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. 2011 Apr 15;50(8):918-25.
doi: 10.1016/j.freeradbiomed.2010.10.699. Epub 2010 Oct 23.

Potent antioxidant dendrimers lacking pro-oxidant activity

Choon Young Lee 1, Ajit Sharma, Rebecca L Uzarski, Jae Eun Cheong, Hao Xu, Rich A Held, Samik K Upadhaya, Julie L Nelson
Affiliations
Free PMC article

Potent antioxidant dendrimers lacking pro-oxidant activity

Choon Young Lee et al. Free Radic Biol Med. .
Free PMC article

Abstract

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.

Figures

Figure 1
Structures of dendrimers 1–3 and quercetin.
Figure 2
Electrophoresis of antioxidant dendrimers. Lane 1 (G4 PAMAM); lane 2 (dendrimer 2); lane 3 (dendrimer 3); lane 4 (dendrimer 1). Each lane contains 10 nmol dendrimer.
Figure 3
Effect of antioxidants on LDL oxidation. (A) Lane 1 (native LDL); lanes 2–8 (AAPH-oxidized LDL with 0, 37, 18.5, 9, 4.5, 2 and 1 µM dendrimer 1, respectively). (B) Lane 1 (native LDL); lanes 2–8 (AAPH-oxidized LDL with 0, 37, 18.5, 9, 4.5, 2 and 1 µM quercetin, respectively).
Figure 4
Protection against AAPH-induced DNA oxidation by dendrimer 1. Lane 1 (native DNA); lanes 2–10 (AAPH-oxidized DNA with 0, 45, 23, 11, 5, 3, 1.5, 0.7, and 0.35 µM antioxidant, respectively).
Figure 5
Pro-oxidant effect of dendrimer 1 (A) and quercetin (B) on DNA (pBR 322). Lane 1 (native DNA); lanes 2–10 (Cu2+ oxidized DNA with 0, 45, 23, 11, 5, 3, 1.5, 0.7, and 0.35 µM antioxidant, respectively).
Figure 6
Comparative effects of dendrimers 1 and 2 on CHO cell viability. CHO cells were incubated with DMSO control, dendrimer 1 or dendrimer 2 at 50 µM for 1, 3, and 5 days.
Scheme 1
Syntheses of dendrimers 1 and 2. Reagents and conditions: (a) TBDMS-Cl, triethylamine, CH2Cl2, 0 °C (b) TREN, Na(OAc)3BH, 1,2-dichloroethane (c) n-Bu4NF, ethanol.
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