Galanthamines

Galanthamine (23) is an alkaloid extracted from the common snowdrop Galanthus nivalis. This compound is a long-acting, competitive AChE inhibitor which appears to be somewhat more specific for acetylcholinesterase than plasma butyrylcholinesterase (132). It is well tolerated during long-term treatment (133) and is being evaluated clinically for AD (134). 

The acetylcholinesterase inhibitor tacrine (64) was approved for the treatment of mild-to-moderate SDAT in the United States in 1993 followed by several other countries. The acetylcholinesterase inhibitor galanthamine (65), which has long been in clinical use in Austria for the treatment of indications such as facial neuralgia and residual poliomyelitis paralysis, has also been approved for use in... 

Gabriel synthesis, 7, 33 aziridines, 7, 81-82 thiazoles, 6, 302 Galanthamine structure, 4, 548 Galbacin NMR, 4, 574 Gelatin hardeners for... 

Trost, B.M., Tang, W., Toste, ED. (2005) Divergent Enantioselective Synthesis of (—)-Galanthamine and (—)-Morphine. Journal of the American Chemical Society, 127, 14785-14803. 

There are numerous examples of intramolecular Heck reactions,151 such as in Entries 10 to 14. Entry 11 is part of a synthesis of the antitumor agent camptothecin. The Heck reaction gives an 11 1 endocyclic-exocyclic mixture. Entries 12-14 are also steps in syntheses of biologically active substances. Entry 12 is part of a synthesis of maritidine, an alkaloid with cytotoxic properties the reaction in Entry 13 is on a route to galanthamine, a potential candidate for treatment of Alzheimer s disease and Entry 14 is a key step in the synthesis of a potent antitumor agent isolated from a marine organism. 

The benzo[ >]furan-based core structure of galanthamine was constructed by a novel synthetic methodology making use of a NBS-initiated semi-pinacol rearrangement, leading to the desired products in high yields <06OL1823>. 

The asymmetric synthesis of a galanthamine alkaloid relies also on the intramolecular Heck reaction for the preparation of the benzo[h]furan-based key intermediate with a crucial chiral quaternary center, which eventually leads to the synthesis of (-)-galanthamine <00JA11262>. A similar approach towards the construction of galanthamine ring system via an intramolecular Heck reaction has also been investigated <00SL1163>. 

Chopin P, Briley M. (1992). Effects of four non-cholinergic cognitive enhancers in comparison with tacrine and galanthamine on scopolamine-induced amnesia in rats. Psychopharmacoiogy (Beriin). 106(1) 26-30. 

Babic, T., Lakusic, D.M., Sertic, J., Petrovecki, M., Stavljenic-Rukavina, A. (2004) APOE genotyping and response to galanthamine in Alzheimer s disease-a real Ufe retrospective study. Coll. Antropol, 28, 199-204. 

The observed acid-catalysed conversion of complestatin (289) into chloropeptin L (291) has been envisioned" " as proceeding through a cyclopropyl intermediate (290) (see Scheme 94). An intramolecular oxygen-transfer reaction illustrated in Scheme 95 has been proposed" to explain hydroxylation of the aromatic nucleus, viz. formation of (292), during the course of a modified Polonovski reaction on galanthamine. 

Traditionally, plants are a rich source of AChE inhibitors. People from the Caucasus used bulbs of snowdrops Galanthus sp.) to treat forgetfulness [25]. The active compound in this plant has been isolated and called galanthamine. Other plant-derived AChE inhibitors used for treatment of Alzheimer s disease include Huperzine A from Huperzia serrata and Rivastigmine (Excelon). The latter is a derivative from physostigmine isolated from the calabar bean, Physos-tigma vmmosum. 

Figure 5.7 demonstrates the implementation of the assay and shows the readout in the MS that was obtained for injections of the AChE inhibitor galanthamine at 0, 1, and 10 pM. Figure 5.7a shows the extracted ion chromatogram of galanthamine, Fig. 5.7b shows the extracted ion chromatogram of HMQI (prod-... 

Fig. 5.7 AChE-catalyzed hydrolysis of the fluorescent substrate AMQI in volatile buffer monitored by mass spectromet. Line 1 Start of the substrate pump delivering AMQI. Line 2 Start of the enzyme pump delivering AChE. Peak 3 Injection of 0.1 pM galanthamine. Peak 4 Injection of 1.0 pM galanthamine. MS instrument Q-ToF2 (Waters) equipped with a Waters Z-spray electrospray (ESI) source, (a) Mass chromatogram of m/z 288 (galanthamine) (b) mass chromatogram of m/z 104...

Upon starting the AChE pump, a ready decrease in the substrate and a matching increase in the product trace was observed. Injections of galanthamine resulted in a negative peak in the product trace and a positive peak in the substrate trace, accurately matching the peaks observed in the galanthamine trace. 

IC50 curves were also recorded for various other inhibitors and the corresponding IC50 values were calculated. The determined IC50 values of 9-aminoacridine, galanthamine, gallamine, (—)-Huperzine A and thioflavin T were 0.12 pM, 0.38 pM, 6.4 pM, 0.46 pM, and 3.2 pM, respectively. It was difficult to compare these values with comparable values in literature since often different types of AChE, or AChE isolated from different organisms were used and different assay conditions were applied. However, the relative activities of the used inhibitors compared well with those reported in literature, except for (—)-huperzine A, which was found to be relatively less active then was expected. 

To test whether the system was effective in a real screening experiment, an extract was made of Narcissus cv Bridal Crown bulbs. Although species of the genus Narcissus are known to contain galanthamine, no information was available about the galanthamine content in this variety. 

Heinrich M, Teoh HL. (2004) Galanthamine from snowdrop — the development of a modem drug against Alzheimer s disease from local Caucasian knowledge. J Ethnopharmacol 92 147-162. 

Greenblatt HM, Kryger G Lewis T, Sihnan 1, Sussman JL. (1999) Structure of acetylcholinesterase complexed with (-)-galanthamine at 2.3 A resolution. FEES Lett 463 321-326. 

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. 

Galanthamine (10) Galanthus woronowii Losinsk (snowdrop) Anti-Alzheimer s disease... 

Galanthamine exerts its activity through a competitive and reversible cholinesterase inhibitor action. 

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