Synthesis and evaluation of polyunsaturated fatty acid-phenol conjugates as anti-carbonyl-stress lipophenols

Abstract

Carbonyl and oxidative stress play a substantial role in various neurodegenerative diseases such as Alzheimer's Disease, Parkinsonism, and Age-related Macular Degeneration (AMD). In retinal pathologies, both mechanisms are involved in the transformation of all-trans-retinal (AtR, reactive aldehyde) into bis-retinoid A2E. Since an accumulation of AtR and A2E contributes to photoreceptor apoptosis, we designed and synthesized a series of O-alkylated resorcinol derivatives featuring enhanced anti-carbonyl-stress properties. Additionally, these phenolic structures are linked to a polyunsaturated fatty acid such as docosahexaenoic acid (C22:6 n-3; DHA) or to a lysophosphatidylcholine-DHA conjugate, in order to specifically increase their bioavailability, and thus, to target the retina. Selective syntheses of phloroglucinol-DHA, resveratrol-DHA, and phloroglucinol-DHA-PC (PC = phosphatidylcholine) conjugates using silyl protecting group strategies are presented, along with results of testing that demonstrate their ability to lower AtR toxicity in ARPE-19 cell lines. In order to use resorcinol derivatives to fight against the carbonyl-stress mechanism observed in retina pathologies, new lipophenol conjugates were synthesized with the aim of increasing bioavailability and reaching retina tissue. Strategies to link polyunsaturated fatty acids to polyphenol backbones are presented, along with the results of testing against retinal pigment epithelial cell lines. Copyright © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.