Neuroprotective peptide-macrocycle conjugates reveal complex structure-activity relationships in their interactions with amyloid β

Interactions between amyloid beta (A beta) and metal ions are thought to mediate the neuropathogenic effects of A beta in Alzheimer's disease. The construction of small molecules capable of synergistically chelating metal ions and recognizing A beta would allow new insights into the biology of this disease and provide a possible therapeutic approach. We report herein the synthesis and biological evaluation of tetraazamacrocycle-(G)KLVFF hybrids and their metal complexes. The results obtained from ThT and bis-ANS extrinsic fluorescence assays, tyrosine intrinsic fluorescence assay and proteolytic assay imply complex, multifaceted structure-activity relationships in the interaction of these conjugates with Ab. Many of the compounds tested rescued cells from A beta-induced cytotoxicity. The attendant simplicity and ready diversification of the synthesis of these conjugates makes them attractive for further investigation.