Alzheimer’s disease is an intractable disease; one of the pathological characteristics is the amyloid deposition in hippocampus. Reactive oxygen species (ROS) is known to be generated in the aggregation process of amyloid beta (Aβ), to injured nerve cells. In general, it is reported that polyphenol have the ability to inhibit aggregation of Aβ. Previously, a catechin analogue, called “planar catechin (PC)”, in which the geometry of (+)-catechin was constrained to be planar, was synthesized. Comparing with catechin, it exhibited potent radical scavenging activity, several novel biological activities and enhanced inhibitory activity against Aβ aggregation. Silibinin (Sib), extracted from milk thistle, is widely used as supplements. It has many biochemical functions, such as inhibitory activity of Aβ aggregation, anti-cancer and anti-inflammation activities. Interestingly, holding high planarity in Sib is the most stable, a certain researcher group hypothesize that planarity in the molecule is correlated with the inhibitory activity of Aβ aggregation. In this study, we designed the novel derivatives Sib-PC and Sib-EC in which the steric structure of Sib was constrained by introducing planar or nonplanar catechin, respectively, in order to clarify the effect of molecular planarity on biological activity. These derivatives will allow the protection of Aβ induced neurotoxicity by way of both potent inhibition of Aβ aggregation and antioxidation toward Aβ-induced intracellular ROS generation. Four step synthesis were accomplished for the preparation of these derivatives. The scavenging activity of these derivatives on hydroxyl radical were measured by electron spin resonance method (ESR). Furthermore, inhibition of oxidative DNA-damage for hydroxyl radical or singlet oxygen were measured by electrophoresis of agarose gel. These results indicated that they have weak radical scavenging activity and protective effects for oxidative DNA-damage. Next, we assessed the inhibitory effect on Aβ aggregation by Thioflavin-T assay. It was shown that Sib-PC having a planar structure has strong activity for inhibition of Aβ aggregating. These results revealed that the planar structure of Sib was essential for its inhibitory effect on Aβ aggregation. In this presentation, the details of these results will be reported.

Synthesis of silibinin anlogues targeting amyloid beta

2019 Fall National Meeting

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