Pyrrolizidine alkaloids: occurrence, biology, and chemical synthesis

Robertson, Jeremy; Stevens, Kiri

doi:10.1039/c5np00076a

Cited by 133 publications

(90 citation statements)

References 131 publications

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“…[6][7][8][9][10][11][12][13][14][15] Additionally, different methods have also been employed towards the synthesis of many unnatural hyacinthacines, increasing the scope and potential finding of more potent analogues to be used as possible antiviral, anticancer, antidiabetic and anti-obesity drugs. 16,17 The current classification system for hyacinthacine alkaloids divides these compounds into the following: hyacinthacines A 1-7 , B 1-7 , and C 1-5 ; whereby the letter assignment, A, B or C, corresponds to the presence of 0, 1 or 2 hydroxy/hydroxymethyl, substituents found on the B ring, respectively (Figure 1). [18][19][20][21] Regardless of whether a natural isolate or synthetically derived, structures and relative configurations have been assigned through NMR spectroscopic and MS spectrometric analysis with the only X-ray crystallographic data pertaining to the later classified compounds.…”

Section: Introductionmentioning

confidence: 99%

Total Synthesis of Natural Hyacinthacine C₅ and Six Related Hyacinthacine C₅ Epimers

et al. 2018

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The total synthesis of natural (+)-hyacinthacine C was achieved, which allowed correction of its initially proposed structure, as well as six additional hyacinthacine C-type compounds. These compounds were readily accessible from two epimeric anti-1,2-amino alcohols. Keeping a common A-ring configuration, chemical manipulation occurred selectively on the B-ring of the hyacinthacine C-type products through methods of syn-dihydroxylation, S2 ring-opening of a cyclic sulfate, and also employing either ( R)- or ( R, S)-α-methylallyl amine for the Petasis borono Mannich reaction. Our small analogue library was then assessed for its glycosidase inhibitory potency against a panel of glycosidases. (-)-6- Epi-hyacinthacine C and (+)-7- epi-hyacinthacine C (compound names are based on the corrected structure of hyacinthacine C) proved most active, with inhibitory activities ranging between weak (IC = 130 μM) and moderate (IC = 9.9 μM) against the α-glucosidases of rat intestinal maltase, isomaltase, and sucrase, thus identifying potential new leads for future antidiabetic drug development.

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Section: Introductionmentioning

confidence: 99%

Total Synthesis of Natural Hyacinthacine C₅ and Six Related Hyacinthacine C₅ Epimers

et al. 2018

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“…2, The novel structure and inhibition properties of pochonicine (1) led to the rapid report of total syntheses [2], together with its enantiomer [33] and analogues [34]. However, syntheses of such highly substituted bicyclic pyrrolizidines with up to seven contiguous stereogenic centres are long and complex [35,36]. In contrast, construction of monocyclic pyrrolidine iminosugars with only four chiral centres are easier to accomplish.…”

Section: Synthesis Of 1-n-mentioning

confidence: 99%

Synthesis of Pyrrolidine Monocyclic Analogues of Pochonicine and Its Stereoisomers: Pursuit of Simplified Structures and Potent β-N-Acetylhexosaminidase Inhibition

et al. 2020

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Ten pairs of pyrrolidine analogues of pochonicine and its stereoisomers have been synthesized from four enantiomeric pairs of polyhydroxylated cyclic nitrones. Among the ten N-acetylamino pyrrolidine analogues, only compounds with 2,5-dideoxy-2,5-imino-d-mannitol (DMDP) and pochonicine (1) configurations showed potent inhibition of β-N-acetylhexosaminidases (β-HexNAcases); while 1-amino analogues lost almost all their inhibitions towards the tested enzymes. The assay results reveal the importance of the N-acetylamino group and the possible right configurations of pyrrolidine ring required for this type of inhibitors.

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“…Relative to A-type hyacinthacines, both B and C-type alkaloids have a greater constitutional complexity and as a result, have led to a greater number of insecure structural assignments. Synthetic work towards hyacinthacine A and B-type alkaloids has been included in a number of reviews, [67][68][69] with a comprehensive analysis completed in 2012 by Pyne et al [70] The hyacinthacine Ctype alkaloids on the other hand have attracted considerable interest and there has been a number of publications towards their synthetic work that has not yet been summarised. When considered from a structural point of view, the hyacinthacine C-type alkaloids are the most diverse subclass of the hyacinthacines.…”

Section: Total Syntheses Of the Hyacinthacine Alkaloidsmentioning

confidence: 99%

The History of the Glycosidase Inhibiting Hyacinthacine C-type Alkaloids: From Discovery to Synthesis.

Carroll

Pyne

2019

COS

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Background: The inherent glycosidase inhibitory activity and potentially therapeutic value of the polyhydroxylated pyrrolizidine alkaloids containing a hydroxymethyl substituent at the C-3 position have been well documented. Belonging to this class, the naturally occurring hyacinthacine C-type alkaloids are of general interest among iminosugar researchers. Their selective micromolar α -glycosidase inhibitory ranges (10 – 100 μM) suggest that these azasugars are potential leads for treating type II diabetes. However, the structures of hyacinthacine C1, C3 and C4 are insecure with hyacinthacine C5 being recently corrected. Objective: This review presents the hyacinthacine C-type alkaloids: their first discovery to the most recent advancements on the structures, biological activities and total synthesis. Conclusion: The hyacinthacine C-type alkaloids are of exponentially increasing interest and will undoubtedly continue to be reported as synthetic targets. They represent a challenging but rewarding synthetic feat for the community of those interested in accessing biologically active iminosugars. Since 2009, ten total syntheses have been employed towards accessing similarly related products but only three have assessed the glycosidase inhibitory activity of the final products. This suggests the need for an accessible and universal glycosidase inhibitory assay so to accurately determine the structure-activity relationship of how the hyacinthacine C-type alkaloids inhibit specific glycosidases. Confirming the correct structures of the hyacinthacine C-type alkaloids as well as accessing various analogues continues to strengthen the foundation towards a marketable treatment for type II diabetes and other glycosidase related illnesses.

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Pyrrolizidine alkaloids: occurrence, biology, and chemical synthesis

Cited by 133 publications

References 131 publications

Total Synthesis of Natural Hyacinthacine C₅ and Six Related Hyacinthacine C₅ Epimers

Total Synthesis of Natural Hyacinthacine C₅ and Six Related Hyacinthacine C₅ Epimers

Synthesis of Pyrrolidine Monocyclic Analogues of Pochonicine and Its Stereoisomers: Pursuit of Simplified Structures and Potent β-N-Acetylhexosaminidase Inhibition

The History of the Glycosidase Inhibiting Hyacinthacine C-type Alkaloids: From Discovery to Synthesis.

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Pyrrolizidine alkaloids: occurrence, biology, and chemical synthesis

Cited by 133 publications

References 131 publications

Total Synthesis of Natural Hyacinthacine C5 and Six Related Hyacinthacine C5 Epimers

Total Synthesis of Natural Hyacinthacine C5 and Six Related Hyacinthacine C5 Epimers

Synthesis of Pyrrolidine Monocyclic Analogues of Pochonicine and Its Stereoisomers: Pursuit of Simplified Structures and Potent β-N-Acetylhexosaminidase Inhibition

The History of the Glycosidase Inhibiting Hyacinthacine C-type Alkaloids: From Discovery to Synthesis.

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Total Synthesis of Natural Hyacinthacine C₅ and Six Related Hyacinthacine C₅ Epimers

Total Synthesis of Natural Hyacinthacine C₅ and Six Related Hyacinthacine C₅ Epimers