Alkaloids narciclasine

Phenanthridine and Related Alkaloids Narciclasine Related Alkaloids Dibenzo[c,e]azocine Alkaloids —Tetracyclic Alkaloids... 

Narciclasic aldehyde (16 R = CHO), a key degradation product in the structural elucidation of the alkaloid narciclasine, has been synthesized via the isoquinolone... 

Among these alkaloids, narciclasine (lycoricidine)-type alkaloids are highly oxygenated compounds, the significant antitumor activity of which attracts the attention of biologists and pharmacologists. Recent developments in analytical techniques, as well as isolation procedures, have resulted in the rapid characterization of many structures. In the sections on the alkaloids that have been isolated for the first time from the Amaryllidaceae plants, not only the novel, but also the known, structures have been included. This chapter is a review of the Amaryllidaceae alkaloids that have appeared in the literature (1-7) since a previously published review in this series (S). 

This method was used by Hudlicky in a synthesis of the alkaloid narciclasine. The diol 90 was trapped as the usual acetal and reacted as a diene with the nitroso ester Me02C-N0 in a hetero-Diels-Alder reaction to give 91. Suzuki coupling of the vinylic bromide with the right aryl boronic acid gave 92 and the N-0 bond was reduced with Mo(CO)6 to give the advanced intermediate 93 on the way to narciclasine28 94. 

Amaryllidaceae Alkaloids.—Narciclasine (73) occurs in Narcissus plants along with the Amaryllidaceae alkaloids haemanthamine (70), lycorine (71), and nor-pluviine (72). The three alkaloids (70), (71), and (72) are derived41,42 from O-methylnorbelladine (68) following pathways outlined in Scheme 10. In path a phenol coupling of (68) in the para-para direction leads ultimately to haemanthamine (70) ortho-para coupling as in path b leads to lycorine (71) and nor-pluviine (72). 

The structural revision of narciprimine led to a more detailed investigation17 into the identity of the related alkaloid narciclasine, which had been assigned structure (20) by other workers. On the basis of interpretation of u.v. and n.m.r. spectra in comparison with those of other alkaloids of this structural type and of chemical degradation, the revised structure (21) for narciclasine has been advanced. Synthetic work towards the final solution of this structural problem is under way.17... 

Amaryllidaceae Alkaloids.— Narciclasine (92) has been found to incorporate 0-methylnorbelladine (101) and oxocrinine (93), and thus arises by a pathway similar to that of haemanthamine (105). In the late stages to narciclasine the two-carbon bridge is lost from the oxocrinine skeleton, and preliminary experiments to determine the nature of the late intermediates have been reported. ... 

Extracts of Narcissus bulbs have been used in the past for the treatment of cancers [127], Recent investigations have resulted in the isolation of a new alkaloid, narciclasine, having antimitotic activity against S 180 in ascites form at 0-5 mg/kg. Narciclasine has been found in other members of the family Amaryllidaceae, and is identical with the alkaloid lycoricidinol from Lycoris radiata [128]. 

Fessner et al. have reported an elegant strategy for the stereospecific synthesis of novel pancratistatin analogs [42]. The pancratistatin alkaloid and its closely related natural congeners, including notably trans-dihydrolycoricidine and the anhydro and deoxy derivatives narciclasine and lycoricidine (Figure 4.2), have attracted considerable attention due to their biological activities [43]. 

Pancratistatln. The first total synthesis of ( )-pancratistatin (94) (Scheme 14), the structurally most complex of narciclasine alkaloids, was achieved by Danishefsky [27]. The requisite starting material, the substituted benzaldehyde 95 prepared from pyrogallol in six steps in 18% overall yield, was converted via the homoallylic alcohol 96 into the diene 97. Reaction of 97 with 2-nitrovinylsulphone yielded the cycloadduct 98, which on treatment with tributyltinhydride and 2,2 -azobisisobutyronitrile furnished the cyclohexadiene 99. Whilst the cyclisation of the silylether 99 or the derived phenol, under the influence of iodine, could not be accomplished, the more nucleophilic stannylether did participate in the desired ring closure and provided via the iminium salt, the iodolactone 100 on aqueous work-up. 

Other interesting approaches yet to culminate in successful chiral syntheses of narciclasine alkaloids are reported in the recent literature [32-40],... 

Narciclasine (215) is an antitumor agent which exerts an antimitotic effect during metaphase by immediately terminating protein synthesis in eukaryotic cells at the step of peptide bond formation (97,101,141,142), apparently by interaction with the ansiomycin area of the ribosomal peptidyl transferase center (142). The alkaloid has also been found to inhibit HeLa cell growth and to stabilize HeLa cell polysomes in vivo (97). Although DNA synthesis was retarded by narciclasine, RNA synthesis was practically unaffected (97,142). Sev-... 

The majority of the approaches that have been adopted for the synthesis of narciclasine (215), lycoricidine (214), and related alkaloids have involved the strategy of constructing the ring system in the order A — C —> B. There have also been examples of the A — BC and C —> A —> B type. 

An alternate entry to the narciclasine class of alkaloids has provided access to compounds related to isonarciclasine (263) (Scheme 24). In the event, the aryla-tion of p-benzoquinone with diazonium salts derived from the aryl amines 250 and 251 yielded the aryl-substituted benzoquinones 252 and 253, respectively (146). The selective hydroxylation of 252 and 253 with osmium tetraoxide provided the corresponding m-diols 254 and 255. Catalytic hydrogenation of 254 and 255 using Pd/C or Raney Ni and subsequent lactonization gave the triols 256 and 257 together with small amounts of the C-2 a-epimers 258 and 259. Aminolysis of 256 and 257 afforded the corresponding racemic tetrahydrophen-anthridones 260 and 261, whereas similar treatment of the a-epimers 258 and 259 led to the formation of ( )-isolycoricidine (262) and ( )-isonarciclasine (263), respectively. 

The antimitotic lactam narciclasine (376) is widely distributed in Amaryllidaceae plants. It seems, however, nonassociated apparently with any particular alkaloid, the only chemotaxonomic peculiarity being its absence in plants usually containing alkaloids possessing the ( - )-crinane skeleton (101). 

The availability of the enantiomeric alkaloids vittatine (284) and crinine in labeled form through separate feeding experiments with labeled 343 in Pancratium maritimum L. and Nerine bowdenii, respectively, provided experiments which indicated the absolute configuration of narciclasine. Thus, the two alkaloids were obtained from [3, 5 -3H2]-O-methylnorbelladine. Experiments with multiply labeled 343 have previously shown that no 3H loss takes place during the biosynthesis,... 

Amaryllidaceae Alkaloids.—Detail has been added to the fairly thoroughly delineated pathways to the Amaryllidaceae alkaloids.75 76 11-Hydroxyvittatine (94), previously shown to be a precursor for narciclasine (96),76 has been proposed as an intermediate in the biosynthesis of haemanthamine (92) and montanine (95) following the observed specific incorporation of vittatine (93) into the two... 

The observation79 in an earlier more extensive study that norpluviine (100) is a precursor for lycorenine (102) has been confirmed.80 Incorporations were also recorded with both norpluviine (100) and pluviine (101) for other alkaloids of related structure to norpluviine, including galanthine (103). Although radio-active narciclasine (96) was also isolated in the experiment with norpluviine, its known derivation76,81 by way of a different pathway through vittatine (93) indicates that this is not significant. 

A number of Amaryllidaceae alkaloids, including haemanthamine, lycorine, narciclasine, and pretazettine, have been shown to inhibit the fundamental step of the formation of a peptide bond in protein synthesis.14... 

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). 

The total synthesis of several amaryllidaceae alkaloids including that of narciclasine was accomplished in the laboratory of T. Hudlicky. The C2 stereochemistry was established by a two-step sequence Luche reduction of the a,(3-unsaturated cyclic ketone followed by a Mitsunobu reaction. The ketone was first mixed with over one equivalent of CeCIs in methanol and then the resulting solution was cooled to 0 °C, and the sodium borohydride was added. In 30 minutes the reaction was done, and the excess NaBH4 was quenched with AcOH. The delivery of the hydride occurred from the less hindered face of the ketone and the allylic alcohol was obtained as a single diastereomer. 

Cherylline-type alkaloids derived from tetrahydroisoquinoline Narciclasine-type alklaloids and... 

A reexamination of the polar alkaloid components of the bulbs of Hymeno-callis caymanensis (47) has disclosed a glucoalkaloid l- 8-D-glycosyl-2-/3-D-glycosylpseudolycorine (15). Also, a new glucosyloxy derivative 206 of narciclasine is found in the polar alkaloid components of P. marititimum (96), and both the parent alkaloid and this new derivative were shown to possess strong mitotoxic activity... 

Regarding the synthesis of the narciclasine (lycoricidine)-type alkaloids, an important strategic element is how to construct the functionalized ring C in these alkaloids. Therefore, extensive efforts to explore a new method for preparing a key intermediate have been made. 

Recently, oxidation of a halobenzene using a microbiological procedure was found to give optically active 3-halo-l,2-ciy-dihydroxycyclohexa-3,5-diene in good yield. This compound has received the attention of chemists for constructing ring C in the narciclasine-type alkaloids (153). 

A new alkaloid phamine (430), which is a phenanthridone alkaloid belonging to the narciclasine group, has been isolated from the bulbs of Hippeastrum equestre along with known Amarylldaceae alkaloids (47). Its structure was determined by spectroscopic (MS, UV, H and NMR) analyses. Also, phamine indicated interesting antimitotic activity. The alkaloids isolated since 1987 are shown in Fig. 25. 

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