Thesis (Ph. D.)--University of Washington, 2002. / Vita. Includes bibliographical references (leaves 93-101).

Thesis (Ph. D.)--University of Washington, 2004. / Vita. Includes bibliographical references (leaves 121-133).

Thesis (M. Phil.)--Hong Kong University of Science and Technology, 2003. / Includes bibliographical references (leaves 95-105). Also available in electronic version. Access restricted to campus users.

Thesis (Ph. D.)--University of Washington, 2003. / Vita. Includes bibliographical references (leaves 109-123).

Thesis (Ph. D.)--University of Washington, 2002. / Vita. Includes bibliographical references (leaves 189-202).

Thesis (Ph. D.)--University of Washington, 2002. / Vita. Includes bibliographical references (leaves 65-82).

GWAS have identified several chromosomal loci associated with ovarian cancer risk. However, the mechanism underlying these associations remains elusive. We identify candidate functional Single Nucleotide Polymorphisms (SNPs) at the 9p22.2 ovarian cancer susceptibility locus, several of which map to transcriptional regulatory elements active in ovarian cells identified by FAIRE-seq (Formaldehyde assisted isolation of regulatory elements followed by sequencing) and ChIP-seq (Chromatin Immunoprecipitation followed by sequencing) in relevant cell types. Reporter and electrophoretic mobility shift assays (EMSA) determined the extent to which candidate SNPs had allele specific effects. Chromosome conformation capture (3C) reveals a physical association between Basonuclin 2 (BNC2) and SNPs with functional properties. This establishes BNC2 as a major target of four candidate functional SNPs in at least two distinct elements. BNC2 codes for a putative transcription regulator containing three pairs of zinc finger (ZF) domains. Furthermore, bnc2 mutation in zebrafish leads to developmental defects including dysmorphic ovaries and sterility, clearly implicating this protein in cellular processes associated with ovarian development. We show that BNC2 is a transcriptional regulator with a specific DNA recognition sequence of targets enriched in genes involved in cell communication through DNA binding assays, ChIP-seq, and expression analysis. This study reveals a comprehensive regulatory landscape at the 9p22.2 locus and indicates that a likely mechanism of susceptibility to ovarian cancer may include multiple allele-specific changes in DNA regulatory elements some of which alter BNC2 expression. This study begins to identify the underlying mechanisms of the 9p22.2 locus association with ovarian cancer and aims to provide data to support advances in care based on one’s genetic composition.

S,S-diphenyl sulfimide (Ph2SNH) has been employed in current investigations divided in three different directions, concerning hydrogen bonding motifs of new sulfimide systems, polymorphism of trans- Cu(Ph2SNH)2Cl2 as well as carboxylations of Ph2SNH. The isomorphic analogues of [Mn(Ph2SNH)6]Cl2 and [Co(Ph2SNH)6]Cl2 were synthesised as parent systems, with their derivatisations by metathesis to give BF4 and PF6 salts. The BF4 daughter systems displayed face on and snug fit hydrogen bonding motifs in the Mn(II) and Co(II) variants respectively. The PF6 analogues were the first examples to have spectator sulfimide units not participating in hydrogen bonds, rationalised as means to relief steric constrains. [Co(Ph2SNH)4]SO4 was observed to be stabilised by the formation of l-D hydrogen bond array between the unsaturated complex centres with SO4 anions. The square planar polymorph of trans- Cu(Ph2SNH)2Cl2 has recently been observed to display reversible mechanochromism when ground. The yielding of a green ground collective was reasoned as the formation of an amorphous conformer closely related to the green pseudotetrahedral polymorph. The concomitant crystallisation of both forms has also been revisited. Internal voids, ether partial pressure and volume of mother liquor have been proposed as contributing factors concerning the crystallisation outcomes. The reaction between Ph2SNH and CO2 led to the formation of [Ph2SNH2]HCO3, Ph2SN(H)COO as well as Ph2SNCOOH, depending on reaction conditions. The zwitterion of Ph2SN(H)COO is expected to be the principle product of Ph2SNH/CO2 reactions, while [Ph2SNH2]HCO3 was deduced as a hydrolysis product of Ph2SN(H)COO. The isolation of Ph2SNCOOH was only possible when CO2 fixation was carried out in DMSO, rationalised as a unique proton transfer equilibrium only attainable in the protophilic solvent.

The research presented herein focus upon crystal engineering of co-crystals with an emphasis upon the exploration of co-crystals in the context of delineation of the reliability of hydrogen bonded supramolecular synthons and their hierarchies. The approach involves a combination of systematic Cambridge Structural Database analysis and a series of model co-crystal experiments. In addition, the viability of solid state methodologies toward supramolecular synthesis of co-crystals and the effect on polymorphism is also addressed. The application of the acquired knowledge is towards the crystal engineering of pharmaceutical co-crystals. The rational design and synthesis of pharmaceutical co-crystals accomplished by the selection of appropriate co-crystal formers facilitated by analysis of existing crystals structures in the CSD will be demonstrated. The processing of pharmaceutical co-crystals will also be addressed in terms of slurry conversion, solvent drop grinding and solution crystallization.

Neutral or charge-assisted hydrogen bonds occurring between organic molecules represent strong and directional forces that mediate the molecular self-assembly into well defined supramolecular architectures. A proper understanding of hydrogen bonding interactions, their types, geometries, and occurrence in supramolecular motifs, is a prerequisite to crystal engineering, i.e. to the rational design of functional solid materials.Multiple-component organic crystals represent ideal systems to study the intermolecular interactions between the constituent molecules that can be pre-selected for their hydrogen bonding sites and geometrical capabilities. In particular, the systematic structural analysis of supramolecular systems that are comprised of simple molecules facilitates the development of strategies for the rational design of new multiple-component compounds involving more complex components such as drug molecules.The work presented herein shows a combination of systematic database and experimental studies in the context of reliability and hierarchy of several hydrogen bonded supramolecular synthons that exist in a series of model co-crystals and organic salts. The acquired paradigms are ultimately utilized in crystal engineering of pharmaceuticals. In addition, the viability of a mechanichemical approach toward supramolecular synthesis in the context of its efficacy and the effect on polymorphism in multiple-component compounds is also addressed.