Doctor of Philosophy / Department of Chemistry / Duy H. Hua / The first chapter in this thesis includes the design, synthesis, and evaluation of anti-Alzheimer and anti-norovirus activities of tricyclic pyrones (TPs). Alzheimer’s disease is a major cause of dementia and sixth leading cause of death; it is a growing problem all over the world. On the other hand, norovirus, a highly contagious agent is responsible for more than 90% of non-bacterial gastroenteritis causing severity mainly in the closed environments. No drugs exist to eradicate the symptoms developed by both of these disorders. Studies have shown that the development of Alzheimer’s disease and the infection of norovirus are dependent on cholesterol metabolism. More specifically, the inhibition of acyl-CoA: cholesterol acyltrasferase (ACAT) led to the reduction of plaques in Alzheimer’s disease as well as reduced the infection of norovirus. Mimicking the structure of CP2, a TP with promising anti-Alzheimer activities, a library of tricyclic pyrones containing phenyl, naphthyl, heterocyclic, and dipeptidyl moieties were synthesized and evaluated for their anti-Alzheimer and anti-norovirus efficacies. Several TPs containing phenyl and naphthyl groups showed sub-micromolar to nanomolar potencies for the protection of neuronal MC65 cells from Aβ-oligomers induced death. Similarly, the TPs containing pyrrolyl, imidazolyl, and quinolinyl moieties were effective to inhibit the norovirus replication in low micromolar range. The most effective TPs from MC65 cells protection assay were also effective in the inhibition ACAT and up-regulation ABCA1 gene. The second chapter in this thesis includes the design, synthesis, and anti-norovirus activity of thiouridine nucleosides. Many nucleosides have demonstrated effective inhibition of viral RNA polymerase, and some are progressing at different level of clinical trials for the treatment of hepatitis C virus. Some of the nucleosides, including 2’-C-methyl and 2’-amino substituted analogs, were found to effectively inhibit the norovirus replication. In the search of more potent anti-noroviral compounds, two thiouridine nucleosides were synthesized and evaluated as anti-norovirus agents. Both of these analogs were ineffective up to 50 μM for the inhibition of norovirus replication in cell based assay. Proposed work of converting these nucleosides to their phosphoramidate derivatives is also described.

No description available.

Flow chemistry can be characterized as a continuous chemical reaction system performed in solution in connecting tubing and flow reactors which is efficient. Photochemistry is the chemical reaction initiated by light, and is the result of the absorption of photon by a reagent or starting material. Poly (ADP-ribose) polymerase is a big family of proteins related to cellular repair and death. Phenanthridinones have been shown to exhibit PARP inhibitory potency as competitive inhibitors. Instead of using conventional costly and low-efficiency coupling reactions, we have managed to develop a method to synthesize phenanthridinone-type compounds by photo-cyclization under flow conditions for the purposes of generating novel PARP inhibitors. In total, we have generated a series of phenanthridinones in yields ranging from 13 % to 99%, 18 examples. Additionally, we have also developed a flow photocyclization method for the synthesis of complex heterocycles, naphthyridinones (5 examples, yields ranging from 24-52%) and thieno-quinolinones (18 examples, yields ranging from 23-90%), molecules that would be much more difficult to construct using conventional batch methods. Overall, we have demonstrated that a flow photocyclization pathway is a robust synthesis route for producing phenanthridinone-type compounds for the purposes of developing novel PARP inhibitors. / October 2016

The focus of the research described in this section of the thesis is the synthesis of compounds expected to bind strongly to both the estrogen β and α receptors and act as estrogen agonists. Based on earlier results in our group and docking studies we prepared a series of A-CD analogs, compounds 1, in which the usual 13-methyl group was replaced by an ethyl group. Docking studies also indicated that substituents at C8 could lead to enhancement of binding to the estrogen receptor. With this in mind two such derivatives, compounds 2 were prepared. A major concern in the use of estradiol in hormone replacement therapy is its potential metabolism of dangerous ortho-quinones. The 1,2-naphthalenediol derivatives 3 avoid this possibility. They were predicted to be potent binders to the estrogen receptors with the naphthalene diol portion serving as rings A and B and the hydroxyl group taking the place of the 17-OH group of estradiol. The preparation of several derivatives of 2 is reported. The estrogen receptor binding [ERB] relative to estradiol as standard has been determined at the University of Illinois for a number of the compounds prepared in this thesis. Unfortunately, the results were not as encouraging as expected. Importantly, all of the 13-ethyl derivatives tested showed lower binding affinity compared to the 13-methyl analogs. Similarly, the derivatives with substituents at C8 do not show higher activity than those having only hydrogens at C8. Finally, the situation with the naphthalene derivatives is, at this stage, still not completely resolved. The binding for the compounds thus tested is quite low, but it must be admitted that the structures thus far synthesized have a much lower LogP than estradiol, a factor known to greatly decrease the binding constants to the estrogen receptors.

The focus of the research described in this section of the thesis is the synthesis of compounds expected to bind strongly to both the estrogen β and α receptors and act as estrogen agonists. Based on earlier results in our group and docking studies we prepared a series of A-CD analogs, compounds 1, in which the usual 13-methyl group was replaced by an ethyl group. Docking studies also indicated that substituents at C8 could lead to enhancement of binding to the estrogen receptor. With this in mind two such derivatives, compounds 2 were prepared. A major concern in the use of estradiol in hormone replacement therapy is its potential metabolism of dangerous ortho-quinones. The 1,2-naphthalenediol derivatives 3 avoid this possibility. They were predicted to be potent binders to the estrogen receptors with the naphthalene diol portion serving as rings A and B and the hydroxyl group taking the place of the 17-OH group of estradiol. The preparation of several derivatives of 2 is reported. The estrogen receptor binding [ERB] relative to estradiol as standard has been determined at the University of Illinois for a number of the compounds prepared in this thesis. Unfortunately, the results were not as encouraging as expected. Importantly, all of the 13-ethyl derivatives tested showed lower binding affinity compared to the 13-methyl analogs. Similarly, the derivatives with substituents at C8 do not show higher activity than those having only hydrogens at C8. Finally, the situation with the naphthalene derivatives is, at this stage, still not completely resolved. The binding for the compounds thus tested is quite low, but it must be admitted that the structures thus far synthesized have a much lower LogP than estradiol, a factor known to greatly decrease the binding constants to the estrogen receptors.

Nordihydroguaiaretic Acid (NDGA) is a polyphenol, antioxidant, natural product lignan isolated from the creosote bush (Larrea tridentata). The in vivo and in vitro Pharmacology and Toxicology of NDGA has been continuously studied for more than 36 years. The Pharmacology of NDGA has been studied in Diabetes, Alzheimer's disease and Amyotrophic Sclerosis. Most of the research on NDGA has been in anticancer and cancer prevention models. Toxicology studies reveal NDGA-mediated hepatotoxicity and nephrotoxicity. This data has influenced a recent interest in semi-synthetic derivatives of NDGA focused on modifying the phenolic groups which are responsible for in vivo toxicity. The tetra-methylether of NDGA (M4N) has shown reduction in toxicity and enhanced anti-melanoma activity when compared to NDGA.The specific aim of this project was to increase the number of NDGA analogs with anti-melanoma activity and explore a novel synthetic approach by binding the ortho-phenols together by one atom, creating a 5-membered ring as opposed to the prior work which involved tetra-substituted phenolic hydroxyl group modifications.Eleven new analogs were synthesized, characterized and evaluated for their anti-melanoma activity. The anti-melanoma activity was evaluated by 5-day colorimetric-based, and DNA, RNA and protein synthesis inhibition-based cytotoxicity assays. The cytotoxicity assays were compared to NDGA and M4N in terms of structure and activity. Selected analogs were evaluated in an in vivo, mouse, tumor growth inhibition model. In the first in vivo model, tetra acetyl NDGA (TA-NDGA) and ortho-cyclic carbonate NDGA (OCC-NDGA) were evaluated at two dose-levels, 100 mg/kg and 200 mg/kg. They both showed dose-dependent, but moderate tumor growth inhibition at the 200 mg/kg dose-level. An ortho-cyclic sulfate of NDGA showed in vivo toxicity at 100 mg/kg. In the second in vivo model, the dose was escalated to 300 mg/kg, TA-NDGA showed moderate tumor growth inhibition, but OCC-NDGA-mediated tumor growth inhibition was not repeated. However, in the second study an ortho-difluoromethylene NDGA analog did show moderate tumor growth inhibition.Structure-activity relationships indicated that the ortho-cyclic analogs are inferior to the tetra-substituted phenolic group-modified analogs in terms of anti-melanoma activity and therefore future synthesis' should be focused on generating more tetra-substituted phenolic group analogs of NDGA.

p-Sulfonatocalix[X]arene (X = 4 and 6) was explored as a host for trimethyllyated lysine. We found by 1H NMR and ITC titrations that p-sulfonatocalix[4]arene (PSC) bound the trimethyllysine amino acid with high affinity and good selectivity over dimethyllysine and similar dimethylated arginines. When trimethyllysine was in the context of a peptide of the histone 3 tail, affinities increased and PSC was up to 20 -fold selective over identical unmethylated peptides. Multiple scaffolds were synthetically explored as derivatives of PSC. I created five different scaffolds and synthesized a small library of compounds derived from these scaffolds as hosts for a variety of histone 3 peptides containing biologically important post-translationally modified amino acids. This library was tested using a high-throughput indicator displacement assay and I found three hosts that displayed tuned affinities and selectivities for post-translationally modified amino acids we had not previously targeted. I studied the ability of these synthetically elaborated calix[4]arenes to identify histone PTMs and monitor an enzymatic reaction. I found covalently linked fluorescent calixarenes were able to accomplish this goal. Furthermore, we studied the ability of these calix[4]arenes to disrupt protein-protein interactions that occur between the trimethyllyated lysine on histone tails and proteins that read these sites. I found that these calixarenes could disrupt these interactions between a variety of proteins and trimethyllyated lysine sites. These calix[4]arenes show promise as chemical tools that could be used to further probe epigenetic pathways in vitro and further work is needed to explore their utility in cellular assays and in vivo. / Graduate / 0490 / 0487 / kddaze@gmail.com

The focus of the research described in this section of the thesis is the synthesis of compounds expected to bind strongly to both the estrogen β and α receptors and act as estrogen agonists. Based on earlier results in our group and docking studies we prepared a series of A-CD analogs, compounds 1, in which the usual 13-methyl group was replaced by an ethyl group. Docking studies also indicated that substituents at C8 could lead to enhancement of binding to the estrogen receptor. With this in mind two such derivatives, compounds 2 were prepared. A major concern in the use of estradiol in hormone replacement therapy is its potential metabolism of dangerous ortho-quinones. The 1,2-naphthalenediol derivatives 3 avoid this possibility. They were predicted to be potent binders to the estrogen receptors with the naphthalene diol portion serving as rings A and B and the hydroxyl group taking the place of the 17-OH group of estradiol. The preparation of several derivatives of 2 is reported. The estrogen receptor binding [ERB] relative to estradiol as standard has been determined at the University of Illinois for a number of the compounds prepared in this thesis. Unfortunately, the results were not as encouraging as expected. Importantly, all of the 13-ethyl derivatives tested showed lower binding affinity compared to the 13-methyl analogs. Similarly, the derivatives with substituents at C8 do not show higher activity than those having only hydrogens at C8. Finally, the situation with the naphthalene derivatives is, at this stage, still not completely resolved. The binding for the compounds thus tested is quite low, but it must be admitted that the structures thus far synthesized have a much lower LogP than estradiol, a factor known to greatly decrease the binding constants to the estrogen receptors.

Thesis (Ph. D.)--Rutgers University, 2008. / "Graduate Program in Medicinal Chemistry." Includes bibliographical references (p. 156-174).

The focus of the research described in this section of the thesis is the synthesis of compounds expected to bind strongly to both the estrogen β and α receptors and act as estrogen agonists. Based on earlier results in our group and docking studies we prepared a series of A-CD analogs, compounds 1, in which the usual 13-methyl group was replaced by an ethyl group. Docking studies also indicated that substituents at C8 could lead to enhancement of binding to the estrogen receptor. With this in mind two such derivatives, compounds 2 were prepared. A major concern in the use of estradiol in hormone replacement therapy is its potential metabolism of dangerous ortho-quinones. The 1,2-naphthalenediol derivatives 3 avoid this possibility. They were predicted to be potent binders to the estrogen receptors with the naphthalene diol portion serving as rings A and B and the hydroxyl group taking the place of the 17-OH group of estradiol. The preparation of several derivatives of 2 is reported. The estrogen receptor binding [ERB] relative to estradiol as standard has been determined at the University of Illinois for a number of the compounds prepared in this thesis. Unfortunately, the results were not as encouraging as expected. Importantly, all of the 13-ethyl derivatives tested showed lower binding affinity compared to the 13-methyl analogs. Similarly, the derivatives with substituents at C8 do not show higher activity than those having only hydrogens at C8. Finally, the situation with the naphthalene derivatives is, at this stage, still not completely resolved. The binding for the compounds thus tested is quite low, but it must be admitted that the structures thus far synthesized have a much lower LogP than estradiol, a factor known to greatly decrease the binding constants to the estrogen receptors.