Claudia Bello

Synthesis of novel pyrrolidine 3,4-diol derivatives as inhibitors of α-L-fucosidases

The stereoselective synthesis of new 3,4-dihydroxypyrrolidine derivatives starting from D-mannose, D-ribose and L-fucose is presented. Two synthetic strategies employing organometallic addition to hemiacetalic sugars followed by selective nucleophilic displacement or conjugate addition of ammonia to conjugate aldonic esters as key steps, are used. The new compounds were assayed for their inhibitory activity towards 13 commercially available glycosidases. Compounds that share the absolute configuration at C(2,3,4,5) of L-fucopyranosides and incorporate aromatic moieties are potent and selective inhibitors of alpha-L-fucosidases in the nM range.

New synthetic seven-membered 1-azasugars displaying potent inhibition towards glycosidases and glucosylceramide transferase

Several members of a new family of seven‐membered azasugars, which can be seen as 1‐azasugar ring homologues, have been obtained by simple chemical transformations starting from a sugar‐derived azidolactol. Unlike their piperidine counterparts, these molecules are chemically stable when they possess a hydroxy group at the pseudo‐C‐2 position. Biological assays with a range of carbohydrate‐processing enzymes have revealed interesting potential for these compounds. A trihydroxymethyl‐substituted azepane displayed strong competitive inhibition on almond β‐glucosidase (Ki=2.5 μM) while a trihydroxylated carboxylic acid derivative proved to be a potent and selective L‐fucosidase inhibitor (Ki=41 nM). N‐Butylation of these seven‐membered 1‐azasugars generated derivatives with some activity towards the Gaucher’s disease‐related glucosylceramide transferase (IC50 75 μM) that did not interact significantly with digestive glucosidases.

Design and synthesis of acetamido tri- and tetra-hydroxyazepanes: Potent and selective β-N-acetylhexosaminidase inhibitors

A series of seven-membered iminosugars bearing an acetamido group beta- or gamma- to the endocyclic nitrogen have been synthesized via simple transformations of previously described polysubstituted azepanes. These tetra- and trihydroxylated acetamido azepanes are ring homologues of 2-acetamido-1,2-dideoxy-glyconojirimycins and 2-acetamido-1-N-iminosugars respectively. Screening of these azepanes towards a range of commercially available glycosidases demonstrated their potential as selective and potent hexosaminidase inhibitors with K(i)s in the submicromolar range. A correlation between the relative configuration of the azepanes and their ability to inactivate hexosaminidases was also observed for the first time for this class of compounds with one notable exception for the most potent compound.

A short and convenient synthesis of 1-deoxymannojirimycin and N-oxy analogues from D-fructose.

Ketonitrone 8 was prepared from D-fructose as an inexpensive starting material and was used in a stereoselective synthesis of 1-deoxymannojirimycin (DMJ, 4), of its previously unknown N-hydroxy analogue 15, and of the polyhydroxylated ketonitrone 14. The latter were assayed as potential glycosidase inhibitors on a panel of 13 selected purified enzymes. Disappointingly, the polyhydroxylated nitrone 14 inhibited none of these enzymes. However, N-hydroxy-DMJ (15) exhibited a moderate and non-selective activity toward the snail beta-mannosidase EC 3.2.1.25.

Novel 2-[(benzylamino)methyl]pyrrolidine-3,4-diol derivatives as α-mannosidase inhibitors and with antitumor activities against hematological and solid malignancies

Novel alpha-mannosidase inhibitors of the type (2R,3R,4S)-2-({[(1R)-2-hydroxy-1-arylethyl]amino}methyl)pyrrolidine-3,4-diol have been prepared and assayed for their anticancer activities. Compound 30 with the aryl group=4-trifluoromethylbiphenyl inhibits the proliferation of primary cells and cell lines of different origins, irrespective of Bcl-2 expression levels, inducing a G2/Mcell cycle arrest and by modification of genes involved in cell cycle progression and survival.

The spirocyclopropyl moiety as a methyl surrogate in the structure of L-fucosidase and L-rhamnosidase inhibitors

Nitrogen-in-the-ring analogues of l-fucose and l-rhamnose were prepared, which feature a spirocyclopropyl moiety in place of the methyl group of the natural sugar. The synthetic route involved a titanium-mediated aminocyclopropanation of a glycononitrile as the key step. Four new spirocyclopropyl iminosugar analogues were generated, which displayed some activity towards l-fucosidase and l-rhamnosidase.

Anti-cancer activity of 5-O-alkyl 1,4-imino-1,4-dideoxyribitols

New derivatives of 1,4-dideoxy-1,4-imino-D-ribitol have been prepared and evaluated for their cytotoxicity on solid and haematological malignancies. 1,4-Dideoxy-5-O-[(9Z)-octadec-9-en-1-yl]-1,4-imino-D-ribitol (13, IC(50) ∼2 μM) and its C(18)-analogues (IC(50) <10 μM) are cytotoxic toward SKBR3 (breast cancer) cells. 13 also inhibits (IC(50) ∼8 μM) growth of JURKAT cells.

Synthesis and glycosidase inhibitory activity of 1-amino-3,6-anhydro-1-deoxy-D-sorbitol derivatives.

3,6-Anhydro-1-(aryl or alkylamino)-1-deoxy-D-sorbitol derivatives have been prepared in four steps from isosorbide, a by-product from the starch industry. The inhibitory activities of these new compounds have been evaluated towards 13 glycosidases. A first lead-compound was identified, which inhibited beta-N-acetylglucosaminidase from bovine kidney (82% inhibition at 1mM).

Induction of cell killing and autophagy by amphiphilic pyrrolidine derivatives on human pancreatic cancer cells

We have synthesized a wide array of structurally related amphiphilic compounds, containing a functionalized pyrrolidine polar group coupled to different ether-linked hydrocarbon chains, to generate novel structures with antitumor activity. These newly synthesized amphiphilic pyrrolidine-derived compounds were classified in three different sub-libraries regarding the number of hydroxyl groups substituting the pyrrolidine moiety at C3 and C4. Pyrrolidine compounds with one or none hydroxyl groups showed a potent cell killing activity against pancreatic cancer cells, but they lacked selectivity for tumor cells. Pyrrolidine compounds with two hydroxyl groups induced cell death in a wide variety of pancreatic cancer cell lines, and they were somewhat less cytotoxic to normal non-tumor cells. Among these latter compounds, the diol-derived pyrrolidine 20 ((2R,3R,4S)-2-{(9Z)-hexadec-9-en-1-yloxy]methyl}pyrrolidine-3,4-diol) induced autophagy and a potent apoptotic response in pancreatic ductal adenocarcinoma cells, which was inhibited by Bcl-XL overexpression and by caspase inhibition, in a way similar to that of the amphiphilic ether lipid edelfosine, with which it was compared. Pharmacological and genetic inhibition of autophagy potentiated 20-mediated apoptosis. These structure-activity relationship studies point out the importance of the diol polar group and aliphatic side chain of 20 in promoting apoptosis against pancreatic cancer cells in a rather controlled way, and some additional subtle modifications were found to be potential modulators of the cytotoxic activity.