Title: Engineering hydrophilic/amphiphilic Vitamin B6-based super antioxidant dendrimers for controlling chronic inflammation Project Summary/Abstract Free radicals produced during chronic inflammation can damage cellular materials and cause oxidative stress, which can intensify pathogenesis of various irreversible human diseases. Many studies report that naturally occurring antioxidants such as vitamins C and E and quercetin are beneficial for prevention of a variety of human ailments including asthma and cancer, but some studies are contradictory. Many natural antioxidants in the presence of transition metal ions, like copper and iron, generate more free radicals (pro-oxidant effect). The pro-oxidant effect is more severe with antioxidants that can directly coordinate with the metal ions through their phenolic hydroxyl (OH) groups, such as catechol or gallol. We believe that this pro-oxidant action of antioxidants explains the detrimental health effects reported for antioxidant supplements in clinical studies. We previously synthesized large dendritic antioxidants with multiple phenolic units on the surface and interior with metal chelating capability. These dendritic antioxidants showed much higher antioxidant activities over naturally occurring popular antioxidants. For example, the dendrimer with 8 syringol units had 18-fold lower IC50 in the DPPH assay than that of vitamin C. More importantly, they are devoid of harmful pro-oxidant effects. We believed that the absence of pro-oxidant effects was achieved by entrapping metal ions within their interior as well as using hindered phenolic units whose OH do not chelate transition metal ions. A major drawback of the antioxidant dendrimers was their poor water-solubility. These antioxidants were highly effective in quenching organic radicals and protecting non-polar biomolecules such as membrane lipids and lipoproteins. However, their ability to quench water-soluble radicals such as OH· was limited. Various attempts to increase the aqueous solubility of these compounds by incorporation of cores and branches rich in polar groups were unsuccessful. In this proposal, we plan to develop a new class of hydrophilic/amphiphilic antioxidant dendrimers with built-in potent antioxidant activity as well as metal chelating ability by synthesis and assembly of pie-shaped dendritic segments known as dendrons (convergent method). A dendron with metal chelating ability will be synthesized and its surface will be modified with three different classes of building blocks (BBs) that are hydrophilic, hydrophobic, and amphiphilic. Water-soluble Vitamin B6 molecules (pyridoxal and pyridoxal-5’-phosphate) will be used to form hydrophilic BBs and syringaldehyde, a hydrophobic BB. The focal point of dendrons will be attached to a chemical carrying either an azido or alkynyl group. Attachment of the properly matched dendrons via their focal points would yield hydrophilic/amphiphilic dendrimers with potent antioxidant activi...