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Master of Pharmaceutical Sciences


Pharmaceutical Sciences

First Advisor



Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by beta-amyloid (Aβ) aggregation/oligomerization, biometal dyshomeostasis, oxidative stress, and neuroinflammation. The multifactorial nature of AD may indicate the therapeutic potential of multifunctional ligands that tackle various risk factors simultaneously as effective AD-modifying agents. This notion is further supported by the fact that while numerous AD-modifying agents targeting one single risk factor have been developed and a number of them entered clinical trials, none of them has been successfully approved by the FDA. Furthermore, neuronal cell membrane/lipid rafts (CM/LR) have been demonstrated to associate with all the indicated risk factors, indicating that this relationship can be exploited therapeutically to design strategically distinct multifunctional ligands by incorporating CM/LR anchorage into molecular design. With the long-term goal of developing multifunctional ligands to slow or stop the progression of AD, recently we have embarked on the development of bivalent multifunctional Aβ oligomerization inhibitors (BMOIs) as potential AD-modifying agents. These BMAOIs contain curcumin as the multifunctional moiety and cholesterol as the CM/LR anchorage moiety linked by a spacer to co-target AβOs, CM/LR, and oxidative stress. The hypothesis of the BMAOI strategy is that BMAOIs will anchor/target the multifunctional AβO inhibitor moiety inside, or in the vicinity of, CM/LR in which Aβ oligomerization, Aβ/biometal interaction and oxidative stress occur to efficiently interfere with these processes. In support of this hypothesis, proof-of-concept of the BMAOIs strategy has been reached through our preliminary studies. Our results demonstrated that: 1) BMAOIs containing curcumin as the multifunctional AβO inhibitor and cholesterol as CM/LR anchor primarily localize to CM/LR while curcumin does not; 2) BMAOIs with optimal spacer length efficiently inhibit the production of intracellular AβOs and protect MC65 cells from AβO-induced cell death (EC50~3 µM) while curcumin exhibits no significant activity; 3) these active BMAOIs retain curcumin’s antioxidant and metal complexation properties. Our preliminary studies also demonstrated the critical roles of spacer length and connectivity in the molecular design of BMAOIs and one lead compound was identified for further structural modification and optimization. Furthermore, this lead compound was shown to cross the blood-brain barrier (BBB) in a preliminary in vivo study as well as bind to Aβ plaques. Taken together, these results clearly reach the proof-of-concept of BMAOIs and confirm the rationale of designing BMAOIs to develop potential AD-modifying agents. In this thesis, we continued the exploration and validation of the BMAOI strategy by designing and biological characterizing a series of BMAOIs containing cholesterylamine as the CM/LR anchorage moiety and curcumin as the multifunctional moiety. Ten BMAOIs with the spacer length of 15, 17, 19, 21, and 23 atoms were designed and synthesized. Initially, these BMAOIs were tested for the neuroprotective activity against the AβO-induced cytotoxicity in human neuroblastoma MC65 cells. Then, Western blot analysis was performed for active BMAOIs to confirm the association of neuroprotection and suppression of AβOs. Furthermore, active BMAOIs were examined for antioxidant and metal complexation properties. Finally, Aβ plaque binding was examined using transgenic AD mice brain sections. Our results demonstrated that the same spacer length but different connectivity are preferred in this new series of BMAOIs for neuroprotective activity as that of the lead compound from cholesterol series. Moreover, the neuroprotection activity is closely associated with the inhibition of AβOs as demonstrated by Western blot analysis. In addition, the active BMAOIs retain the antioxidant and biometal binding properties of curcumin. More importantly, the binding affinity to the Aβ plaques was again confirmed for the new BMAOIs containing cholesterylamine. In summary, the design and characterization of the new series BMAOIs further confirmed the rationale of BMAOI strategy and their potential to lead to a new direction in development of effective AD-modifying and treatment agents.


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