Synthesis of new tyrosol-based phosphodiester derivatives: effect on amyloid β aggregation and metal chelation ability

Abstract

Alzheimer's disease (AD) is a multifactorial pathology that requires multifaceted agents able to address its peculiar nature. Increasing evidence has shown that aggregation of amyloid-β (Aβ) and oxidative stress are strictly interconnected, and their modulation may have a positive and synergic effect in contrasting AD-related impairments. Herein, a new and efficient fragment-based approach towards Tyrosol Phosphodiester Derivatives (TPDs) has been developed starting from suitable tyrosol building blocks and exploiting the well-established phosphoramidite chemistry. The antioxidant activity of new TPDs has been tested as well as their ability to inhibit Aβ protein aggregation. In addition, it has been evaluated their metal chelating ability as a possible strategy to develop new natural-based entities for the prevention or therapy of AD. Interestingly, the TPDs containing the catecholic moiety have demonstrated a highly promising activity in inhibiting aggregation of Aβ40 and a strong ability to chelate bio-metals such as Cu (II) and Zn (II).