Morphinane alkaloids

A major study on 13C-NMR spectroscopy of hasubanan alkaloids was carried out by Matsui et al. (5) (Table III). They proposed assignments of all carbon atoms including the direct and long-range hetero coupling. The C-9 and JV-methyl carbons of hasubanan alkaloids reveal shifts of 6 and 20 ppm higher frequency than those reported for morphinan alkaloids (9). On the other hand, the iV-methyl carbons of hasubanans exhibit a lower frequency shift of 10 ppm relative to those of hasubanalactam-type alkaloids (5). These results have been utilized for structure elucidation in later works (4,7,10-12). 

Biotransformations of morphinan alkaloids have been reported for plant, fungal, and mammalian enzymatic systems with emphasis on rather specific reactions such as the reduction of ketones, N- and O-demethylation, and perox-idative transformations. Furuya et al. used immobilized tissue culture cells of Papaver somniferum to accomplish the selective reduction of codeinone (135) to codeine (136) (207) (Scheme 30). Suspension cultures of a well-established cell line of P. somniferum were grown for one week as a source of cell mass for immobilization in calcium alginate. The cells continued to live in the alginate matrix for 6 months maintaining their biological activity. The reduction of co-... 

Dihydrocotarnine was isolated from opium by Hesse (9). Falcke [see Starkenstein (6)] reported that the irritating and inhibiting effects of this alkaloid upon the central nervous system are similar to those of the morphinane alkaloids. 

Conversion of (S)-reticuline to its ( )-epimer is the first committed step in morphinan alkaloid biosynthesis in certain species. 1,2-Dehydroreticuline reductase catalyzes the stereospecific reduction of 1,2-dehydroreticuline to (7 )-reticuline.39 Intramolecular carbon-carbon phenol coupling of (if)-reticuline by the P450-dependent enzyme salutaridine synthase (STS) results in the formation of salutaridine.40 The cytosolic enzyme, salutaridine NADPH 7-oxidoreductase (SOR), found in Papaver bracteatum and P. somniferum, reduces salutaridine to (7S)-salutaridinol.41 Conversion of (7S)-salutaridinol into thebaine requires closure of an oxide bridge between C-4 and C-5 by acetyl coenzyme A salutaridinol-7-0-acetyltransferase (SAT). The enzyme was purified from opium poppy cultures and the corresponding gene recently isolated (Fig.7.2).42,43 In the last steps of morphine... 

Many opium-derived and other IQs are psychoactive, the best known being the analgesic, addictive, narcotic, opium-derived morphinan alkaloids codeine and morphine (heroin being the semi-synthetic diacetate of morphine). The tertiary or quaternary amine structural component is important for the activity of some Erytkrina alkaloids and bisbenzyliso-quinolines (notably the major curare component (+)-tubocurarine) as antagonists of the nACh-R involved in neuronal excitation of skeletal muscle. The planar disposition of some polycyclic benzophenanthridines enables intercalation (parallel interleaving) between the base pairs of DNA. A variety of naturally occurring and synthetic IQ compounds are protein kinase inhibitors. 

Morphine and related morphinan alkaloids (A) akuammine, mitragynine (A), ibogaine and related indole alkaloids... 

S)-Reticuline is also the precursor for the biosynthesis of benzophenanthri-dine (e.g. sanguinarine, marcarpine), protoberberine, berberine, palmatine) and morphinan alkaloids (morphine, codeine) (see next few paragraphs). 

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). 

The cytochrome P450 responsible for the oxidation of (S)-N-methylcoclaurine to (S)-3 -hydroxy-N-methylcocluarine has been overexpressed in opium poppy plants, and morphinan alkaloid production in the latex is increased subsequently to 4.5 times the level in wild-type plants (58). Additionally, suppression of this enzyme resulted in a decrease in morphinan alkaloids to 16% of the wild-type level. Notably, analysis of a variety of biosynthetic gene transcript levels in these experiments supports the hypothesis that this P450 enzyme plays a regulatory role in the biosynthesis of benzylisoquinoline alkaloids. Collectively, these studies highlight that the complex metabolic networks found in plants are not redirected easily or predictably in all cases. 

Frick S, Kutchan TM, Fist AJ. Increasing morphinan alkaloid production by overexpressing codeinone reductase in transgenic Papaver somniferum. Plant Biotechnol. J. 2007 5 26-37. 73. 

S, Hamanaka T. An antitumor morphinane alkaloid, sinococuline, 101. fromCocculus trilobus. Chem. Pharm. Bull. 1987 35 1660-1662. 

Opium poppy Papaver somniferum L., Papaveraceae) is one of the most important medicinal plants and has been cultivated since early centuries. Opium, the dried cytoplasm of a specialized internal secretory system called the laticifer, is normally collected from the unripe capsule. It is the source for the commercial production of medicinally important alkaloids, morphine, codeine, thebaine, noscapine and papaverine [130, 131], Fig. (61). Morphine, which has strong addictive property, is still the most effective analgesic for the treatment of mortal cancer patients in modem medicine. Codeine is commonly used as an antitussive. However, field cultivation of this plant has been limited since 1953 by the United Nations Opium Conference Protocol to prevent narcotic crimes. Therefore, establishing tissue culture technique for the production of morphinan alkaloids seems to be desirable not only for medicinal purpose but also for decreasing abuse of opiates. 

Many researchers have so far investigated tissue culture of P. somniferum [131, ref. cited therein], and most cultured P. somniferum cells, either as callus or cell suspensions, readily produced sanguinarine and its analogs [130-137], but rarely, if even, produce morphinan alkaloids [138]. Kamo et al. [139], Schuchmann and Wellmann [134], and Yoshikawa and Furuya [140] reported the production of morphinan alkaloids in redifferentiated organs, either shoots or somatic embryos, and their results emphasize the importance of the degree of cell differentiation for the biosynthesis of morphinan alkaloids. 

Morphinan alkaloid contents in transformed and non-transformed shoots... 

The alkaloid content of regenerated shoots was analyzed by ELISA and HPLC (Table 21). The regenerated shoots apparently could accumulate much more morphinan alkaloids than their original calli (approximately 1000-fold higher level of morphine equivalents for the non-transformants, 100-fold higher level of morphine equivalents for the transformants). The transformed shoots contained almost the same level of morphinan alkaloids as the non-transformed shoots when being analyzed by ELISA, but no morphine could be detected by HPLC. 

MAFF clone 1 maintained stable embryogenic capability for years and accumulated morphinan alkaloids though two of the three clones have lost their embryogenic capability after the long cultural passage. Therefore, MAFF clone 1 was used for the alkaloid production study by liquid culture. 

The transformed cells of P. somniferum easily formed somatic embryos instead of roots. MAFF clone 1, which was the most embryogenic, accumulated about 10-fold higher levels of morphinan alkaloids than did non-transformed embryogenic callus (Table 20). Williams and Ellis... 

Similar to proaporphine bases which are intermediates in the biosynthesis of the aporphine alkaloids, the promorphinanes, having a cyclohexadienone ring D, form an intermediate in the biosynthesis of the morphinane alkaloids. They also arise from benzyltetrahydroisoquino-line bases by phenolic oxidation. The first known alkaloid of this group was salutaridine (36) (first isolated from Groton salwtaris) (see Scheme 3) which in all probability is identical with the already known floripavine... 

The group of morphinane alkaloids has already been discussed in detail in previous Volumes of The Alkaloids (Vol. II, Chapter 8-1 Vol. II, Chapter 8-II Vol. VI, Chapter 7). Furthermore, there appeared a monograph 62) and two reviews 134, 182) on this problem, and the chemistry of the stereoisomeric sinomenine was dealt with in a book 188). Therefore, in this chapter only a tabulation (Table VIII) of the known bases and the biosynthesis of the morphinane alkaloids in the genus Papaver are given. 

The mass spectrometry of morphinane alkaloids (including sinomenine and salutaridine) 9, 285, 525, 542), the NMR spectroscopy (37), the ORD-analysis (116), and the polarography (423) have been recorded. 

In the plant family Papaveraceae, morphinane alkaloids were found only in some sections and species of the genus Papat er. The occurrence of thebaine was observed in the sections Orthorl oeades, Mecones, Pilosa, and Macrantha whereas morphine and codeine were found only in... 

The biosynthesis of cularine alkaloids (239) by phenolic oxidation also proceeds via the dienone compound (Scheme 4) similar to the aporphine or morphinane alkaloids. 

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