Swainsonine Analog Research Articles

(5S)-5-Benzylswainsonines as potent and selective inhibitors of Golgi α-mannosidase II: synthesis, enzyme evaluation and molecular modelling

Development of novel anti-cancer therapeutics based on Golgi α-mannosidase II (GMII) inhibition is considerably impeded by an undesired co-inhibition of lysosomal α-mannosidase leading to severe side-effects. In this contribution, we describe a fully stereoselective synthesis of (5S)-5-[4-(halo)benzyl]swainsonines as highly potent and selective inhibitors of GMII. The synthesis starts from a previously reported aldehyde readily available from l-ribose, and the key features include an intramolecular reductive amination with substrate-controlled stereoselectivity and a late-stage derivatisation of the benzyl group via ipso-substitution. These novel swainsonine analogues were found to be nanomolar inhibitors of the Golgi-type α-mannosidase AMAN-2 (Ki = 23–75 nM) with excellent selectivity (selectivity index = 205–870) over the lysosomal-type Jack bean α-mannosidase. Finally, molecular docking and pKa calculations were performed to provide more insight into the structure of the inhibitor:enzyme complexes, and a pair interaction energy analysis (FMO-PIEDA) was carried out to rationalise the observed potency and selectivity of the inhibitors.

Divergent Synthesis of Bicyclic Iminosugars: Preparation of (−)‐Swainsonine‐Based Alkaloids and Their Inhibition Study towards α‐Human Mannosidases

AbstractA divergent and concise route to synthesize bicyclic iminosugars, especially polyhydroxylated pyrrolizidine and indolizidine‐based molecules, was described. Six natural product‐like bicyclic alkaloids including (−‐Swainsonine were conveniently prepared through this straightforward method. The key steps are diastereoselective allylation, ring size manipulation through hydroboration‐oxidation strategy and systematic installation of the amino functionality at the C8 position using nitrone chemistry. These Swainsonine analogues were applied for inhibition study against both α‐hLM and α‐hGMII. Interestingly, the C8 hydroxyl group with proper orientation plays a crucial role for inhibitory activities. The compounds possessing the C8 amino group drastically decrease their inhibitory activities.

Structural Investigation of the Binding of 5‐Substituted Swainsonine Analogues to Golgi α‐Mannosidase II

Golgi alpha-mannosidase II (GMII) is a key enzyme in the N-glycosylation pathway and is a potential target for cancer chemotherapy. The natural product swainsonine is a potent inhibitor of GMII. In this paper we characterize the binding of 5alpha-substituted swainsonine analogues to the soluble catalytic domain of Drosophila GMII by X-ray crystallography. These inhibitors enjoy an advantage over previously reported GMII inhibitors in that they did not significantly decrease the inhibitory potential of the swainsonine head-group. The phenyl groups of these analogues occupy a portion of the binding site not previously seen to be populated with either substrate analogues or other inhibitors and they form novel hydrophobic interactions. They displace a well-organized water cluster, but the presence of a C(10) carbonyl allows the reestablishment of important hydrogen bonds. Already approximately tenfold more active against the Golgi enzyme than the lysosomal enzyme, these inhibitors offer the potential of being extended into the N-acetylglucosamine binding site of GMII for the creation of even more potent and selective GMII inhibitors.

Stereoselective Michael Addition of Carbon-, Nitrogen-, Oxygen-, and Sulfur-Centered Nucleophiles on Enantiopure Hydroxylated 6,7-Dehydro-5-oxoindolizidine. Synthesis of Carbon- or Hetero-7-Substituted Swainsonine Analogues

Enantiopure alpha,beta-unsaturated delta-lactams 1 and 2 react stereoselectively with carbon-, nitrogen-, sulfur-, and oxygen-centered nucleophiles. The synthetic potential of these conjugate additions is demonstrated through the synthesis of two new substituted indolizidines: (7R)-7-amino-8-deoxyswainsonine 3 and (7R)-7-acetylaminoswainsonine 4.

Diastereoselective synthesis of new polyhydroxylated indolizidines from ( l)-glutamic acid

A diastereoselective synthesis of two new swainsonine's analogues 1a and 1b with the piperidine ring fused to a phenyl nucleus at C6-C7, namely (1 R, 2 S, 10 R, 10a R)-(+)-1,2,10-trihydroxy-1,2,3,5,10,10a-hexahydrobenzo[ f] indolizine ( 1a ) and (1 S, 2 R, 10 R, 10a R)-(+)-1,2,10-trihydroxy-1, 2, 3, 5, 10, 10a-hexahydrobenzo[ f] indolizine ( 1b ), is described. Throughout this work, the effectiveness of the tricyclic indolizidine dione 5 , readily available in three steps from the cheap l-glutamic acid, as an attractive platform for chemo- and stereodivergent transformations is illustrated. The key steps involved totally diastereoselective ketone reduction of compound 5 and catalytic cis-dihydroxylation of the unsaturated amide 10 . The synthetic strategy also allowed for the diastereoselective synthesis of benzoanalogues of the 1,8a-di- epi-lentiginosine 3a ((1 R, 2 S, 10a R)-(+)-1,2-dihydroxy-1, 2, 3, 5, 10, 10a-hexahydrobenzo[ f]indolizine) and 2,8a-di- epi-lentiginosine 3b ((1 S, 2 R, 10a R)-(+)-1,2-dihydroxy-1,2,3,5,10,10a-hexahydrobenzo[ f]indolizine).

Synthesis of the New Mannosidase Inhibitors, Diversity‐Oriented 5‐Substituted Swainsonine Analogues, via Stereoselective Mannich Reaction.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Synthesis of the new mannosidase inhibitors, diversity-oriented 5-substituted swainsonine analogues, via stereoselective Mannich reaction.

5alpha-substituted swainsonine analogues were synthesized by Mannich reaction of an in situ generated (-)-swainsonine iminium ion intermediate. 5alpha-substituted swainsonine analogues were epimerized to their 5beta-isomers in protic solvent. [reaction: see text]

Synthesis of (1S,2S,3R,8S,8aR)-1,2,3,8-Tetrahydroxy-6-oxa-5-thioxoindolizidine: A Stable Reducing Swainsonine Analog with Controlled Anomeric Configuration

The title indolizidine, a ring-modified analog of the potent mannosidase inhibitor (-)-swainsonine, has been prepared by intramolecular nucleophilic addition of the sp2-type nitrogen atom of a preformed 1,3-oxazine-2-thione heterocycle to the masked aldehyde group in a d-mannose precursor; the stereochemistry of the generated aminoacetalic stereocenter is governed by the generalized anomeric effect, the pseudoanomeric hydroxyl group adopting an axial orientation that mimics that of α-d-mannopyranoside aglycons.

Structure-activity relationship of swainsonine. Inhibition of human α-mannosidases by swainsonine analogues

The inhibitory properties of a series of synthetic epimers and analogues of swainsonine towards the multiple forms of human alpha-mannosidases were studied in vitro and in cells in culture. Of the five epimers tested, only the 8a-epimer and 8,8a-diepimer of swainsonine were specific and competitive inhibitors (Ki values of 7.5 x 10(-5) and 2 x 10(-6) M respectively) of lysosomal alpha-mannosidases in vitro and induced storage of mannose-rich oligosaccharides in human fibroblasts in culture. The structures of these storage products indicated that processing alpha-mannosidases had also been inhibited. This was consistent with the observed inhibition in vitro of these enzymes by these compounds. In contrast, the 8-epimer, 1,8-diepimer and 2,8a-diepimer of swainsonine had no appreciable effect on any alpha-mannosidases. The corresponding open-chain analogues of swainsonine, namely 1,4-dideoxy-1,4-imino-D-mannitol, of the 8a-epimer, namely 1,4-dideoxy-1,4-imino-D-talitol, and of the 8,8a-diepimer, namely 1,4-dideoxy-1,4-imino-L-allitol, were weaker competitive inhibitors of lysosomal alpha-mannosidase, with Ki values of 1.3 x 10(-5), 1.2 x 10(-4) and 1.2 x 10(-4) M respectively. These analogues also proved less effective at inducing oligosaccharide accumulation and in disturbing glycoprotein processing. These compounds offer the opportunity to determine which alterations in the chirality of the swainsonine molecule affect its inhibitory specificity. A comparison of their biological activities has identified reagents that will be useful for studying steps in the biosynthesis and catabolism of glycoproteins and that may be of potential value in chemotherapy.