Galanthamine pathway

From norbelladine, through the activity of the SAM, the 4 -0-methylnorbelladine synthesizes, and again is transformed to lycorine, crinine and, by oxidative coupling, to A-demethylarwedine, which is the object of enzyme NADPH activity. Galanthamine is synthesized by transformation trough the activity of the SAM from A-demethylgalanthamine. 

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From L-tyrosine, or alternatively from L-phenylalanine, there is one further alkaloid biosynthesis pathway. This is the galanthamine pathway (Figure 38). Galanthamine synthesizes with tyramine, norbelladine, lycorine, crinine, N-demethylnarwedine and Al-demethylgalanthamine. Schiff base and reduction reaction, oxidative coupling and enzyme NADPH and SAM activity occur in this pathway. Schiff base is a reaction for the ehmination of water in formation with the C—N bonds process. 

One of the characteristics of intermedia is that in many cases it is not a stable compound (e.g., cadaverine). Intermedia is a compound which can be the final product of any pathway. However, an alkaloid can convert from an intermedia (e.g., norbelladine from tyramine in the galanthamine pathway), though this process is restricted. Generally, the synthesis pathway continues to establish the next compound, the obligatory intermedia. 

Scheme 1. Natural product (galanthamine) inspired compound library that led to the identification of a small molecular probe (denoted as secramine) to study a pathway that shuttles proteins from the endorplasmatic reticulum (ER) to the plasma membrane via the Golgi apparatus (GA).

The work on the biosynthesis of Amaryllidaceae alkaloids reached a peak in the period 1960-1976 with a great number of studies related with this subject. However, since then, little new work has been produced apart from the isolation of compounds predicted as biosynthetic intermediaries of a certain pathway or, more recently, a new biosynthetic proposal to obtain galanthamine (70), which differs from the initial one. 

The clinical demand for (—)-galanthamine together with the erosion of habitat of at least some of the source plants has created supply issues. As a result, new means of production of the alkaloid are being sought with in vitro cultivation and pathway optimization techniques (in which the biosynthetic pathway is tweaked ) being prominent among these. To date, no industrially applicable (cost-effective) chemical synthesis of compound 1... 

The initial studies of this pathway suggested that the para-ortho coupling does not proceed from (9-methylnorbelladine (87), but from A, (9-dimethylnorbella-dine (99) to finally give galanthamine (75) (207). (9,A -dimethylnorbella-dine (99) was... 

Figure 2. Proposed AA biosynthetic pathways. Three major groups of AA (para-ortho para-para , ortho-para ) are represented along with the nine proposed AA types norbelladine-, galanthamine-, crinine-, narciclasine-, haemanthamine-, montanine-, homolycorine-, lycorine-, and narcissidine-type (shaded gray). Broken arrow indicates more than one step.

Based on the Amaryllidaceae alkaloid galanthamine, a biomimetic solid-phase synthesis of 2527 compounds was reported by Shair and coworkers (Figure 11.13) The core scaffold, initially prepared in several steps, was diversified by means of four successive reactions Mitsunobu reaction of the phenolic moiety with five primary alcohols, Michael addition of the a, 3-unsatnrated cyclohexenone with thiols, iV-acylation or A -alkylation of the cyclic secondary amine, and treatment of the ketone with hydrazines and hydroxylamines. Further evaluation of library constituents for their ability to block protein trafficking in the secretory pathway of mammalian cells led to the discovery of sercramine as a potent inhibitor of the VSVG-GFP protein movement from the Golgi apparatus to the plasma m brane. 

The deduced pathway to galanthamine 6.190) which involves ortho-para oxidative coupling is illustrated in Scheme 6.35 chlidan-thine 6.191) is formed from galanthamine 6.190) [135]. Similar coupling but in the opposite sense para-ortho) leads to norpluviine 6.182) and by allylic hydroxylation on to lycorine 6.185) [125] further oxidation, this time of galanthine 6.192), gives narcissidine 6.193) [136]. The retention of two out of four tritium atoms in the formation of norpluviine 6.182) from 0-methylnorbelladine [labelled... 

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