Amaryllidaceae galanthamine from

Heinrich M (2010) Galanthamine from Galanthus and other Amaryllidaceae - ehtanistry and biology based on tradition use. In Cordell GA (ed) The alkaloids, vol 68. Elsevier Seientifie... 

Galanthamine (10), an Amaryllidaceae-type alkaloid from Galanthus woronowii Losinsk and other species of this genus, has been approved in the last few years for the treatment of early-onset Alzheimer s disease. 

Oxazocine 119 is a synthetic derivative of galanthamine 162. The latter is a tertiary alkaloid, isolated from amaryllidaceae, which is a central acting competitive and reversible inhibitor of acetylcholinesterase that enhances cognitive functions in Alzheimer s patients. However, oxazocine 119 showed a decreased potency as an acetylcholinesterase inhibitor and a marked selectivity with respect to butyrylcholinesterase, probably because butyrylcholinesterase accommodates steric bulk around the catalytic site, better than acetylcholinesterase <2003BML2389>. 

Amaryllidaceae Alkaloids.—Chlidanthine (102) is an alkaloid of Chlidanthus fragrans. By analogy with the well-known conversion of codeine to morphine it might be expected to arise from galanthamine (101) by 0-demethylation. This was shown to be true when both galanthamine and narwedine (100), with tritium labels, were incorporated into chlidanthine (102). ... 

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 alkaloid galanthamine (169) has been obtained from various Amaryllidaceae species including daffodils, the red spider lily Lycoris radiata) and the Caucasian snowdrop (Galanthus woronowii). Its effectiveness as a centrally acting, selective, reversible and competitive inhibitor of acetylcholinesterase has resulted in galanthamine being introduced into the clinic in both the USA and Europe for the symptomatic treatment of mild to moderate forms of Alzheimer s disease [57]. These and various other intriguing feamres of this alkaloid have prompted extensive synthetic studies of it [57]. 

Some Amaryllidaceae plants possess a group of alkaloids containing a Cg— C2-N-C1-C6 unit. In this unit, the C6-C2-N moiety is derived from tyrosine or tyramine, and the C -Ci part is derived from phenylalanine through cinnamic acid, p-coumaric acid, and protocatechualdehyde [1]. Tyramine (C6-C2-N unit) and protocatechualdehyde (C -Ci unit) are then combined and methylated to form O-methylnorbelladine, which is a common biosynthetic precursor of various Amaryllidaceae alkaloids. Through para,ortho -, ortho,para - and para,paw-phenol coupling of norbel-ladine, the lycorine, galanthamine, and crinine type alkaloids are formed, respectively [2]. 

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. 

Later on, Zhou and co-workers studied this methodology and applied it in the total synthesis of (-)-galanthamine and ( )-lycoramine, which vras isolated from the bulbs of different species of the Amaryllidaceae family, and is a selective, reversible, and competitive acetylcholinesterase inhibitor and has been used in the early treatment of Alzheimer s disease. ... 

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