Galanthamine structure

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

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>. 

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. 

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. 

FIGURE 27.3 Chemical structures of physostigmine, galanthamine, and codeine. 

The structure of sanguinine (295) was initially based on spectroscopic comparisons with galanthamine (291) and related alkaloids, but this assignment was subsequently verified by its conversion to 291 by methylation with diazomethane in DMSO (62). Thus, 295 represented the second example of a phenolic base among the galanthamine-type alkaloids. 

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. 

Structure 161 has been assigned to the byproduct (mp 190-200°) which accompanies narwedine (149) in the chromic acid oxidation of galanthamine (147). The same compound can be obtained in the Mn02 oxidation. Its formation was explained by assuming a benzylic hydrox-ylation which is followed by the opening of the carbinolamine to an amino aldehyde whose amino group adds onto the double bond of the previously formed enone system finally yielding the required 161 (31). 

The phenanthridine alkaloid lycorine (narcissine, galanthidine) (MD—Phe G5N C6) has a widespread occurrence and inhibits protein synthesis. Like lycorine, the structurally similar alkaloids dihydrolycorinine, haemanthamine, narciclasine, pretazettine and pseudolycorine also inhibit protein synthesis at the level of peptide bond formation. Galanthamine (lycorimine) (Phe C6N C40 C6 ), from daffodil bulbs but also of widespread occurrence, is both a nACh-R allosteric modulator and an inhibitor of AChE. Galanthamine is clinically employed in the treatment of Alzheimer s disease (dementia linked to deficiency in acetylcholine-mediated signalling in the central nervous system). 

A number of related couplings have been reported during the synthesis of alkaloids, such as oxocrinine and cryptoplurine [26], the intramolecular coupling of diarylamines to dibenzazepine, and dibenzazocine structures [27], synthesis of galanthamine [28] and phe-nanthropyrrolidines [29], and the intramolecular arylation of enamines [30]. 

A comparative n.m.r. study of dihydrogalanthamine and dihydroepigalanthamine and their acetyl derivatives has been reported. The crystal structure of ( )-norgalanthamine (6), incorrectly named ( )-galanthamine, but corrected in Chemical Abstracts, has been determined by direct methods. 

Mary, A., Renko, D. Z., Guillou, C., Thai, C. Potent acetylcholinesterase inhibitors design, synthesis, and structure-activity relationships of te-interacting ligands in the galanthamine series. Bioorg. Med. Chem. 1998, 6, 1835-1850. 

Furthermore, examination of the extracts of the flowers of Lycoris incarnata (58) has shown the presence of ungiminorine A -oxide (10) and galanthamine N-oxide (281), together with the corresponding free bases. The interesting N-oxide oxoassoianine N-oxide (49) has been found in the bulbs of Narcissus bicolor (64). The structures of these metabolites are shown in Fig. 2. 

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