a chemical analog of curcumin as an improved inhibitor of amyloid abeta oligomerization姜黄素的化学模拟作为提高了淀粉样β淀粉状蛋白质寡聚化的抑制剂.pdfVIP

A Chemical Analog of Curcumin as an Improved Inhibitor of Amyloid Abeta Oligomerization 1 1 1 2 1 Robert A. Orlando *, Amanda M. Gonzales , Robert E. Royer , Lorraine M. Deck , David L. Vander Jagt 1 Department of Biochemistry and Molecular Biology, University of New Mexico, School of Medicine, Albuquerque, New Mexico, United States of America, 2 Department of Chemistry and Chemical Biology, University of New Mexico, Albuquerque, New Mexico, United States of America Abstract Amyloid-like plaques are characteristic lesions defining the neuropathology of Alzheimer’s disease (AD). The size and density of these plaques are closely associated with cognitive decline. To combat this disease, the few therapies that are available rely on drugs that increase neurotransmission; however, this approach has had limited success as it has simply slowed an imminent decline and failed to target the root cause of AD. Amyloid-like deposits result from aggregation of the Ab peptide, and thus, reducing amyloid burden by preventing Ab aggregation represents an attractive approach to improve the therapeutic arsenal for AD. Recent studies have shown that the natural product curcumin is capable of crossing the blood-brain barrier in the CNS in sufficient quantities so as to reduce amyloid plaque burden. Based upon this bioactivity, we hypothesized that curcumin presents molecular features that make it an excellent lead compound for the development of more effective inhibitors of Ab aggregation. To explore this hypothesis, we screened a library of curcumin analogs and identified structural features that contribute to the anti-oligomerization activity of curcumin and its analogs. First, at least one enone group in the spacer between aryl rings is n