Benzylisoquinoline alkaloids derivatives

The opium poppy (Papaver somniferum L. [Papaveraceae]) latex contains benzylisoquinoline alkaloids and is a widely known source of the analgesic drugs morphine and codeine. The biosynthesis of benzylisoquinoline alkaloids begins with a condensation reaction catalyzed by norcoclaurine synthase of DA [161]. The structural features of benzylisoquinoline alkaloids derived from DA might provide some explanation for the documented affinity of some natural alkaloids of this class, and some synthetic derivatives, for DA receptors [162]. Indeed, the chemical structure of morphine has been used as a template for the development of the PD drug, apomorphine (47). Apomorphine includes a catecholaminergic moiety in its... 

The above syntheses were preceded by model investigations (143), as a result of which several unnatural 1,2-secoisoquinolines, e.g., 175-177 were synthesized (Scheme 30). Finally, a reaction reported by Bentley and Murray (144) is worth mentioning since it may serve as a model for biosynthetic conversion of benzylisoquinoline alkaloids to the seco analogs (Scheme 30). Heating of ketolaudanosine (174) with methyliodide unexpectedly formed a seco derivative 175 along with to the quaternary salt. By all probability it arose from the methiodide of 174 by air oxidation followed by ring opening. 

This section considers in vivo transformations other than those involved in biosynthesis, which forms the subject of Section VII. At present, tetrandrine (48) and thalicarpine (94) are the only bisbenzylisoquinoline alkaloids whose microbial transformations have been studied. In work that is apparently the first such investigation of any benzylisoquinoline-derived alkaloids, likely organisms were selected by their ability to metabolize monomeric benzylisoquinoline alkaloids... 

The bisbenzylisoquinoline alkaloid, isochondodendrine (33), (Fig. 5 and Table V) and its (9-methyl and O-acetyl derivatives have been studied by 13C NMR (23). The aliphatic carbon atoms of this symmetrical molecule were assigned by comparison to the benzylisoquinoline alkaloids and by the off-resonance spectrum. The oxygen substituent at C-8 caused a shielding of C-l. In the aromatic region of the spectrum C-9 and C-l2 had chemical shifts which remained essentially constant in all derivatives examined. Methylation and acetylation of the phenolic group produced characteristic shift changes which allowed the assignment of C-4a, C-6, C-7, C-8,... 

The mammalian alkaloids are formed from aromatic amino acids and their metabolically derived amines by reaction with carbonyl substrates at physiological pH. The reaction is catalyzed by acid and is commonly referred to as the Pictet-Spengler cyclization (I0a,b,II). Winterstein and Trier in 1910 proposed that the Pictet-Spengler reaction might be of significance in the biosynthesis of benzylisoquinoline alkaloids in plants (5a). The carbonyl compounds participating in the Pictet-Spengler synthesis of mammalian alkaloids are aldehydes and a-keto acids, which are produced... 

Investigations of a number of enzymes involved in tyrosine conversion have suggested that the first committed step in the biosynthesis of benzylisoquinolines involves a Picfef-Spengler-type condensation of dopamine with 4-hydroxyphenylacetaldehyde (which derived from tyrosine) to give (S)-norcoclaurine, a compound that has proved to be pivotal in the formation of all benzylisoquinoline alkaloids (Fig. 2.5). The condensafion sfep is cafalysed... 

The capsules and stems of Papaver somniferum contain opiate alkaloids essential in medicine. They are classified into two groups, phenanthrene types (morphine, codeine, thebaine) and benzylisoquinoline types [papaverine and noscapine(narcotine)]. These two types of alkaloids show sharply specific pharmacological properties. It is noteworthy that morphinane alkaloids are formed from (-)-(/ )-reticuline, whereas most other alkaloids derive from (-l-)-(5)-re-ticuline 11). 

Opium contains over 50 alkaloids that fall into one of two chemical classes the phenanthrene class, including morphine and related derivatives and the benzylisoquinoline alkaloids, such as papaverine (58,Fig. 7.14 see Ref 291 for a complete listing of alkaloids present in opium). In addition to morphine, which on average accounts for 10-20%of opium, other re-... 

Finally, an alkaloid of undetermined structure was studied to demonstrate the utility of these methods. The FABMS of the alkaloid was first determined, followed by derivitization of the alkaloid to its bismethiodide (MeI/Me2CO - room temperature), and subsequent determination of the FABMS of the derivative. The unknown alkaloid exhibited fragmentation characteristic of a type A aporphine-benzylisoquinoline alkaloid with one methoxy and one hydroxy group in... 

Phenethylisoquinoline alkaloids are classified into six major alkaloid groups based on structural differences, namely, simple 1-phenethyliso-quinoline (1), homomorphinandienone (2), bisphenethylisoquinoline (3), homoproaporphine (4), homoaporphine (5), and homoerythrina alkaloids (6). These alkaloids are related to the benzylisoquinoline alkaloids such as morphinandienone, bisbenzylisoquinoline, proaporphine, apor-phine, and erythrina alkaloids. Although colchicine and its derivatives also belong to the phenethylisoquinoline alkaloids group, these alkaloids are not included in this review as they have been reviewed earlier 1). 

The genus Papaver differs substantially from other members of the Papaveraceae by the presence of rhoeadine-papaverrubine alkaloids and the genera Oorydalis, Dicentra and probably P )wana which, in addition to the common benzylisoquinoline alkaloids contained in this family, are also able to synthesize some alkaloids having an additional CH3 group (13-methyltetrahydroprotoberberine audits natural derivatives— see p. 384, and 13-methylprotopine—see p. 391). 

The term aporphinoids covers aporphines and their close biogenetic precursors, the proaporphines. Alkaloids derived from relatively straightforward biological transformations of proaporphines or of aporphines are also encompassed, so that proaporphine-benzylisoquinolines, aporphine-benzylisoquinolines, aporphine-pavines, oxoaporphines, dioxoaporphines, aristolactams, and aristolochic acids, as well as phenanthrenes, will be discussed. Azafluoranthenes are also included within the scope of aporphinoids for reasons which will become clear toward the end of the present chapter. 

A large number of alkaloids have been converted to quaternary salts and examined pharmacologically. The quaternary derivatives of certain bis-benzylisoquinoline alkaloids, which are closely related structurally to one class of curare alkaloids, are potent curarizing agents. Quaternary salts of cinchona alkaloids are effective and have been used in clinical investigations. Quaternary salts of many other alkaloids have been shown to exhibit curariform activity. 

Members of the family contain alkaloids based on several major pathways such as benzylisoquinoline (tyrosine derived), quinolone, furoquinoline, quinazoline (all from anthranilic acid), imidazole (histidine), indoloquinazoline (tryptophan), and both simple aliphatic and aromatic amines. In the tribe Ruteae (Rutoideae), no fewer than five types of alkaloids are common to the three major genera. Quinolone, furoquinoline, and acridone alkaloids are especially widespread within the family, being found in four of the five... 

A second major structural type, commonly known as benzylisoquinoline (BIQ) or tetrahydrobenzylisoquinoline (TBIQ), alkaloids constitute one of the two most numerous types of alkaloids. As is true for the simple isoquinoline alkaloids mentioned above, all are derived from a 3,4-dihy-droxytyramine (dopamine) precursor condensed with a carbonyl compound. In this case, the precursor of most, if not all, benzylisoquinoline alkaloids is 4-hydroxyphenylacetal-dehyde. Benzylisoquinoline alkaloids are found in a limited group of plant families some have great medical impor-... 

Isoquinoline alkaloids are derived from tyrosine through the intermediacy of 3,4-dihydroxyphenylethylamine (dopamine) and a carbonyl unit of various origins. The genesis of tyramine, and dopamine from tyrosine has been described previously (see Chapter 28). In contrast to benzylisoquinoline alkaloids (see below), the formation of isoquinoline alkaloids usually involves the amine and an a-ketoacid instead of an amine and aldehyde. However, several compounds can... 

The simplest derivatives of the tetrahydrobenzylisoquinoline alkaloids are the aporphine alkaloids (Fig. 32.12). Aporphine alkaloids (about 650) are widespread and occur in almost the same families as benzylisoquinoline alkaloids (Guinaudeau and Bruneton, 1993 Kametani and Honda, 1985). Several subgroups of aporphine alkaloids are known [noraporphines, dehydroaporphines (34), oxoaporphines (35), dimeric apor-phines, and phenanthrenes (36)] (Fig. 32.13) (Cave et al., 1987). The aporphine alkaloids present in members of the Annonaceae and in the genus Thalictrum (Ranunculaceae) have been reviewed (Cave et al., 1987 Schiff, 1987). 

Various species of Argemone and Eschscholtzia (Papavera-ceae) and Thalictrum (Ranunculaceae) contain pavine alkaloids (about 20) and isopavine alkaloids (about 10) with a tetracyclic nucleus derived from benzylisoquinoline alkaloids (Gozler, 1987 Guinaudeau and Bruneton, 1993 Schiff, 1987). The formation of argemonine (93) and related alkaloids is rationalized as follows (Fig. 32.31) (Geissman and Crout, 1969). An alternate mode of cyclization also has been observed in the formation of (— )-eschscholtzine (94) and (- )-munitagine (95). 

A series of at least 60 complex alkaloids derived from benzylisoquinoline alkaloid precursors is found in the genus... 

Ipecacuanha alkaloids arise by pathways similar to those previously discussed for the origin of isoquinoline and benzylisoquinoline alkaloids with the exception that a different aldehyde moiety is involved. In this case, the condensation involves dopamine (22) and secologanin (113). The origin of secologanin was discussed previously in Chapter 20. Emetine (114) and an alkaloidal glycoside, ipecoside (114), cooccur in Cephaelis ipecacuanha (Kapil and Brown, 1979). The presence of ipecoside, an acetylated derivative of the first proposed intermediate, lends credence to the proposed biogenetic pathway (Fig. 32.36). The absolute stereochemistry of ipecoside has been determined by x-ray crystallo-... 

Fig. 7.1 Benzylisoquinoline alkaloid structural subgroups derived from the basic benzylisoquinoline subunit. Blue designates the part of each molecule originating from the tetrahydroisoquinoline moiety red designates the part of each molecule originating from the benzylic...

Thus, from the Solanaceae, hyoscyamine, a tropane alkaloid, which we now know to be derived from ornithine and/or arginine (Arg, R, Scheme 12.7), and nicotine, derived from a combination of nicotinic acid (see Scheme 12.103, et seq.) and ornithine, serve as examples of alkaloids based on nonaromatic amino adds. In the benzylisoquinoline alkaloids, only morphine, arguably the first alkaloid isolated in purified form and known to be derived from tyrosine (Tyr, T), itself a prephenic acid derivative, is discussed. For the indole alkaloids, the single example of this rich family to be illustrated is vinblastine, a (relatively) recently isolated base of some medicinal value and which is shown to be composed of two different expressions of tryptophan (Trp, W) and mevalonate (Scheme 11.40). Finally, caffeine is chosen as the member of the purine alkaloids, a relatively small family of compounds but one of major commercial import and one whose biosynthesis is closely tied to the library of life. 

To date, biosynthetic pathway for four classes of plant alkaloids has been characterized to some extent the benzylisoquinoline, monoterpenoid indole, purine, and tropane alkaloids. Benzylisoquinoline alkaloids (BIAs) are derived from tyrosine and are comprised of 2,500 defined structures found mainly in the Papaveraceae, Ranunculaceae, Berberidaceae, and Menispermaceae [11]. First step of BIA biosynthesis begins with the stereoselective Pictet-Spengler condensation of dopamine and 4-hydroxyphenylacetaldehyde to form (5)-norcoclaurine. Subsequently, through a series of methylations and hydroxylations, (5)-norcoclaurine gets converted into (5)-reticuline, which is the pivotal intermediate for many pharmaceutically important BIAs formed further down in the pathway (i.e., downstream pathways) (Fig. 8.6) [3]. 

Morphine and codeine are members of the large and diverse group of benzylisoquinoline alkaloids, of which morphine and sanguinarine share a common biosynthetic pathway, beginning with the condensation of two L-Tyr derivatives to produce the central precursor (S)-norcoclaurine yields (S)-reticuline, the last common intermediate in the biosynthesis of both sanguinarine and morphine. Berberine bridge enzyme (BBE) catalyzes the conversion of (S)-reticuline to (S)-scoulerine, the first committed step in the sanguinarine pathway. Alternatively, (S)-reticuline can be isomerized to its (R)-epimer as the first step in the formation of morphine. Since the pathway from tyrosine to (S)-reticuline is also known at the enzyme level, the conversion of L-tyrosine to macarpine involves a total of 19 enzymes which are now at least partially characterized. 

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