.2.3.6) Rt = 29.95
OCH3
O N N H3C O H H H A. delagoensis Rhizomes
O
H3CO
O-Methylcocsoline (§ 5.2.1.1) Rt = 31.85
CH3O
O N N O H CH3 H H A. delagoensis Rhizomes
O
OCH3
Cocsuline (§ 5.2.1.2) Rt = 30.97 320
CH O 3 O N N O H CH3 H H A. delagoensis Rhizomes
O OH
Cocsoline (§ 5.2.1.3) Rt = 29.32
Morphinane Plant species Plant part
CH3O C. capensis Leaves HO C. hirta Leaves
N CH 3 CH3O
O
Salutaridine (§ 5.2.5.1) Rt = 18.14
5.4 Discussion
The major alkaloids from seven of the thirteen South African Menispermaceae species were isolated and identified with NMR and HPLC. Before this study, nothing or very little were known of the alkaloids of these seven species. The alkaloid patterns ranged from low complexity (Albetisia delagoensis, Cissampelos hirta and the Antizoma species) to complex (Cissampelos capensis, C. mucronata and C. torulosa) to very complex (Stephania abyssinica, Tiliacora funifera, Cocculus hirsutus and Tinospora fragosa). No NMR identification of the alkaloids isolated from the latter species was possible, because of their impurity and complexity. Alkaloids from these species were previously well studied and it was therefore not necessary to repeat purification of these complex alkaloids. Twenty-one alkaloids were reported in the literature for 321
C. hirsutus (§ 5.2.8), with nineteen alkaloids for S. abyssinica (§ 5.2.9) and eleven alkaloids for T. funifera (§ 5.2.10). No alkaloids were reported in the literature for Tinospora fragosa, but its complexity has causing impure alkaloid isolations, which has prevented identification of any alkaloids by NMR. Alkaloids for T. caffra and T. tenera could not be identified in this study, because of lack of sufficient material and the small yields obtained. There are a few unidentified alkaloids in C. capensis (Figure 6.2) and C. torulosa (Figure 6.13), which were isolated and when spotted on a TLC plate it occurred as one pure alkaloid, but NMR and HPLC shows it as a mixture of two alkaloids. Column chromatography or TLC was unable to separate these alkaloids which made identification impossible.
The HPLC retention times for the seventeen identified alkaloids were used as standards in the population study in Chapter 6. Reproducibility of the retention times for these standards was very good. Retention time varied according to the pH used in the buffer. Buffer solutions used for HPLC should always have the same pH. Overlapping for some alkaloid peaks in the HPLC chromatogram is possible (Sun et al. 1998), who found different retention times for tetrandrine and isotetrandrine (two bisbenzyltetrahydroisoquinoline alkaloids) below pH 3.5, but complete overlapping at pH 4.5. The increase of retention times with increasing pH was due to the formation of the free (non-protonated) form of the alkaloids, which were more retained by the stationary phase.
HPLC were used to identify the known alkaloids from the crude alkaloid extracts for the different plant parts used in the population studies. TLC plates of specific alkaloid extracts, corresponded well with the alkaloid peaks on the HPLC chromatograms although a few discrepancies were found (i.e. presence of lauroscholtzine on TLC plate Figure 6.7 is absent on HPLC chromatogram, Table 6.3). Somehow these alkaloids were not detected by the HPLC in the crude alkaloid extracts. This problem occurred only in a few extracts and the HPLC method was therefore not changed. The buffer used during this study for HPLC was very basic with a pH of 9. More research on the effect of buffer pH on alkaloid extracts is needed to solve this problem. Sun et al. (1998) stated that acidic mobile phases or acidic amine-phosphate buffers can be useful for improving the peak shapes and separations for the analysis of basic substances such as alkaloids.
Alkaloid isolation and identification for the seven species of the genera Albertisia, Antizoma and Cissampelos were emphasized in this study. Very little too nothing is known of the alkaloids 322 occurring in them. Four of these species (Antizoma angustifolia, Cissampelos capensis, C. mucronata and C. torulosa) are very important and well documented medicinal plants in southern Africa, but with no or very little (two references) chemical data available to support its medicinal uses. Data obtained in this study is also used to get an insight into the chemotaxonomy of the South African Menispermaceae, especially between the genera Antizoma and Cissampelos, which are morphological very similar (Chapter 4).
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