This library includes compounds with variations on carbon spacer length between phenolic rings, a variety of ring substitutions, as well as substitutions to the central methylene carbon of curcumin. In general, our BKM120 studies indicate that at least one enone group on the spacer is necessary for measureable anti- Ab aggregation activity. The most striking SB431542 feature among compounds in both the 7- and 5-carbon series listed in Figure 1 is the presence of an a/bunsaturated carbon spacer. None of the compounds with saturated spacers demonstrated inhibitory activity, indicating that an unsaturated spacer between aryl rings is essential for anti- Ab aggregation activity. A similar finding was reported by Begum, et al., when they compared the antiamyloidogenic activities of dietary curcumin with that of tetrahydrocurcumin. Further study of Figure 1 reveals novel structure/function relationships with regard to specific substitutions to the aryl rings. Ortho-substitutions do not appear to contribute to improved inhibitor activity; however, maintaining methoxyl and hydroxyl substitutions in the meta- and parapositions on the aryl rings is necessary for comparable or improved inhibitory activity when measured against curcumin. In the 5carbon series, one compound was significantly improved over that of curcumin, compound 8, which has hydroxyl groups in both meta- and para-positions of the aryl rings. The most improved inhibitors identified in the 7-carbon series have their meta- and para-substituted methoxyl and hydroxyl groups reversed from that of curcumin, as with compound 1, or methoxyl groups placed in both positions, as with compound 2. The simple substitution of the para-hydroxy group on curcumin with a methoxy substitution improved inhibitor function by 6-7-fold over that measured for curcumin, making compound 2 our most potent lead analog for anti-Ab aggregation activity. Additional challenges lie ahead to improve the bioactivity of our curcumin-derived analog in order to increase the therapeutic dose to the CNS. Questions in regard to bioavailability have plagued the use of curcumin as a potential therapeutic for a number of years. Clinical trials have shown that the inherent bioavailability of orally administered curcumin is relatively low when factoring in intestinal absorption, liver metabolism and BBB penetrance. However, in spite of these difficulties, dietary supplementation of curcumin administered to aged APPtransgenic mice significantly lowered Ab deposition in the CNS. These findings clearly show that curcumin is able to enter the circulation and cross the BBB in sufficient quantities to reduce amyloid burden. To improve upon this property, we anticipate that the methoxy substitution on our lead compound 2 will decrease polarity and increase lipid membrane solubility thereby improving passive diffusion across the blood brain barrier and access to the CNS. Similar observations have been made for other inhibitors of Ab aggregation such as Chrysamine G. In this study, the more lipophilic compound Chrysamine G was compared with Congo Red and found to readily cross the BBB in normal mice, achieving a brain:blood ratio of greater than 10:1. Moreover, metabolic inactivation poses other challenges to maintaining bioactivity. In this respect, the hydroxyl groups on curcumin are modified by enzymes found in the liver, kidney and intestinal mucosa to form curcumin glucuronides and curcumin sulfates. The methoxy substitution for these hydroxyl groups on our lead compound 2 should prevent these glucuronide and sulfate additions and contribute to sustained bioactivity.