Alison A. Watson

Polyhydroxylated alkaloids - natural occurrence and therapeutic applications

Over one hundred polyhydroxylated alkaloids have been isolated from plants and micro-organisms. These alkaloids can be potent and highly selective glycosidase inhibitors and are arousing great interest as tools to study cellular recognition and as potential therapeutic agents. However, only three of the natural products so far have been widely studied for therapeutic potential due largely to the limited commercial availability of the other compounds.

New polyhydroxylated pyrrolizidine alkaloids from Muscari armeniacum: structural determination and biological activity

Abstract Four new polyhydroxypyrrolizidines, hyacinthacines A 1 , A 2 , A 3 and B 3 , have been isolated from the bulbs of Muscari armeniacum (Hyacinthaceae) in addition to the known hyacinthacine C 1 , which was isolated from Hyacinthoides non-scripta (Hyacinthaceae). The structures of hyacinthacines A 1 , A 2 , A 3 and B 3 were identified on the basis of extensive NMR studies as (1 S ,2 R ,3 R ,7a R )-1,2-dihydroxy-3-hydroxymethylpyrrolizidine, (1 R ,2 R ,3 R ,7a R )-1,2-dihydroxy-3-hydroxymethylpyrrolizidine, (1 R ,2 R ,3R,5 R ,7a R )-1,2-dihydroxy-3-hydroxymethyl-5-methylpyrrolizidine and (1 S ,2 R ,3 R ,5 R ,7 R ,7a R )-3-hydroxymethyl-5-methyl-1,2,7-trihydroxypyrrolizidine, respectively, or the corresponding enantiomers. The inhibitory activities of these new hyacinthacines against a variety of glycosidases are described.

Polyhydroxylated pyrrolidine and pyrrolizidine alkaloids from Hyacinthoides non-scripta and Scilla campanulata

Aqueous ethanol extracts from the immature fruits and stalks of bluebell (Hyacinthoides non-scripta) were subjected to various ion-exchange column chromatographic steps to give 1,4-dideoxy-1,4-imino-D-arabinitol (1),2(R),5(R)-bis(hydroxymethyl)-3(R),4(R)-dihydroxypyrrolidine (DMDP) (2), 6-deoxy-6-C-(2,5-dihydroxyhexyl)-DMDP (3),2,5-dideoxy-2,5-imino-DL-glycero-D-manno-heptitol (homoDMDP)(4),homoDMDP-7-O-apioside (5), homoDMDP-7-O-beta-D-xylopyranoside (6), (1S*,2R*,3R*,5R*,7aR*)-1,2-dihydroxy-3,5- dihydroxymethylpyrrolizidine (7), and (1S*,2R*,3R*,5R*,6R*,7R*,7aR*)-3-hydroxymethyl-5-methyl-1,2,6,7 tetrahydroxypyrrolizidine (8). Bulbs of Scilla campanulata (Hyacinthaceae) yielded (1S*,2R*,3R*,5S*,7aR*)-1,2-dihydroxy-3,5-dihydroxy-methylpyrrol izidine (9) in addition to compounds 1-7. Compounds 3,6,7,8, and 9 are new natural products. Compound 4 is a potent competitive inhibitor with K(i) values of 1.5 microM for Caldocellum saccharolyticum beta-glucosidase and 2.2 microM for bovine liver beta-galactosidase. The 7-O-beta-D xyloside 6 was a stronger competitive inhibitor than 4 of C saccharolyticum beta-glucosidase and rat intestinal lactase, with K(i) values of 0.06 and 0.07 microM, respectively, but a weaker inhibitor of bovine liver beta-galactosidase. Furthermore, compound 4 is also a competitive inhibitor (K(i) = 1.8 microM) of porcine kidney trehalase, but 6 was inactive against this enzyme.

Glycosidase-inhibiting pyrrolidine alkaloids from Hyacinthoides non-scripta

Abstract The glycosidase-inhibiting pyrrolidine alkaloids (2 R ,3 R ,4 R ,5 R )-2,5-dihydroxymethyl-3,4-dihydroxypyrrolidine (DMDP), 2,5-dideoxy-2,5-imino- dl - glycero - d - manno -heptitol (homoDMDP), homoDMDP-7- O -apioside and 1,4-dideoxy-1,4-imino- d -arabinitol have been identified in the leaves of bluebells ( Hyacinthoides non-scripta ). HomoDMDP and homoDMDP-7- O -apioside are new natural products. Glycosidase inhibition by the aglycones is compared and could explain the symptoms of poisoning of livestock by bluebells.

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

Abstract The first polyhydroxylated pyrrolizidine alkaloid with a hydroxymethyl group at C-3 was isolated from pods of Alexa leiopetala (Leguminosae) and designated alexine 1. The Australian legume Castanospermum australe is also known to produce the same structural type of pyrrolizidines. There are reports of the isolation of australine (7a-epi-alexine) 2, 1-epi-australine 3, 3-epi-australine 4, and 7-epi-australine 5 from this plant to date. Their unambiguous syntheses established that the natural product reported as 5 is 2 and the published NMR data for 2 are those of 3. These confusions prompted us to unambiguously confirm the structures and biological activities of australine isomers and related alkaloids. A careful search for polyhydroxylated pyrrolizidines in seeds of C. australe led to the discovery of three new alkaloids, 2,3-diepi-australine 6, 2,3,7-triepi-australine 7, and the 2-O-β- d -glucopyranoside of 3 (8). Herein, we report the full 13C NMR assignment of alkaloids 1–8 and the glycosidase inhibitory activities of alkaloids 1–8 together with the highly oxygenated pyrrolizidine, casuarine 9, and its 6-O-α- d -glucopyranoside 10.

Polyhydroxylated pyrrolidine and piperidine alkaloids from Adenophora triphylla var. japonica (Campanulaceae)

Adenophora triphylla var. japonica (Campanulaceae) yielded two new alkaloids, the 6-C-butyl derivative of 2R,5R-bis(hydroxymethyl)-3R,4R-dihydroxypyrrolidine (DMDP) and alpha-1-C-ethyl-fagomine, together with the known alkaloids 1,4-dideoxy-1,4-imino-D-arabinitol, 1-deoxynojirimycin, and 1-deoxymannojirimycin. 6-C-Butyl-DMDP showed inhibitory activity toward almond beta-glucosidase (IC50 = 68 microM), whereas alpha-1-C-ethyl-fagomine inhibited bovine liver beta-galactosidase (IC50 = 29 microM).

L-(+)-swainsonine and other pyrrolidine inhibitors of naringinase: Through an enzymic looking glass from D-mannosidase to L-rhamnosidase?

Abstract The synthesis and inhibitory properties towards naringinase (L-rhamnosidase) of L-(+)-swainsonine and of a number of more highly oxygenated analogues, and of some monocyclic equivalents, are reported. L-(+)-swainsonine and 1,4,6-trideoxy-1,4-imino-L-mannitol are powerful and specific inhibitors of naringinase.

Therapeutic Applications of Sugar-Mimicking Glycosidase Inhibitors

Sugar-mimicking alkaloids inhibit the glycosidases involved in a wide range of important biological processes, principally owing to their structural resemblance to the sugar moiety of the natural substrate. The possibility of modifying and blocking these processes by using such inhibitors for therapeutic applications has attracted a lot of attention.

Dihydroxynortropane alkaloids from calystegine-producing plants

Three dihydroxynortropanes, 2alpha,7beta-dihydroxynortropane, 2alpha,3beta-dihydroxynortropane, and 3alpha,7beta-dihydroxynortropane, were isolated from calystegine-producing plants in the families Convolvulaceae and Solanaceae. 2alpha,7beta-Dihydroxynortropane was isolated from six species in the Convolvulaceae whereas only Calystegia soldanella contained it and 2alpha,3beta-dihydroxynortropane. Although neither of these were detectable in three species tested in the Solanaceae, 3alpha,7beta-dihydroxynortropane was, however, isolated from Duboisia leichhardtii.

Tetrazoles of manno- and rhamno- furanoses

Abstract The synthesis of [3.3.0] bicyclic tetrazoles derived from D-manno and D-rhamnofuranose starting from D-mannose, and of L-rhamnofuranose starting from L-rhamnose is described. The key step in the formation of all three examples of this novel class of sugar mimics is an intramolecular [1,3]-dipolar cycloaddition of azide and nitrile moieties.