Total Synthesis of Hyacinthacines B3, B4, and B5 and Purported Hyacinthacine B7, 7-epi-Hyacinthacine B7, and 7a-epi-Hyacinthacine B3 from a Common Precursor

Savaspun, Kongdech; Au, Christopher W. G.; Pyne, Stephen G.

doi:10.1021/jo5005923

Cited by 28 publications

(27 citation statements)

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“…[1][2][3][4][5][6] To date, nineteen hyacinthacine alkaloids of general structure 1 (Figure. 1) have been isolated from extracts of the Hyacinthaceae family and fourteen of these hyacinthacine alkaloids have been the subject of total synthesis. [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).…”

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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“…Hyacinthacine alkaloids have specific glycosidase inhibitory activities; they have been identified as potential anticancer, antiviral, antidiabetic, and antiobesity drugs [81].…”

Section: Resultsmentioning

confidence: 99%

Muscari Armeniacum Leichtlin (Grape Hyacinth): Phytochemistry and Biological Activities Review

Bokov

2019

Asian J Pharm Clin Res

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This review focuses on the Muscari armeniacum Leichtlin (Asparagaceae Juss) biologically active substances composition presented in the Aireal and underground parts and finding their possible therapeutic effects. The systematic review is dedicated to the composition of biologically active substances, including recent advances in the biological activity investigation, phytochemical studies, and biotechnology methods of plant material producing. Various electronic search engines such as Google, Google Scholar, scientific literature, publishing sites, and electronic databases such as PubMed, Wiley, Springer, and Science Direct had been searched and data obtained. Other online academic libraries such as E-library and specific ethnopharmacological literature had been searched systematically for more exhaustive information on the crude herbal drug. The chemical composition of M. armeniacum biologically active substances is established; it contains anthocyanins (delphinidin and cyanidin derivatives), homoisoflavonoids, polyhydroxylated pyrrolizidine alkaloids (hyacinthacines A1, A2, A3, and B3), oligoglycosides (Muscarosides), and ribosome-inactivating proteins (musarmins). Recent physicochemical analytical procedures for components determination and hyacinthacines synthesis pathways are mentioned. Moreover, future prospects and trends in the research of this plant have been proposed. We have reviewed researches conducted on M. armeniacum especially in areas of its use in medicine, phytochemicals, biological activity, and developed analytical methods. M. armeniacum possesses antioxidant, antimutagenic activity, and specific glycosidase inhibitory activity; M. armeniacum can be used for the production of potential anticancer, antiviral, antidiabetic, and anti-obesity drugs. It should be noted that more pharmacognostic, pharmacological studies are needed for giving further information on the clinical practice and standardization procedures for the crude herbal drug.

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“…To date, fourteen of the natural hyacinthacines, A 1 , A 2 , A 3 , A 6 , A 7 , B 1 , B 2 , B 3 , B 4 , B 5 , B 7 , C 2 , C 3 and C 5 have been synthesized, along with their related epimers and enantiomers. [51][52][53][54][55][56][57][58][59][60][61][62][63][64] At this point, the authors note that an increasing number of reports suggest the confirmation of hyacinthacine A 5 through methods of total synthesis. [61,63,65] To the best of our knowledge, hyacinthacine A 5 has not yet been synthesized and although epimers of the structure have been reported, [66] the absolute configuration of the natural isolate is still yet to be confirmed.…”

Section: Current Issues With the Hyacinthacine Alkaloidsmentioning

confidence: 99%

“…In addition to the aforementioned issues, recent synthetic studies have also revealed that the original structures proposed for hyacinthacine B 7 , C 3 and C 5 are incorrect. [58][59][60][61][62] It therefore becomes apparent that structural revision of the original isolates is necessary because as demonstrated in the earlier table, hyacinthacine alkaloid epimers determine the degree of specificity as well as the potency for the inhibition of various glycosidases.…”

Section: Current Issues With 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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Total Synthesis of Hyacinthacines B₃, B₄, and B₅ and Purported Hyacinthacine B₇, 7-epi-Hyacinthacine B₇, and 7a-epi-Hyacinthacine B₃ from a Common Precursor

Cited by 28 publications

References 62 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

Muscari Armeniacum Leichtlin (Grape Hyacinth): Phytochemistry and Biological Activities Review

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

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Total Synthesis of Hyacinthacines B3, B4, and B5 and Purported Hyacinthacine B7, 7-epi-Hyacinthacine B7, and 7a-epi-Hyacinthacine B3 from a Common Precursor

Cited by 28 publications

References 62 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

Muscari Armeniacum Leichtlin (Grape Hyacinth): Phytochemistry and Biological Activities Review

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

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Total Synthesis of Hyacinthacines B₃, B₄, and B₅ and Purported Hyacinthacine B₇, 7-epi-Hyacinthacine B₇, and 7a-epi-Hyacinthacine B₃ from a Common Precursor

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

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