Thesis (Ph. D.)--University of Wisconsin--Madison, 2006. / Includes bibliographical references. Also available on the Internet.

No description available.

No description available.

No description available.

A disadvantage of traditional equilibrium dialysis for highly protein bound drugs is the analytically low drug concentration found on the buffer side. We propose to replace a certain percentage of buffer with plasma containing drug in order to increase the total drug concentration on the buffer side. Computer simulations were performed to examine the effects of the percentage of plasma replacement of the buffer upon the increase of the total drug concentration on the buffer side after equilibrium dialysis. Further simulation results indicated that the development of a concise equation estimating the drug's equilibrium association binding constant (Ka) was feasible. Two high binding drugs, diazepam and nortriptyline, were examined to verify the advantages offered by the new proposed method and their Ka values were computed using the experimental results and the mathematical equation developed. The resulting data agreed well with theoretical predictions.

The two structurally different peptides DPDPE and Dermenkephalin show a similar remarkably high affinity and selectivity for the delta opioid receptor subtype. An effort has been made to gain some insight into the factors responsible for the recognition ability of these two molecules by synthesizing some DPDPE-Dermenkephalin peptide hybrids and some conformationally restricted Dermenkephalin analogues. The results of the binding and the in-vitro bioassays have been compared with those of the parent peptides. A general decrease in receptor affinity has been observed in the peptide hybrids while the dermenkephalin analogues have shown a wider range of affinities and selectivities. The above findings contribute to the understanding of the structural requirements of the delta receptor, provide information about the sensitivity of Dermenkephalin to enzymatic degradation, and indicate directions for future research.

The crystal size distribution (CSD) of any material determines its end use. Consequently, comminution processes are used to transform material from one size distribution to another. Often, recrystallization from solution is one of the processes used. Recently, a novel recrystallization process named the GAS process was developed to mill compounds that were thermally labile and insoluble in supercritical fluids. CSD could be manipulated using this process. To further illustrate the applicability of this process, size manipulation studies of acetaminophen (a widely available drug) were performed. The aim of this work was to produce crystals in the mass mean size range from 5mum to 50mum, and identify the conditions for producing the desired size distribution. A modified GAS process and a liquid anti-solvent (LAS) process were also investigated. Together with acetaminophen-butanol, other systems studied were aspirin-methanol and benzoic acid-methanol.

Although combinatorial libraries owe their inception to applications in peptide and bacteriophage libraries, the breadth of current applications include solution phase chemical reaction optimization, material science investigation, natural products modifications, and agricultural research. As a conceptual application, combinatorial library techniques can enhance a researcher's ability to transcend beyond the examination of one or several compounds to that of thousands or millions of these species simultaneously. The work described here, limited to scaffolded combinatorial chemical libraries, focuses primarily on the design and synthesis of these systems and how they have been analyzed against biological targets. Of the three scaffolded libraries, two were developed from aromatic templates (3,5-diaminobenzoic acid and 1,2,4-benzenetricarboxylic acid) while the last was built upon the cyclohexyl, Kemp's triacid platform. Although these libraries did not provide compounds with high affinity for the receptors investigated, they served to improve the understanding of combinatorial chemistry as a practice.

The cyclohexane-based aminophenolate compounds 1,3,5-cis-tris(2-hydroxybenzylamino)cyclohexane ((salH$\sb2)\sb3$tach) and its tris-para substituted derivatives (NO$\sb2$salH$\sb2)\sb3$tach and (MeOsalH$\sb2)\sb3$tach, have been synthesized via 1,3,5-cis-cyclohexanetriol precursor. The synthesis of these ligands' complexes with Al(III), Ga(III), In(III) and Fe(III) is presented. The ligands and their complexes have been characterized by proton NMR spectroscopy, carbon-13 NMR spectroscopy, infrared spectroscopy, FAB mass spectrometry and elemental analysis. Ultraviolet-visible spectroscopy of the complexes and magnetic susceptibility of the iron complexes are also presented. In addition, the crystal structures of $\rm Al(salH\sb2)\sb3tach{\cdot}3.5H\sb2O,\ Ga(salH\sb2)\sb3tach{\cdot}3.5H\sb2O,\ In(salH\sb2)\sb3tach{\cdot}3.5H\sb2O,\ Fe(salH\sb2)\sb3tach{\cdot}3H\sb2O,\ Al(NO\sb2salH\sb2)\sb3tach{\cdot}EtOH,\ Fe(NO\sb2salH\sb2)\sb3tach{\cdot}EtOH,\ and\ Fe(MeOsalH\sb2)\sb3tach$ complexes have been determined by single crystal X-ray diffraction. The octanol:water partition coefficients and solubilities of the iron complexes are also presented. In live animal studies, the ($\rm NO\sb2salH\sb2)\sb3tach$ derivative was determined to significantly enhance the effect of aluminum on an aspect of blood-brain barrier function. Further in vivo studies were conducted using radioactive $\sp{59}$Fe complexes of the three ligands to determine their tissue distribution and elimination properties. The results presented show that the complexes are metabolized rapidly, yet tissue distribution differs markedly from the control over extended time periods. The potential of the ligands as metal sequestering agents and radiopharmaceuticals is discussed / acase@tulane.edu

Synthetic studies directed toward the preparation of taxol are described in three sections. / The first section describes an intramolecular aldol strategy for the formation of the taxol C ring. A taxane AB ring intermediate having C9 and C10 functionalities was synthesized through a key epoxidation fragmentation reaction and 2,3 dihydrofuryllithium was added to the C3 carbonyl group. After oxidation of C7 and C9, the resulting diketo aldehyde readily cyclized under basic conditions to give the taxane C ring. / The second section describes an intermolecular aldol strategy for the synthesis of an tricyclic intermediate, suitably functionalized for conversion to taxol. The precursor taxane AB ring intermediate was synthesized through the epoxidation fragmentation reaction. An intermolecular aldol condensation established the C7 stereochemistry and introduced the C ring component. A 'Chan' rearrangement was realized by employing lithium tetramethylpiperidide to convert a 3,7-cyclic carbonate to a 2-keto-3-hydroxy lactone. The G3 oxygenation was then removed and the bridgehead carbon C1 was hydroxylated. The benzylidenation of trans-1,2-diols using benzal bromide and silver acetate was explored as a potential method for the protection of the C1, C2 diol functionality of baccatin III derivatives. / Section three describes an attempt to obtain a C ring model from a natural product which could serve to guide the later stages of taxol synthesis. Degradation of 10-deacetyl baccatin III to a 4-keto-1,2-carbonate by opening and cleavage of the D ring is described in attempting to obtain a C ring model for the substrates in the total synthesis route. / This work also describes extensive conformational analysis and reactivity of molecules having the taxane AB ring system. / Source: Dissertation Abstracts International, Volume: 56-01, Section: B, page: 0221. / Major Professor: Robert A. Holton. / Thesis (Ph.D.)--The Florida State University, 1994.