Synthesis and mannosidase inhibitory profile of a small library of aminocyclitols from shikimic acid-derived scaffolds.

A short synthetic route to a small library of aminocyclitols 14·HCl-19·HCl has been elaborated from the common shikimic acid-derived scaffolds 20 and 21. The developed strategy features three oxidative processes ‒ ozonolysis, dihydroxylation and epoxidation ‒ as the key transformations. The stereochemistry of the newly created stereocentres was confirmed either via crystallographic analysis or by means of NOESY experiments conducted on advanced intermediates. Glycosidase inhibition study revealed no glucosidase inhibition and only weak inhibitory activity against recombinant Drosophila melanogaster Golgi mannosidase (GMIIb).

Synthesis and anticancer profile of novel sphingoid base-like compounds with a quaternary stereocentre.

The synthesis of novel sphingoid base-like compounds with a quaternary stereocentre was achieved in a sequence featuring [3,3]-sigmatropic rearrangements and olefin cross-metathesis transformation as the key reaction steps, which were accompanied by the rational selection of suitable functional group transformations. The stereochemistry of the desired tetra-substituted carbon bearing nitrogen functionality was determined via NOESY experiments of the advanced oxazolidine-2-thiones. Cell viability experiments revealed significant antiproliferative/cytotoxic activity of the target compounds 7, ent-7 and 29 against the Jurkat cell line, with the IC50 values of 6.6 µM, 5.6 µM and 6.1 µM, respectively.

Stereoselective synthesis and antiproliferative activity of the isomeric sphinganine analogues.

A flexible synthetic approach to biologically active sphingoid base-like compounds with a 3-amino-1,2-diol framework was achieved through a [3,3]-sigmatropic rearrangement and late stage olefin cross-metathesis as the key transformations. The stereochemistry of the newly created stereogenic centre was assigned via a single crystal X-ray analysis of the (4S,5R)-5-(hydroxymethyl)-4-vinyloxazolidine-2-thione. In order to rationalise the observed stereoselectivity of the aza-Claisen rearrangement, DFT calculations were carried out. The targeted isomeric sphingoid bases were screened in vitro for anticancer activity on a panel of seven human malignant cell lines. Cell viability experiments revealed that C17-homologues are more active than their C12 congeners.

A stereoselective approach towards a small library of cytotoxic isomeric sphingoid bases.

Two approaches to a small library of cytotoxic dihydrosphingosine analogues are described. [3,3]-Sigmatropic rearrangements along with an OCM reaction were used as the key steps for the construction of the two isodihydrosphingosines ent-6 and 10, whereas the functional group manipulations, including Grubbs' metathesis chemistry, were applied to known isothiocyanate scaffolds 15 and 16 to provide access to the enantiomeric forms of ent-6 and 10 and diastereomeric isophytosphingosines ent-7.HCl and 14. Cell viability experiments revealed that the target isomeric sphingoid bases were more potent than the traditional anticancer agent cisplatin, with IC50 values in the low micromolar range for the most active compounds.

The convergent synthesis and anticancer activity of broussonetinines related analogues.

The convergent synthesis of broussonetinines related congeners 3 and 4 with the simple C13 alkyl side chain and differently configured pyrrolidine skeleton has been achieved. Our approach relied on the [3,3]-sigmatropic rearrangements of chiral allylic substrates derived from d-xylose. Cross metathesis of the common oxazolidinone intermediates 7 and 8 with tridec-1-ene followed by alkylative cyclization completed the construction of both C-alkyl iminosugars. The targeted compounds 3 and 4 were screened for antiproliferative/cytotoxic activities against multiple cancer cell lines by MTT assay. Compound 3 exhibited very good in vitro potency on Caco-2 and Jurkat cell lines with IC50 value of 5.1 µM and 5.8 µM, respectively.