The three dimensional structure of both a ligand and its cognate receptor are required for the success of structure-assisted drug design. This thesis reports the crystal structure of hectochlorin, a small, bioactive molecule, and the steps toward determining the crystal structure of an RNA molecule that is an attractive target for drug design. The absolute structure of hectochlorin, a cytotoxic, secondary metabolite isolated from Lyngbya majuscula, is reported herein. Specifically, the absolute configuration of hectochlorin, as determined by x-ray crystallography, is reported as 6S, 7S, 10S, 31S. Marine natural products are interesting as a source of novel chemical compounds that are potentially valuable as therapeutic agents, or have industrial applications. The absolute structure provides a model that serves as a starting point for rational drug design synthesis. In a second study, results are reported from attempts to crystallize a biologically important RNA structure, the trans-acting response element, (TAR), for the determination of its structure by x-ray diffraction, and ultimately, providing an initial model for structure-assisted drug design targeted against HIV. Crystals, of biologically relevant TAR sequences, greater that 0.1 x 0.1 x 0.1 mm�� in size, both in the presence and absence of a cognate ligand analogue, have been obtained. These crystals have been shown to be of poor diffraction quality, but the initial crystallization conditions provide a starting point for optimization that may yield higher quality crystals. / Graduation date: 2001

No description available.

Graduation date: 1991

Not available / text

Metal trihalide (MX₃) systems represent a stern challenge in terms of constructing transferable potential models. Starting from a previously published set of potentials, 'extended' ionic models are developed which, at the outset, include only anion polarization. Deficiencies in these models, particularly for smaller (highly polarizing) cations, are shown to be significant. For example, crystal structures different to those observed experimentally are adopted. The potentials are improved upon by reference to ab initio information available for alkali halides with the 'constraint' that the parameters transfer systematically in a physically transparent manner, for example, in terms of ion radii. The possible influence of anion compression ('breathing') and the relative abundance of anion-anion interactions are considered. Simulation techniques are developed to allow for the effective simulation of any system symmetry and for the study of transitions between different crystals (constant stress). The developed models are fully tested for a large range of metal trichloride (MCl₃) systems. Particular attention is paid to the comparison with recent neutron and X-ray diffraction data on the liquid state. Polarization effects are shown to be vital in reproducing strong experimental features. The excellent agreement between simulation and experiment allows for differences in experimental procedures to be highlighted. The transferability is further tested by modelling mixtures of the lanthanides with alkali halides with potentials unchanged from the pure systems. The complex evolution of the melt structure is highlighted as the concentration of MCl₃ increases. The effectiveness of the models is tested by reference to dynamical properties. Particular attention is paid to the comparison with Raman scattering data available for a wide range of systems and mixture concentrations. The simulated spectra are generated both by a simple molecular picture of the underlying vibrations and by a more complex (fluctuating polarizability) model in which the spectra are broken down into contributions from different mechanisms. This comparison allows for the validity of treating network-like systems as a series of 'isolated' molecules to be assessed. The transferability of the potentials is pushed to the limits by modelling metal tribromides, in which the parameters are obtained from the trichlorides by the same simple scaling arguments.

Thesis (Ph. D.)--Chemistry and Biochemistry, Georgia Institute of Technology, 2009. / Committee Chair: Barry, Bridette; Committee Member: Doyle, Donald; Committee Member: Kelly, Wendy; Committee Member: McCarty, Nael; Committee Member: Schimdt-Krey, Ingaborg. Part of the SMARTech Electronic Thesis and Dissertation Collection.

Thesis (Ph. D.)--University of Missouri-Columbia, 2005. / The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file. Title from title screen of research.pdf file viewed on (July 17, 2006) Vita. Includes bibliographical references.

The teratogenic potency of retinoid analogs was determined in Syrian hamsters and compared to the teratogenic potency of all-trans-retinoic acid (all-trans.-RA, ED50 = 10.5 mg/kg). A total of 15 analogs having variations in the cyclohexene ring were evaluated following various amounts of single oral doses on day 8 of gestation. Retinoids containing a five- or six-membered ring were as teratogenic as all-tmru.-RA, provided they had sufficient lipophilic substituents on the ring. The same pattern emerged for retinoids that had six-membered aromatic ring substitution for the natural cyclohexene ring of vitamin A. Incorporation of a supplementary aromatic ring in the side-chain adjacent to a gem-dimethyl-hexene ring resulted in an increase in teratogenicity by IS-fold compared to all-trans.-RA. Major modifications of the cyclohexene ring can be made without altering teratogenic activity. The ring need not be six-membered and can have decreased lipophilicity through the incorporation of polar groups compared to all-trans.-RA, but must have sufficient lipophilic substituents to provide the necessary mass for interaction with the retinoid receptor. Incorporation of a supplementary aromatic ring adjacent to a gem-dimethyl-hexene ring facilitated π-electron delocalization and restricts side-chain flexibility , thereby increasing teratogenic potency. The pharmacokinetic disposition of 8 retinoids was investigated. Pregnant hamsters were dosed orally with all-trans-RA, 13-cis-retinoic acid, all-trans.-4- oxoretinoic acid, 9-cis-retinal, all-trans.-retinyl acetate, N-ethyl-all-trans- retinamide, N-ethyl-13-cis-retinamide, and arotinoid. The bioavailability of the retinamides was one-tenth that of the free acid retinoids. The plasma elimination half-life for all-trans-RA was 0.5 h. For 13-cis-retinoic acid and all-trans-4-oxoretinoic acid the elimination half-lives were 4.4 and 5.7 h, respectively. The binding affinity of various retinoids to cellular retinoic acid-binding protein (cRABP) was determined in day-12 hamster fetuses. Fetal supernatants from the 105,000x g fraction were incubated with high specific-activity [3H]-all-trans-RA in the presence of various concentration of unlabeled retinoids with subsequent isolation of cRABP by size-exclusion HPLC. Teratogenic retinoids, or acidic metabolites of teratogenic retinoids bound to cRABP whereas nonteratogenic retinoids failed to bind.

Investigating the structure-property relationships of solid state materials can help improve many of the materials we use each day in life. It can also lead to the discovery of materials with interesting and unforeseen properties. In this work the structure property relationships of newly discovered layered oxypnictide phases are presented and discussed. There has generally been worldwide interest in layered oxypnictide materials following the discovery of superconductivity up to 55 K for iron arsenides such as LnFeAsO[subscript 1-x]F[subscript x] (where Ln = Lanthanoid). This work presents efforts to understand the structure and physical property changes which occur to LnFeAsO materials when Fe is replaced with Rh or Ir and when As is replaced with Sb. As part of this work the solid solution between LaFeAsO and LaRhAsO was examined and superconductivity is observed for low Rh content with a maximum critical temperature of 16 K. LnRhAsO and LnIrAsO compositions are found to be metallic; however Ce based compositions display a resistivity temperature dependence which is typical of Kondo lattice materials. At low temperatures a sudden drop in resistivity occurs for both CeRhAsO and CeIrAsO compositions and this drop coincides with an antiferromagnetic transition. The Kondo scattering temperatures and magnetic transition temperatures observed for these materials can be rationalized by considering the expected difference in N(E[subscript F])J parameters between them, where N(E[subscript F]) is the density of states at the Fermi level and J represents the exchange interaction between the Ce 4f¹ electrons and the conduction electrons. In addition to studying these 4d and 5d substituted systems the LaFeSbO compositional system was investigated. While LaFeSbO has not been successfully synthesized the transition metal free layered oxypnictide composition La₂SbO₂ was discovered and its structural and physical properties have been examined along with the properties of La₂BiO₂. Density functional theory was used to calculate the heats of formation for competing phases within the LaFeSbO system, in order to better understand the stability of LaFeSbO and why it has not yet been observed. The materials La₂SbO₂ and La₂BiO₂ were investigated for the presence of oxygen vacancies using powder neutron diffraction. Structure refinement reveals that there is significant disorder within the a-b plane for Sb compositions. / Graduation date: 2012

Chemical hardness (eta), calculated by density functional theory (DFT), was firstly used as one of the chemical reactivity descriptors to set up the one descriptor 2D-QSAR model of platinum drugs. In this simple but promising model, the antitumour activities (log GI50) evaluated by National Cancer Institute (NCI) of structure-based groups containing normal sp 3 nitrogen and R,R-diamminecyclohexane (R,R-DACH) as the ligand showed good correlation. It was also demonstrated that silane and stereoisomers of DACH groups showed special patterns. This study also made use of the COMPARE program from NCI to evaluate the activity profile and the analysis of the data revealed these distinct patterns are influenced by the mechanism of the drugs. / Computer-aided drug design (CADD) techniques have been applied to establish quantitative structure-activity relationships (QSAR) and quantitative structure- property relationships (QSPR) models. Although these techniques are widely used in organic drugs, new metal-based drugs were hindered from development for lack of metal parameters, such as potent new platinum drugs as a major group of drugs used in cancer treatment. The purpose of the present study, therefore, is to generate novel platinum parameters based on previous work and then set up the simple QSAR/QSPR model with predictive abilities. / Finally, two 3D-QSAR and 3D-QSPR models obtained using Sybyl software. One was for demethylcantharidin (DMC) analogues as phosphatase 2A (PP2A) inhibitors. The other was describing the hydrophobicity of platinum drugs. In this research, the platinum atom was introduced to Sybyl and thus made it possible for the first time to use comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) methods to investigate platinum drugs. All 3D models indicated good predictive ability and thus provided an effective method to design new potent platinum drugs. / To clarify the pattern of stereoisomers of the DACH group, new platinum parameters was introduced to the AMBER software successfully. Moreover, stereoisomers of the DACH group which formed 1,2-GG intrastrand cross-links with DNA were studied by molecular dynamics (MD) simulations using AMBER. The calculated binding energies between R,R-DACH-Pt, S,S-DACH-Pt and cis-DACHPt moieties and DNA revealed a strong correlation with antitumour activities. The result provided more clues to understand the biological interactions of chiral platinum drugs. DNA structure analysis indicated that DNA tolerated the distortion resulted in the different Pt-DNA adducts and various local and global structure distortions were found. Natural bond orbital (NBO) analysis of hydrogen bonding on Pt-DNA adducts at a AGGC site revealed that R,R-DACH-Pt moiety alleviated the repulsion by unwinding the DNA, whereas the S,S-DACH-Pt adduct avoided the interaction by distorting the H bonds of binding site basepairs. Hence, the structural differences of chiral platinum drug led to its distinct activity. / Yang, Lifeng. / "June 2008." / Advisers: Steve C. F. Au Yeung; Yee-Ping Ho. / Source: Dissertation Abstracts International, Volume: 70-03, Section: B, page: 1541. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2008. / Includes bibliographical references (p. 159-172). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts in English and Chinese. / School code: 1307.