Australine and related alkaloids: easy structural confirmation by 13C NMR spectral data and biological activities

Kato, Atsushi; Kano, Erika; Adachi, Isao; Molyneux, Russell J.; Watson, Alison A.; Nash, Robert J.; Fleet, George W. J.; Wormald, Mark R.; Kizu, Haruhisa; Ikeda, Kyoko; Asano, Naoki

doi:10.1016/s0957-4166(02)00799-1

Cited by 97 publications

(82 citation statements)

References 26 publications

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“…Although we can not unequivocally prove the structure of uniflorine A, without access to the original material and data, the published data suggest that the natural product is also a 1,2,6,7-tetrahydroxy-3-hydroxymethylpyrrolizidine with the same relative C-7-C-7a-C-1-C-2-C-3 as casuarine 28. We suggest that uniflorine A is 6-epi-casuarine (29). This structure is also consistent with the published NOE and our re-referenced 13 C NMR data.…”

Section: Discussionsupporting

confidence: 92%

Synthetic and spectroscopic studies on the structures of uniflorines A and B: structural revision to 1,2,6,7-tetrahydroxy-3-hydroxymethylpyrrolizidine alkaloids

2008

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The diastereoselective synthesis of the C-2 epimer and the C-1, C-2 di-epimers of the putative structure of the alkaloid uniflorine A has been achieved. The synthesis of the latter di-epimers employed a novel pyrrolo[1,2-c]oxazin-1-one precursor to allow for the reversal of π-facial diastereoselectivity in an osmium(VIII)-catalyzed syn-dihydroxylation (DH) reaction. The NMR spectral data of these epimeric compounds and that of related isomers did not match that of the natural product. From a comparison of the NMR data of uniflorines A and B with that of casuarine and the known synthetic 1,2,6,7-tetrahydroxy-3-hydroxymethylpyrrolizidine isomers we concluded unequivocally that uniflorine B is the known alkaloid casuarine. Although we cannot unequivocally prove the structure of uniflorine A, without access to the original material and data, the published data suggest that the natural product is also a 1,2,6,7-tetrahydroxy-3-hydroxymethylpyrrolizidine with the same relative C-7-C-7a-C-1-C-2-C-3 stereochemistry as casuarine. We thus suggest that uniflorine A is 6-epi-casuarine. Abstract:The diasteresoselective synthesis of the C-2 epimer and the C-1, C-2 di-epimers of the putative structure of the alkaloid uniflorine A has been achieved. The synthesis of the latter di-

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Section: Discussionsupporting

confidence: 92%

Synthetic and spectroscopic studies on the structures of uniflorines A and B: structural revision to 1,2,6,7-tetrahydroxy-3-hydroxymethylpyrrolizidine alkaloids

2008

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“…The use of longer reaction times or other cyclization methods (e.g. CBr 4 , Ph 3 P) 15,27 did not result in improved yields of 20. Compound 20 was then smoothly converted to the triacetate of (+)-1,7-diepiaustraline (22) by first hydrogenolysis of the primary benzyl ether group 15,28 and then peracetylation in 84% overall yield.…”

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confidence: 91%

Asymmetric Synthesis of (−)-7-Epiaustraline and (+)-1,7-Diepiaustraline

Tang

Pyne

2003

J. Org. Chem.

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A diastereoselective and modular approach to the synthesis of the 3-hydroxymethyl-2,3,5,6,7,7a-hexahydro-1H-pyrrolizine-1,2,7-triol structure, characteristic of several natural pyrrolizidine natural products has been developed. This approach culminated in the synthesis of (-)-7-epiaustraline and (+)-1,7-diepiaustraline. The oxazolidinone group has been found to be a useful protecting group in the RCM reaction and, as part of a pyrrolo[1,2-c]oxazol-3-one ring system, has functioned as a stereo-and regiodirecting group, in a key diastereoselective cis-dihydroxylation reaction and a regioselective nucleophilic ringopening of a S,S-dioxo-dioxathiole. Abstract: A diastereoselective and modular approach to the synthesis of the 3-hydroxymethyl-2,3,5,6,7,7a-hexahydro-1H-pyrrolizine-1,2,7-triol structure, characteristic of several natural

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“…japonica [33], DNJ (12) was obtained from the root bark of Morus alba [34], and castanospermine (11) was obtained from the seeds of Castanospermum australe [35] according to the literature. IFG (16) was synthesized from d-lyxose according to the literature [24], and N-butyl-DNJ (13) and N-butyl-IFG (17) were prepared by adding 1-bromobutane and NaHCO 3 to a solution of DNJ and IFG, respectively, in MeOH ⁄ dioxane (3 : 2) [36].…”

Section: Compoundsmentioning

confidence: 99%

Hydrophilic iminosugar active‐site‐specific chaperones increase residual glucocerebrosidase activity in fibroblasts from Gaucher patients

et al. 2006

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Gaucher disease is an autosomal recessive lysosomal storage disorder caused by the deficient activity of glucocerebrosidase. Accumulation of glucosylceramide, primarily in the lysosomes of cells of the reticuloendothelial system, leads to hepatosplenomegaly, anemia and skeletal lesions in type I disease, and neurologic manifestations in types II and III disease. We report herein the identification of hydrophilic active-site-specific chaperones that are capable of increasing glucocerebrosidase activity in the cultured fibroblasts of Gaucher patients. Screening of a variety of natural and synthetic alkaloid compounds showed isofagomine, N-dodecyl deoxynojirimycin, calystegines A 3 , B 1 , B 2 and C 1 , and 1,5-dideoxy-1,5-iminoxylitol to be potent inhibitors of glucocerebrosidase. Among them, isofagomine was the most potent inhibitor of glucocerebrosidase in vitro, and the most effective active-site-specific chaperone capable of increasing residual glucocerebrosidase activity in fibroblasts established from Gaucher patients with the most prevalent Gaucher disease-causing mutation (N370S). Intracellular enzyme activity increased approximately two-fold after cells had been incubated with isofagomine, and the increase in glucocerebrosidase activity was both dose-dependent and time-dependent. Western blotting demonstrated that there was a substantial increase in glucocerebrosidase protein in cells after isofagomine treatment. Immunocytochemistry revealed an improvement in the glucocerebrosidase trafficking pattern, which overlaps that of lysosome-associated membrane protein 2 in Gaucher fibroblasts cultivated with isofagomine, suggesting that the transport of mutant glucocerebrosidase is at least partially improved in the presence of isofagomine. The hydrophilic active-site-specific chaperones are less toxic to cultured cells. These results indicate that these hydrophilic small molecules are suitable candidates for further drug development for the treatment of Gaucher disease.

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Australine and related alkaloids: easy structural confirmation by 13C NMR spectral data and biological activities

Cited by 97 publications

References 26 publications

Synthetic and spectroscopic studies on the structures of uniflorines A and B: structural revision to 1,2,6,7-tetrahydroxy-3-hydroxymethylpyrrolizidine alkaloids

Synthetic and spectroscopic studies on the structures of uniflorines A and B: structural revision to 1,2,6,7-tetrahydroxy-3-hydroxymethylpyrrolizidine alkaloids

Asymmetric Synthesis of (−)-7-Epiaustraline and (+)-1,7-Diepiaustraline

Hydrophilic iminosugar active‐site‐specific chaperones increase residual glucocerebrosidase activity in fibroblasts from Gaucher patients

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