Doctor of Philosophy / Department of Chemistry / Duy H. Hua / The first chapter of this dissertation introduces and discusses the syntheses of a series of substituted quinolines as glycogen synthase kinase-3[beta] (GSK-3[beta]) inhibitors. GSK-3[beta] is highly associated with Alzheimer’s disease (AD), and it is suggested that inhibition of this enzyme could alleviate the symptoms of AD. Total 16 novel substituted quinolines were designed and synthesized, and their bio-activities were evaluated on MC65 cell protection assay. Four of the most active compounds were selected to test their enzyme inhibitory activities on GSK-3[beta] and protein kinase C assays. Among these compounds, 4-{[6-methoxy-4-methyl-5-(3-(trifluoromethyl)phenoxy)quinolin-8-ylamino]methyl} phenol (1.5) shows the highest MC65 cell protection and GSK-3[beta] enzyme inhibitory activities and potential enzyme specificity. Structure-activity relationship (SAR) was built as well, and the binding mode was simulated via computational method to interpret the observed SAR. Although additional bio-evaluation is needed, compound 1.5 is a promising lead compound for the development of more active and less toxic drug for the conteraction of AD. The second chapter introduces the progress on the total synthesis of myriceric acid A. Myriceric acid A is a triterpene-type natural product which was isolated from the young twigs of Myrica cerifera. It is a non-peptide endotheline-1 (ET-1) receptor antagonist. The total synthesis of this natural product started from the stereoselective synthesis of bicyclic intermediate (R)-5,8a-dimethyl-3,4,8,8a-tetrahydronaphthalene-1,6(2H,7H)-dione [(-)-2.28]. Then a new method was developed to enatioselectively synthesize the tricyclic intermediate (4aR,8R,8aR)-8-(tertbutyldimethylsilyloxy)-1,4a,8a-trimethyl-4,4a,4b,5,6,7,8,8a,9,10-decahydro phenanthren-2(3H)-one [(+)-2.72] which used the synthesized optically-pure (4aR,5R)-5-(tertbutyldimethylsilyloxy)-1,4a-dimethyl-4,4a,5,6,7,8-hexahydronaphthalen-2(3H)-one [(-)-2.53] derived from (-)-2.28 and [alpha]-trimethylsilylvinyl ethyl ketone via a cascade reductive Michael addition – aldol condensation reaction. After functional group inter-conversion, the desired tricyclic intermediate (4a'S,8a'R)-1',1',4a',8a'-tetramethyldecahydro-1'H-spiro[[1,3]dioxolane-2,2'-phenanthren]-8'(3'H)-one [(-)-2.33] was synthesized. An intramolecular cascade Michael addition-aldol condensation reaction was designed to construct the triterpene-skeleton of myriceric acid A, and the desired starting material for this reaction was prepared with the trimethyl{(4a'R,8a'R)-1',1',4a',8a'-tetramethyl-3',4',4a',4b',5',6',8a',9',10',10a'-decahydro-1'Hspiro[(1,3)dioxolane-2,2'-phenanthrene]-8'-yloxy}silane [(-)-2.81] and 3,3-dimethyl-7-oxooctanal (2.46) via Mukaiyama aldol condensation reaction. The resulting pentacyclic compound was further transformed to the desired ester (6a'R,8a'R,12a'S,12b'R,14b'R)-ethyl 4',4',6a',11',11',14b'-hexamethyl-8'-oxo-2',4',4a',5',6',6a',8',8a',9',10',11',12',12a',12b',13',14',14a',14b'-octadecahydro-1'H-spiro[(1,3) dioxolane - 2, 3 '- picene]-8a'-carboxylate (-)-2.106. The further investigation on total synthesis of myriceric acid A will be pursued in future.

Ischemic stroke causes irreversible damage to the brain. The hippocampus is a vulnerable region and plays an important role in cognition and locomotor activity. Puerarin is a phytoestrogen that has beneficial effects in treating neurological disorders. How puerarin protects against hippocampal injury and its molecular mechanisms remain to be elucidated. Transient global brain ischemia was induced by 4-vessel occlusion in adult male Sprague-Dawley rats. The rats were pretreated with puerarin alone or together with LY294002 (an PI3K inhibitor) before ischemia/ reperfusion (I/R). The open-and closed-field tasks and Morris water maze (MWM) test were used to assess the effects of puerarin on anxiety-like behavioral and cognitive impairment following I/R. Hematoxylin-eosin staining(HE) was used to examine the survival of hippocampal CA1 pyramidal neurons, and immunoblotting was performed to examine the expression of the related proteins. By using the rat model for transient I/R, we demonstrated that puerarin pretreatment significantly increased the travelling distance and number of crossings in the open-and closedfield tests, reduced latency and increased the proportion of distance and time in zone IV in the MWM. The number of live cells in the hippocampus is sharply increased by puerarin pretreatment. We further observed that the levels of phosphorylated Akt1, GSK-3 beta and MCL-1were elevated and those of cleaved-caspase-3 were reduced in the puerarin-treatment group. Notably, the PI3K inhibitor LY294002 counteracted all of the effects of puerarin. Our findings suggest that puerarin protects the hippocampus from I/R damage by activating the PI3K/Akt1/GSK-3 beta/MCL-1 signaling pathway.