Amaryllidaceae alkaloids narciclasine

Amaryllidaceae Alkaloids.—Narciclasine (73) occurs in Narcissus plants along with the Amaryllidaceae alkaloids haemanthamine (70), lycorine (71), and nor-pluviine (72). The three alkaloids (70), (71), and (72) are derived41,42 from O-methylnorbelladine (68) following pathways outlined in Scheme 10. In path a phenol coupling of (68) in the para-para direction leads ultimately to haemanthamine (70) ortho-para coupling as in path b leads to lycorine (71) and nor-pluviine (72). 

Amaryllidaceae Alkaloids.— Narciclasine (92) has been found to incorporate 0-methylnorbelladine (101) and oxocrinine (93), and thus arises by a pathway similar to that of haemanthamine (105). In the late stages to narciclasine the two-carbon bridge is lost from the oxocrinine skeleton, and preliminary experiments to determine the nature of the late intermediates have been reported. ... 

Amaryllidaceae Alkaloids.—Detail has been added to the fairly thoroughly delineated pathways to the Amaryllidaceae alkaloids.75 76 11-Hydroxyvittatine (94), previously shown to be a precursor for narciclasine (96),76 has been proposed as an intermediate in the biosynthesis of haemanthamine (92) and montanine (95) following the observed specific incorporation of vittatine (93) into the two... 

A number of Amaryllidaceae alkaloids, including haemanthamine, lycorine, narciclasine, and pretazettine, have been shown to inhibit the fundamental step of the formation of a peptide bond in protein synthesis.14... 

The total synthesis of several amaryllidaceae alkaloids including that of narciclasine was accomplished in the laboratory of T. Hudlicky. The C2 stereochemistry was established by a two-step sequence Luche reduction of the a,(3-unsaturated cyclic ketone followed by a Mitsunobu reaction. The ketone was first mixed with over one equivalent of CeCIs in methanol and then the resulting solution was cooled to 0 °C, and the sodium borohydride was added. In 30 minutes the reaction was done, and the excess NaBH4 was quenched with AcOH. The delivery of the hydride occurred from the less hindered face of the ketone and the allylic alcohol was obtained as a single diastereomer. 

Among these alkaloids, narciclasine (lycoricidine)-type alkaloids are highly oxygenated compounds, the significant antitumor activity of which attracts the attention of biologists and pharmacologists. Recent developments in analytical techniques, as well as isolation procedures, have resulted in the rapid characterization of many structures. In the sections on the alkaloids that have been isolated for the first time from the Amaryllidaceae plants, not only the novel, but also the known, structures have been included. This chapter is a review of the Amaryllidaceae alkaloids that have appeared in the literature (1-7) since a previously published review in this series (S). 

Amaryllidaceae Alkaloids.—O-Methylnorbelladine (162) and vittatine (163) are implicated as intermediates in the biosynthesis of narciclasine (164). " Loss of the two-carbon bridge from the latter could plausibly occur by a retro-Prins reaction on 11-hydroxyvittatine (165) to give (166), as shown in Scheme 18, analogy for hydroxylation of (163) coming from the biosynthesis of the related alkaloid haeman-thamine.Strong support for this pathway to narciclasine (164) was obtained when it was shown that tritiated (165) was an efficient precursor for this alkaloid.It is to be noted that collapse of a similar j8-hydroxy-amine is proposed for the biosynthesis of colchicine. 

Lycopsamine see indicine and pyrrolizidine alkaloids. Lycorenine, lycorine see Amaryllidaceae alkaloids. Lycoricidinol see narciclasine. 

The large number of structurally diverse Amaryllidaceae alkaloids are classified mainly into nine skeleton types, for which the representative alkaloids are norbelladine, lycorine, homolycorine, crinine, hemanthamine, narciclasine, tazettine, montanine, and galanthamine (Fig. 1). With the aim of unifying the numbering system of the different skeleton types, Ghosal s model will be used in this review (20). 

A number of Amaryllidaceae alkaloids are of interest as potential antitumor agents. The most important are lycorine (8), narciclasine (22), and pretazettine (15). Lycorine is widely distributed in the family and is known from at least 30 genera. Pretazettine is not so widely distributed but is found in at least 18 genera. Narciclasine (22) is known from only a few species of the family (Martin, 1987 Suffiiess and Cordell, 1985). 

Chapleur Y, Chretien F, Ibn Ahmed S, Khaldi M (2006) Chemistry and synthesis of highly oxygenated alkaloids from Amaryllidaceae lycoricidine, narciclasine, pancratistatin and analogues. Curr Org Synth 3 341... 

The Amaryllidaceae alkaloids are restricted to the monocot family that coined their name. They are derived from one molecule of tyrosine and protocatechuic aldehyde, which originates from phenylalanine. The central intermediate of their biosynthetic pathway is norbelladine. Nearly 500 structures of Amaryllidaceae alkaloids are known, and some of them possess significant pharmacological activities (Jin, 2007) (Fig. 10). For example, the isocarbostyrils pancratistatin from the spider lily Hymenocallis littoralis) and narciclasine from Narcissus species show promising antineoplastic properties (Dumont et al., 2007 McLachlan et al, 2005). Lycorine that occurs, e.g., in Clivia, Crinum and Galanthus... 

Extracts of Narcissus bulbs have been used in the past for the treatment of cancers [127], Recent investigations have resulted in the isolation of a new alkaloid, narciclasine, having antimitotic activity against S 180 in ascites form at 0-5 mg/kg. Narciclasine has been found in other members of the family Amaryllidaceae, and is identical with the alkaloid lycoricidinol from Lycoris radiata [128]. 

Several members of the Amaryllidaceae family of alkaloids display pronounced biological activities, and some Amaryllidaceae plants have played an important role in traditional herbal medicine for the treatment of various ailments. The most prominent examples of Amaryllidaceae alkaloids of biological relevance are narciclasine (55) and its congeners (pancratistatin and 7-deoxypancratistatin) and galantamine (62) (also commonly spelled galanthamine). These natural products also find application in modem medicine, and in this respect, pancratistatin is used in clinical... 

Chemical routes to narciclasine and 7-deoxypancra-tistatin (narciclasine type) as well as galantamine are described in the synthetic section of this chapter. The biosyntheses of these two types of Amaryllidaceae alkaloids are described in the following, while the discussion of other interesting classes of Amaryllidaceae constituents is omitted. 

This section is devoted to the discussion of selected syntheses of biologically intriguing Amaryllidaceae constituents—a more comprehensive overview of Amaryllidaceae alkaloids can be obtained from recent review articles [44, 45, 48, 170]. Narciclasine (55) is one of the major secondary metabolites of various Narcissus species. 

A truly biomimetic route to alkaloids of the narciclasine type has not been published yet. Nevertheless, very interesting protocols for the coupling of the six-membered ring motifs have been employed in the preparation of these compounds. Transition metal-catalyzed couphng reactions play an important role in the preparation of Amaryllidaceae alkaloids, and Hudlicky s synthesis of narciclasine highlights this approach [171,172]. Keck utihzed radical reactions and... 

Several syntheses of Amaryllidaceae alkaloids with palladium-catalyzed coupling reactions have been reported in the literature. Hudlicky presented a highly efficient route to narciclasine and was able to demonstrate the great potential of transition metal-catalyzed reactions in the preparation of Amaryllidaceae alkaloids. Furthermore, he successfully demonstrated the advantage of combining enzymatic methods and traditional synthetic chemistry. 

Ferrier carbocyclization of 38 (also prepared from D-glucose) has been utilized in the synthesis of 39 and 40 (Scheme 7), molecules which can be viewed as seco analogues of the Amaryllidaceae alkaloids, lycorocidine and narciclasine. ... 

The antimitotic lactam narciclasine (376) is widely distributed in Amaryllidaceae plants. It seems, however, nonassociated apparently with any particular alkaloid, the only chemotaxonomic peculiarity being its absence in plants usually containing alkaloids possessing the ( - )-crinane skeleton (101). 

The translation step where proteins are assembled following the code of messenger RNA has a few instances of inhibition by alkaloids [361]. Emetine and tubulosine block peptide bond formation, acting similarly to the antibiotic cycloheximide by blocking translocation of the growing peptide chain from the A site to the P site of the ribosome. They evidently bind to a specific ribosomal site [362]. Homoharringtonine may act similarly [363]. Lycorine may act at the level of termination [364]. Narciclasine and related alkaloids of the Amaryllidaceae prevent binding of the 3 end of aminoacyl-tRNA to the peptidyl transferase site of the ribosome [365, 366]. Mescaline may act similarly [367]. 

Both chemical and spectral studies suggest the above structure of narciclasine, but unlike other members of the amaryllidaceae group of alkaloids it possesses no basic properties. 

---