Narcissus and Daffodil

196 J. Bastida and F. Viladomat
tacrine, left much to be desired, galanthamine hydrobromide offers superior
pharmacological profiles and increased tolerance (Ezio, 1998; Herman and
Mucke, 1997a; Kewitz, 1997; Nordberg and Svensson, 1998; Rainer, 1997a).
From the clinician’s point of view, galanthamine is a reasonable approximation of
the ideal concept of symptomatic Alzheimer’s disease therapy (Rainer, 1997b;
Wilcock and Wilkinson, 1997). Until very recently galanthamine could only be
obtained in very small amounts from plant material (mainly from Leucojum aestivum)
as its total chemical synthesis on an industrial scale was uneconomical (Eichhorn
et al., 1998; Hermann and Mucke, 1997b). This strictly limited availability of
galanthamine was a severe constraint and probably the main reason for the
cautious approach taken by the international pharmaceutical community. It appears
that this situation has now fundamentally changed, as reflected in the increasing
number of scientific reviews concerned exclusively with galanthamine and its
derivatives (Bores and Kosley, 1996; Bores et al., 1996; Brodaty, 1996; Fulton and
Benfield, 1996; Harvey, 1995; Kewitz, 1996, 1997; Mucke, 1997a,b; Nordberg and
Svensson, 1998; Svensson and Nordberg, 1997). This has resulted in much interest
in the chemical synthesis of the product on an industrial scale (Czollner et al., 1998;
Kita et al., 1998; Szewczyk et al., 1995), and in production by in vitro tissue cultures,
mainly from Narcissus confusus (Bergoñón et al., 1996; Sellés et al., 1997, 1999).
Lycorine, the most frequent and characteristic of Amaryllidaceae alkaloids, has
been reported to be a powerful inhibitor of L-asc (ascorbic acid) biosynthesis
(Arrigoni et al., 1975; Evidente et al., 1983b), and thus has been proved to be a
useful tool in studying asc-dependent metabolic reactions in asc-synthesising
organisms (Arrigoni et al., 1997a). Lycorine is actually a powerful inhibitor of the
activity of GL dehydrogenase (L-galactono-γ-lactone dehydrogenase), the terminal
enzyme of asc biosynthesis (Davey et al., 1998; De Gara et al., 1994), which appears
to be localised in the mitochondrial membrane (Arrigoni et al., 1996, 1997b).
Administration of lycorine induces a decrease in asc content and a simultaneous
increase of dehydroascorbic acid levels in plants (De Tullio et al., 1998). It has been
suggested that the alkaloid could act as an inhibitor of asc biosynthesis in vitro,
without interfering with asc utilisation in cells (Arrigoni et al., 1997b). The effects
of lycorine on L-asc biosynthesis have been reported to occur at concentrations
below those at which protein synthesis is affected, but it seems difficult to rule out
completely non-specific effects of this alkaloid since it has been reported that, at
least in yeasts, lycorine is able to interact directly with mitocondrial DNA (Davey
et al., 1998; Del Giudice et al., 1997; Massardo et al., 1994). It is also well documented
that lycorine is a powerful inhibitor of cell growth, cell division and organogenesis
in higher plants, algae and yeasts, which seems to be related with asc levels
(Arrigoni, 1994; Arrigoni et al., 1997a; Córdoba-Pedregosa et al., 1996; Del
Giudice et al., 1997; Onofri et al., 1997). Lycorine also shows antitumour activity
(Yui et al., 1998). Its mechanism of action is thought to be through inhibition of
protein synthesis at the ribosomal level (Furusawa et al., 1980; Hua et al., 1997).
Additionally, it has antiviral (Gabrielsen et al., 1992), antifeedant (Singh and Pant,
1980), and antimalarial as well as anti-inflammatory (Campbell et al., 1998; Çitoglu
et al., 1998) activities. There has also been much recent interest in the chemical
synthesis of lycorine (Hoshino et al., 1996; Ishizaki et al., 1998; Schultz et al., 1996).
Narciclasine, an antimitotic and antitumoural alkaloid from Narcissus bulbs (Ceriotti,
1967), inhibits protein synthesis by directly interacting with the 60S ribosomal