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

Abstract

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.

Combining Organocatalyzed Aldolization and Reductive Amination: An Efficient Reaction Sequence for the Synthesis of Iminosugars

“…This role of organic synthesis (almost forgotten at the beginning of 21 st century) may be required again for several subclasses of iminosugars, as there are inconsistencies in the literature that have not been clarified using instrumental methods alone. [19] Enantioselective syntheses of iminosugars relied mostly on natural sugars as chiral starting compounds, whereas the reagent-controlled asymmetric synthesis has been somewhat less used. [20] The development of organocatalyzed aldol reaction allowed for enantioselective syntheses of iminosugars based on aldolization/reductive amination [21] sequence, i. e., a catalytic asymmetric approach, which is the subject of this minireview.…”

“…Somewhat surprisingly, in addition to important biological activity, a supplementary motif for synthetic efforts toward iminosugars is structure elucidation. This role of organic synthesis (almost forgotten at the beginning of 21 st century) may be required again for several subclasses of iminosugars, as there are inconsistencies in the literature that have not been clarified using instrumental methods alone [19] . Enantioselective syntheses of iminosugars relied mostly on natural sugars as chiral starting compounds, whereas the reagent‐controlled asymmetric synthesis has been somewhat less used [20] .…”

Uso da biomassa como bloco de construção na síntese de moléculas com alto valor agregado

“…Uma destas funções é catalisar a hidrólise das ligações glicosídicas. 129,130 As glicosidases estão envolvidas na digestão intestinal do amido, na biossíntese de cadeias de oligossacarídeos e na hidrólise de glicoconjugados nos lisossomos. Assim, substâncias inibidoras das glicosidades são almejadas para o tratamento antitumoral, desordens metabólicas e infecções virais.…”

“…Assim, substâncias inibidoras das glicosidades são almejadas para o tratamento antitumoral, desordens metabólicas e infecções virais. 129,130 Galidesivir, por exemplo, é uma droga antiviral sintética, destinada para o tratamento da hepatite C, ebola, marburgo e zika vírus. Atualmente, a Galidesivir está em fase 1 de testes em humanos para o Covid-19.…”

“…Por exemplo, o tabaco (N. tabacum), beladona mortal (Atropa belladonna) e coca peruano (Erythroxylon truxillense Rusby). 127,129 Na figura 39, encontram-se as estruturas de alguns alcaloides com núcleo pirrolidínico.…”