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.

Previous studies have shown that: (1) plant defensive compounds may have medicinal properties; and (2) defensive compounds present in aposematic insects are often sequestered from their host-plant(s). This study addresses whether aposematic insects can be used as guides to detect plants containing medicinally-active compounds. First, ten tropical medicinally-active plants and ten non-active plants, selected using previous ICBG bioassay results, were observed regularly to determine their insect populations. Aposematic insects were found more frequently on active than non-active plants ( X2=8.167, P=0.01). Second, three aposematic insects feeding on Tithonia diversifolia were examined chemically to determine the fate of the plant's pharmaceutically-active compounds. They were not found to sequester or excrete these compounds. Therefore, using aposematic insects could increase the likelihood of finding plants with medicinally-active compounds; however, these insects may not necessarily utilize these compounds for defensive purposes. The underlying basis for this significant association between aposematic insects and medicinally-active plants requires further investigation.

Thesis (M.S.)--University of Hawaii at Manoa, 2005. / Includes bibliographical references (leaves 86-102). / vii, 102 leaves, bound ill. 29 cm

Thesis (PhD) -- University of South Australia, 1999

Thesis (Ph. D.)--University of Hong Kong, 2008. / Also available in print.

Thesis (PhD.(Pharmacology)--Faculty of Health Sciences)-University of Pretoria, 2006. / Includes bibliographical references.

Thesis (PhD (Medical Plant Science)--University of Pretoria, 2007. / Summary in English. Includes bibliographical references. Available on the Internet via the World Wide Web.

Thesis (Ph. D.)--University of Hong Kong, 2008. / Includes bibliographical references (leaf 169-194) Also available in print.

Thesis (Ph. D.)--University of Hong Kong, 2008. / Includes bibliographical references (leaf 179-212) Also available in print.