Collaborative research projects between chemists, biologists, and medical scientists have inevitably produced many useful drugs, biosensors, and medical instrumentation. Organic chemistry lies at the heart of drug discovery and development. The current range of organic synthetic methodologies allows for the construction of unlimited libraries of small organic molecules for drug screening. In translational research projects, we have focused on the discovery of lead compounds for three major diseases: Alzheimer's disease (AD), breast cancer, and viral infections. In the AD project, we have taken a rational-design approach and synthesized a new class of tricyclic pyrone (TP) compounds that preserve memory and motor functions in amyloid precursor protein (APP)/presenilin-1 (PS1) mice. TPs could protect neuronal death through several possible mechanisms, including their ability to inhibit the formation of both intraneuronal and extracellular amyloid β (Aβ) aggregates, to increase cholesterol efflux, to restore axonal trafficking, and to enhance long-term potentiation (LTP) and restored LTP following treatment with Aβ oligomers. We have also synthesized a new class of gap-junction enhancers, based on substituted quinolines, that possess potent inhibitory activities against breast-cancer cells in vitro and in vivo. Although various antiviral drugs are available, the emergence of viral resistance to existing antiviral drugs and various understudied viral infections, such as norovirus and rotavirus, emphasizes the demand for the development of new antiviral agents against such infections and others. Our laboratories have undertaken these projects for the discovery of new antiviral inhibitors. The discussion of these aforementioned projects may shed light on the future development of drug candidates in the fields of AD, cancer, and viral infections.

Small β-amyloid (Aβ) 1–42 aggregates are toxic to neurons and may be the primary toxic species in Alzheimer’s disease (AD). Methods to reduce the level of Aβ, prevent Aβ aggregation, and eliminate existing Aβ aggregates have been proposed for treatment of AD. A tricyclic pyrone named CP2 is found to prevent cell death associated with Aβ oligomers. We studied the possible mechanisms of neuroprotection by CP2. Surface plasmon resonance spectroscopy shows a direct binding of CP2 with Aβ42 oligomer. Circular dichroism spectroscopy reveals monomeric Aβ42 peptide remains as a random coil/α-helix structure in the presence of CP2 over 48 h. Atomic force microscopy studies show CP2 exhibits similar ability to inhibit Aβ42 aggregation as that of Congo red and curcumin. Atomic force microscopy closed-fluid cell study demonstrates that CP2 disaggregates Aβ42 oligomers and protofibrils. CP2 also blocks Aβ fibrillations using a protein quantification method. Treatment of 5× familial Alzheimer’s disease mice, a robust Aβ42-producing animal model of AD, with a 2-week course of CP2 resulted in 40% and 50% decreases in non-fibrillar and fibrillar Aβ species, respectively. Our results suggest that CP2 might be beneficial to AD patients by preventing Aβ aggregation and disaggregating existing Aβ oligomers and protofibrils.

A number of functionalized triglycerides were synthesized from glyceryl trioleoate via epoxidation followed by reduction to give glyceryl tris(9-hydroxy)trioleoate (a triol) or hydrolytic ring opening to obtain glyceryl tris(9,10-dihydroxy)trioleoate (a hexaol). A selective monoepoxidation reaction of glyceryl trioleoate was also carried out and the resulting monoepoxide was hydrolyzed to give glyceryl 9,10-dihydroxytrioleoate (a diol). Glyceryl tris(9-hydroxy)trioleoate was brominated followed by displacement with sodium azide and reduction to give glyceryl tris(9-amino)trioleoate (a triamine) and glyceryl tris[9-(N-isopropylamino)]trioleoate. These functionalized triglycerides were crosslinked with 1,4-phenylene diisocyanate. The crosslinked polymers exhibit thermoset characteristics. Thermal analysis results suggest that the polymers are in amorphous states, and their thermal stability was significantly affected by crosslink degree. The crosslinked polymer derived from the diol retained 56% of its weight at 408°C, whereas the polymers derived from the aforementioned hexaol with higher crosslink degree retained only 36% of the original weight. Glass transition temperatures of these polymers range from −1.0°C to 10.2°C. The thermal stable polymer, 12, derived from the aforementioned diol exhibits a linear viscoelastic character and can be used as thermoplastics. © 2008 Wiley Periodicals, Inc. J Appl Polym Sci, 2008