Galanthamine derivatives

Narwedine ([a]p - -100°) was reported to be a constituent of Texas daffodils (105). Repetition of this extraction in another laboratory (103) afforded a mixture of ( )-narwedine and (—)-galanthamine after chromatograph3 Recrystallization from benzene gave narwedine ([ Id +32°). Because of the ease of racemization and its resolution phenomenon in the presence of traces of various galanthamine derivatives the sign of optical rotation of the naturally occurring narwedine is unsettled. 

Berkov S, Codina C, Viladomat F, Bastida J (2008) N-Alkylated galanthamine derivatives potent acetylcholinesterase inhibitors from Leucojum aestivum. Bioorg Med Chem Lett 18 2263... 

Perissutti E, Fiorino F, Severino B, Frecentese F, Massarelli P, Nencini C, Santagada V, Caliendo G (2007) Synthesis of 6beta-D-glucosyl and 6-nitroxy (-)-galanthamine derivatives as acetylcholinesterase inhibitors. Pharmazie 62 403... 

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. 

Several inhibitors of AChE have been developed for use in treating Alzheimer s disease, which requires that the drugs readily enter the CNS. These inhibitors are structurally unrelated and vary in their mechanism of inhibition, although all are reversible inhibitors. Tacrine (Cognex) is a monoamine acridine. Donepezil (Aricept) is a piperidine derivative that is a relatively specific inhibitor of AChE in the brain, with little effect on pseudo-ChE in the periphery. Galanthamine (Reminyl) is a tertiary alkaloid and phenanthrene derivative extracted from daffodil bulbs that is a reversible competitive inhibitor of AChE it also acts on nicotinic receptors. 

Galanthamine is a phenanthrene-derivative alkaloid of molecular weight 368.43 its structure is shown in Figure 27.2. Galanthamine can be purified from the bulbs of different strains of Narcissus the quantity recovered per 100 mg of dried bulb ranges from 3.9 to 78.7 mg depending on the specific daffodil cultivar used. 

Although in principle naturally occurring (—)-galanthamine could have been prepared by an identical sequence of reactions commencing with D-tyrosine, an alternate route to 319, the enantiomer of 314, was developed. Thus, epimeriza-tion of the methyl ester group at C-6 of the A -trifluoroacetamide derived from 315 followed by oxidation of the allylic alcohol with pyridinium chlorochromate furnished 319 in 78% optical purity, albeit in low chemical yield. Since 319 could be converted to (-)-galanthamine (291) by the same sequence of reactions outlined for the transformation of 314 to (+)-galanthamine, its preparation may be considered to represent a formal total synthesis of 291 from L-tyrosine (163). 

The structures and the absolute configuration of these alkaloids have been firmly established by chemical and physical methods since that time. The work which has been carried out in this field led to the structural assignment of a new alkaloid, habranthine (155), to the definition of the stereochemistry of chlidanthine (152), and to the synthesis of galanthamine-type derivatives through several approaches. 

Evidence has been produced indicating for chlidanthine the stereostructure 152 and its catabolic derivation from galanthamine (147). Since spectral data, though strongly supporting the similarity between... 

Galanthamine was epimerized under acidic conditions and the resulting 148 was treated with thionyl chloride. The resulting chloro derivative was converted with NaOMe in methanol into two compounds. An elimination product and galanthamine-O-methyl ether (151), were obtained. 

Since the successful biogenetically patterned synthesis of the galanthamine skeleton from O V-dimethylnorbelladine (397) by oxidative coupling performed by Barton and Kirby several attempts have been carried out along these lines. However, several norbelladine derivatives were used in the hope that a decrease in the nitrogen lone pair availability might increase the yields in the oxidation phase. 

H]Narwedine and from the latter (+ )-[3H]galanthamine (147) and (+ )-[3H]epigalanthamine (148) were prepared from narwedine and tritiated methanol. The three labeled alkaloids were used to show that in Chlidanthus fragrans Herb, chlidanthine (152) arises from galanthamine through demethylation and methylation, not necessarily in this order. The incorporation values decreased from the 1.08% after 2 days from the feeding to 0.081% at the seventh day. The biosynthetic catabolic derivation of chlidanthine from 147 thus established confirmed the stereochemical relationship based on chemical inter-conversions (SO). 

The contribution of plants to modern medicine can hardly be overstated. Many plant natural products are used in medicine in their native, undomesticated form and the anti-Alzheimer s alkaloid galanthamine and the anticancer diterpenoid paclitaxel are additions to the inventory of plant-derived drugs obtained by direct isolation.101... 

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>. 

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