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

Abstract

One of the main factors limiting the effectiveness of many drugs is the difficulty of their delivery to their target site in the cell and achieving the desired therapeutic dose. Moreover, the accumulation of the drug in healthy tissue can lead to serious side effects. The way to improve the selectivity of a drug to the cancer cells seems to be its conjugation with a sugar molecule, which should facilitate its selective transport through GLUT transporters (glucose transporters), whose overexpression is seen in some types of cancer. This was the idea behind the synthesis of 8-hydroxyquinoline (8-HQ) derivative glycoconjugates, for which 1-thiosugar derivatives were used as sugar moiety donors. It was expected that the introduction of a sulfur atom instead of an oxygen atom into the anomeric position of the sugar would increase the stability of the obtained glycoconjugates against untimely hydrolytic cleavage. The anticancer activity of new compounds was determined based on the results of the MTT cytotoxicity tests. Because of the assumption that the activity of this type of compounds was based on metal ion chelation, the effect of the addition of copper ions on cell proliferation was tested for some of them. It turned out that cancer cells treated with glycoconjugates in the presence of Cu2+ had a much slower growth rate compared to cells treated with free glycoconjugates in the absence of copper. The highest cytotoxic activity of the compounds was observed against the MCF-7 cell line.

Synthesis and Preliminary Evaluation of the Cytotoxicity of Potential Metabolites of Quinoline Glycoconjugates

“…The aim of the research was to obtain and evaluate the biological activity of potential metabolites that may be formed in biological systems by the degradation of anti-cancer prodrugs based on glycoconjugates derivatives of 8-hydroxyquinoline described in recent works [ 26 , 27 , 28 ]. This will allow answering the question of which fragment of the molecule is responsible for the obtained biological activity.…”

“…A general procedure for the synthesis of metabolites is shown in Scheme 1 and Scheme 2 . Used for the reaction, quinoline substrates functionalized in the 8-OH position ( Figure 2 ) and sugar derivatives substituted at the anomeric position ( Figure 3 ) were prepared according to the previously published procedures [ 26 , 27 , 28 ]. Propargyl alcohol 2 is a commercially available reagent, whereas 2-azidoethanol 1 was obtained by substituting 2-bromoethanol with sodium azide in DMF [ 33 ].…”

“…d -Glucose, 8-hydroxyquinoline, 8-hydroxyquinaldine, and propargyl alcohol 2 are commercially available (Sigma-Aldrich). 2-Azidoethanol 1 , 8-Hydroxyquinoline derivatives 3 – 10 and sugar derivatives 11 – 24 were prepared according to the respective published procedures [ 26 , 27 , 28 , 33 ].…”

“…Considering the above, our research group conducted a series of experiments on the glycoconjugation of 8-hydroxyquinoline (8-HQ) derivatives [ 26 , 27 , 28 ]. We assumed that due to the addition of a sugar derivative to the active 8-HQ fragment, the obtained molecules would be able to selectively enter a tumor cell using the Warburg effect.…”

Glycoconjugation of Betulin Derivatives Using Copper-Catalyzed 1,3-Dipolar Azido-Alkyne Cycloaddition Reaction and a Preliminary Assay of Cytotoxicity of the Obtained Compounds

“…The motivation for our research was the successes in the synthesis of molecular hybrids presented in Figure 2, obtained with the use of a natural biologically active compound, where the introduction of a triazole ring and a sugar unit into the parent structure of quinoline resulted in the improvement of pharmacological properties of the obtained glycoconjugates [36][37][38][39]. The presence of a sugar unit in the hybrid molecules improves their pharmacokinetic properties, including solubility and intermembrane transport, as well as the selectivity in targeting drugs for a specific purpose.…”