8-Hydroxyquinoline Glycoconjugates: Modifications in the Linker Structure and Their Effect on the Cytotoxicity of the Obtained Compounds

Abstract

Small molecule nitrogen heterocycles are very important structures, widely used in the design of potential pharmaceuticals. Particularly, derivatives of 8-hydroxyquinoline (8-HQ) are successfully used to design promising anti-cancer agents. Conjugating 8-HQ derivatives with sugar derivatives, molecules with better bioavailability, selectivity, and solubility are obtained. In this study, 8-HQ derivatives were functionalized at the 8-OH position and connected with sugar derivatives (D-glucose or D-galactose) substituted with different groups at the anomeric position, using copper(I)-catalyzed 1,3-dipolar azide-alkyne cycloaddition (CuAAC). Glycoconjugates were tested for inhibition of the proliferation of cancer cell lines (HCT 116 and MCF-7) and inhibition of β-1,4-galactosyltransferase activity, which overexpression is associated with cancer progression. All glycoconjugates in protected form have a cytotoxic effect on cancer cells in the tested concentration range. The presence of additional amide groups in the linker structure improves the activity of glycoconjugates, probably due to the ability to chelate metal ions present in many types of cancers. The study of metal complexing properties confirmed that the obtained glycoconjugates are capable of chelating copper ions, which increases their anti-cancer potential.

8-Hydroxyquinoline Glycoconjugates Containing Sulfur at the Sugar Anomeric Position—Synthesis and Preliminary Evaluation of Their Cytotoxicity

“…For the synthesis of glycoconjugates, derivatives of 1-thioglycosides were used both with the protected and deprotected hydroxyl groups in the sugar part. As the second structural element of the glycoconjugates, corresponding derivatives of 8-hydroxyquinoline 39 – 42 functionalized in the 8-OH position with propargyl or azide groups were used, obtained according to previously published procedures [ 27 , 46 ]. Target glycoconjugates were prepared using the copper(I)-catalyzed 1,3-dipolar azide-alkyne cycloaddition, described by Sharpless [ 47 , 48 ].…”

“…As part of the research, the effect of introducing a sulfur atom into the anomeric position of sugar was assessed. Glycoconjugates 51 – 54 derivatives of azidoalkyl 1-thioglycosides showed higher cytotoxic activity than the analogous glycoconjugates obtained earlier containing oxygen atom at the sugar anomeric position [ 27 ]. This was particularly evident for the 8-HQ derivatives 51 and 52 , for which the cytotoxic activity was about twice as high as that of their structural counterparts with an anomeric oxygen atom ( Figure 3 ).…”

“…Previously, we showed that 8-HQ derivative glycoconjugates containing 1,2,3-triazole fragment in the linker structure were able to form complexes with copper ions and potentially inhibit the multiplication of neoplastic cells by eliminating an important factor for their growth [ 27 ]. In the current study, we decided to enhance this effect by creating new analogs, with an additional heteroaromatic fragment in the structure 67 – 72 .…”

“…Their biological activity depended on the structure of the linker connecting the sugar parts and the quinoline moiety, as well as the type of protective groups in the attached sugar unit. The study of metal complexing properties confirmed that the obtained glycoconjugates were capable of chelating copper ions [ 27 ]. In the current research, 1-thiosugars derivatives were used for the synthesis of quinoline glycoconjugates.…”

“…Our recent studies on the cytotoxic activity of 8-HQ derivatives connected via various linkers with d -glucose or d -galactose derivatives containing an oxygen or nitrogen atom at the sugar anomeric position indicated that some of them were able to inhibit the proliferation of tested cell lines [ 26 , 27 ]. Their biological activity depended on the structure of the linker connecting the sugar parts and the quinoline moiety, as well as the type of protective groups in the attached sugar unit.…”