Novel hydroxyamides and amides containing D-glucopyranose or D-fructose units: biological assays in MCF-7 and MDST8 cell lines

Abstract

A novel library of 15 compounds, hydroxyamides and amides containing a β-d-glucopyranose (d-Gluc) or a β-d-fructose (d-Fruc) units was designed and synthesized for antiproliferative assays in breast (MCF-7) and colon (MDST8) cancer cell lines. Twelve of them were hydroxyamides and were successfully synthesized from β-d-glucuronic acid (d-GluA). Six of these hydroxyamides which were acetylated hydroxy-β-d-glucopyranuronamide 2a–2f (1st Family) and the other six were their respective isomers, that is, hydroxy-β-d-fructuronamide 3a–3f (2nd Family), obtained by acid–base catalyzed isomerization. These compounds have the general structure, d-Glucsingle bondCdouble bond; length as m-dashONHsingle bondCHRsingle bond(CH2)nsingle bondOH and d-Frucsingle bondCdouble bond; length as m-dashONHsingle bondCHRsingle bond(CH2)nsingle bondOH, where R = an aromatic, alkyl or a hydrogen substituent, with n = 0 or 1. Eight of these contained a chiral aminoalcohol group. Three compounds were amides containing a d-glucopyranose unit (3rd Family). SAR studies were conducted with these compounds. Antiproliferative studies showed that compound 4a, the bromo-amide containing the β-d-glucopyranose ring, potently inhibits the proliferation of the MDST8 cells. Five compounds (2e, 2f, 3d, 3e, and 3f) were shown to potently selectively inhibit the proliferation of the MCF-7 cells. Compound 4b was the only one showing inhibition in both cell lines. In general, the more active compounds were the amides and hydroxyamides containing the β-d-fructose moiety, and containing an alkyl group or hydrogen. Half-inhibitory concentrations (IC50) of between 0.01 and 10 μM, were observed.