The Structure, Biological Activities and Synthesis of 3- Hydroxylpyrrolizidine Alkaloids and Related Compounds

Abstract

This review reports on recent developments on the structure, biological activities and synthesis of 3hydroxylpyrrolizidine alkaloids and related compounds.Glycosidase enzymes are involved in a wide range of important biological processes, such as intestinal digestion of carbohydrates, post-translational processing of glycoproteins and the lysosomal catabolism of glycoconjugates. Polyhydroxylated alkaloids that mimic the structures of sugars are widespread in plants and have been shown to inhibit glycosidase activities. Some of these compounds show potential as anti-cancer, antiviral and anti-retroviral agents. For example, (-)-swainsonine inhibits Golgi αmannosidase II, an enzyme involved in the processing of glycoproteins on the surface of cancer cells. This process has been associated with cancer metastasis, and thus (-)swainsonine and analogues are potentially useful antimetastasis drugs for the treatment of cancer [1,2]. Unfortunately, (-)-swainsonine is not selective for Golgi αmannosidase II over other α-mannosidases (e.g. lysosomal α-mannosidase) [3] resulting in undesired side effects (e.g. inhibition of the catabolism of oligosaccharides), and thus creating the need for more potent and selective (-)swainsonine analogues.At physiological pH these polyhydroxylated alkaloids are protonated. These protonated compounds are potent glycosidase inhibitors because of their structural resemblance to the oxonium intermediate that is generated in the active site of glycosidase enzymes during the processing of carbohydrates and glycoproteins [4]. For example, the five-membered iminosugar, 2,5-dideoxy-2,5-imino-Daltritol, has two possible half-chair conformers, the 'galacto'-form 1a and the 'manno'-form 1b. Due to the similarities in structures between the two conformers and the galactose oxonium ion 2a and the mannose oxanium ion 2b, respectively, this compound is a strong inhibitor of both αmannosidase and β-1,4-galactosyltransferase [5].These natural products have been classified into five structural classes: polyhydroxylated piperidines (e.g. nojirimycin 3), pyrrolidines (e.g. 2,5-dihydroxymethyl-3,4dihydroxypyrrolidine (DMDP) 4), indolizidines (e.g. swainsonine 5), pyrrolizidines (e.g. australine 6) and nortropanes (e.g. calystegine A 3 7) (Fig. 2). 3-Hydroxymethylpyrrolizidine AlkaloidsAlthough the broad class of pyrrolizidine alkaloids that bear a carbon branch at C-1 (necines) are well documented,

Synthetic Strategies towards the Azabicyclo[3.3.0]-Octane Core of Natural Pyrrolizidine Alkaloids. An Overview

“…This explains the enduring interest in the development of efficient preparation of various PAs over the years. [4][5][6][7][8][9][10][11][12][13][14] The present review updates the numerous synthetic methods used to prepare the bicyclic pyrrolizidine core of various PAs with special emphasis on the recent advances (2000)(2001)(2002)(2003)(2004)(2005)(2006)(2007)(2008)(2009)(2010)(2011)(2012)(2013)(2014)(2015). Natural occurrence, biosynthetic origin and biological activities are discussed very briefly.…”

Total synthesis of hyacinthacine A2: stereocontrolled 5-aza-cyclooctene photoisomerization and transannular hydroamination with planar-to-point chirality transfer

“…The pyrrolizidine framework is common to manifold natural products, 1 including the polyhydroxylated natural products hyacinthacine A2 (1), australine, alexine and their epimers (Figure 1). These natural products and analogs have been targeted for synthesis 1-5 because of their selective glycosidase inhibition 6 and activity against HIV.…”

“…These natural products and analogs have been targeted for synthesis 1-5 because of their selective glycosidase inhibition 6 and activity against HIV. 7 For example, hyacinthacine A2 (8.6 μM), 8 australine (5.8 μM), 9 and alexine (11 μM) 10 and are all selective inhibitors of amyloglucosidase that do not display significant inhibition of β-glucosidases.…”

Synthesis of a novel pyrrolo-[3,2-c]quinoline N-oxide by aza-Baylis–Hillman adduct of o-nitrobenzaldehyde

“…1,2 In particular, the quinoline Noxide core unit has been found in drugs exerting microsomal Na,K-ATPase activity, 3 protein kinase inhibition and anticancer, 4 antiviral 5 or antimalarian activities. 6,7 They have also relevant applications as spin traps in biological studies, 8 and are efficient in age-related diseases, 9 due to both in vitro and in vivo 10 stability of resulting nitroxide radicals.…”