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.
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