Syringaldehyde- and vanillin-based antioxidant dendrimers were synthesized via microwave-assisted alkyne–azide 1,3-dipolar cycloaddition using copper granules as a catalyst. The use of Cu(I) as a catalyst resulted in copper contaminated dendrimers. To produce copper-free antioxidant dendrimers for biological applications, Cu(I) was substituted with copper granules. Copper granules were ineffective at both room temperature and under reflux conditions (<5% yield). However, they were an excellent catalyst when dendrimer synthesis was performed under microwave irradiation, giving yields up to 94% within 8 h. ICP-mass analysis of the antioxidant dendrimers obtained with this method showed virtually no copper contamination (9 ppm), which was the same as the background level. The synthesized antioxidants, free from copper contamination, demonstrated potent radical scavenging with IC50 values of less than 3 μM in the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay. In comparison, dendrimers synthesized from Cu(I)-catalyzed click chemistry showed a high level of copper contamination (4800 ppm) and no detectable antioxidant activity.

Three dendritic polyphenols (generation 1) were synthesized: a syringaldehyde-based dendrimer (1), a vanillin-based dendrimer (2), and an iodinated vanillin-based dendrimer (3). They all showed strong antioxidant activity according to the 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical assay. The syringaldehyde dendrimer was twice and 10 times stronger than quercetin and Trolox, respectively. The vanillin-based dendrimer and its more hydrophobic iodinated derivative were also more potent antioxidants than quercetin and Trolox. The DPPH order of potency was 1 > 2, 3 > quercetin > Trolox. All three dendrimers also protected human LDL from free radical attack in a dose-dependent manner. Their order of free radical scavenging was 1 > 3 > 2 > quercetin > Trolox. The increased hydrophobic nature of the iodinated derivative may have contributed to its better LDL protection than 2. Protection of linoleic acid oxidation was studied by the β-carotene–linoleate assay. Dendrimer 1 was clearly superior to the other antioxidants in protecting the fatty acid. In case of DNA protection against free radical damage, the order of activity was 1 > quercetin > 2 > 3, Trolox. Pro-oxidant effect on copper-induced DNA oxidation showed the following order: quercetin, Trolox > 1 > 2 > 3. Results of the study show that dendritic antioxidants, even at the generation 1 level, provide promising antioxidant properties for their potential use as drug candidates for diseases associated with oxidative stress.Three dendritic phenol-based antioxidants were synthesized. The dendrimers showed strong DPPH radical scavenging activity and protective effect against free radical damage of LDL, linoleic acid, and DNA.

It is well known that antioxidants have protective effects against oxidative stress. Unfortunately, in the presence of transition metals, antioxidants, including polyphenols with potent antioxidant activities, may also exhibit pro-oxidant effects, which may irreversibly damage DNA. Therefore, antioxidants with strong free radical-scavenging abilities and devoid of pro-oxidant effects would be of immense biological importance. We report two antioxidant dendrimers with a surface rich in multiple phenolic hydroxyl groups, benzylic hydrogens, and electron-donating ring substituents that contribute to their potent free radical-quenching properties. To minimize their pro-oxidant effects, the dendrimers were designed with a metal-chelating tris(2-aminoethyl)amine (TREN) core. The dendritic antioxidants were prepared by attachment of six syringaldehyde or vanillin molecules to TREN by reductive amination. They exhibited potent radical-scavenging properties: 5 times stronger than quercetin and 15 times more potent than Trolox according to the 1,1-diphenyl-2-picrylhydrazyl assay. The antioxidant dendrimers also protected low-density lipoprotein, lysozyme, and DNA against 2,2′-azobis(2-amidinopropane) dihydrochloride-induced free radical damage. More importantly, unlike quercetin and Trolox, the two TREN antioxidant dendrimers did not damage DNA via their pro-oxidant effects when incubated with physiological amounts of copper ions. The dendrimers also showed no cytotoxicity toward Chinese hamster ovary cells.