Structural studies on antifolate drugs

Single crystal X-ray structure determinations are reported for eleven compounds all of which are either biologically active or potentially biologically important. The compounds fall into two distinct classes:- 1. Substituted diaminopyrimidines 2. Substituted aminopyrimidinones The first class of compounds were all selected on the basis of their common diaminopyrimidine nucleus which has been demonstrated to be a vital requirement for antifolate activity. They may all be described as non-classical or small molecule lipophilic dihydrofolate reductase (DHFR) inhibitors, as opposed to the classical folate analogues, having the ability to cross the blood-brain barrier, enter cells via a rapid passive diffusion process, and achieve high intracellular concentrations. Thus they are an excellent choice in the search for crystallography in the solid state, providing geometrical and distance data not available from any other analytical techniques to date; supporting and enhancing data obtained in the lower resolution studies of protein crystallography. The biological importance of these compounds is discussed and an attempt is made to relate/predict their pharmacological activity to observed structural features in the crystalline environment. Special attention is focussed on hydrogen bonding, confirmational flexibility and hydrophobicity of substituents; each of which appear to make contributions to tight binding in the enzyme active site. Chapter 9 describes the use of data from the literature and the solid state modelling of an observed enzyme-substrate interaction in an attempt to define it more accurately in terms of its geometric flexibility. Of the second class, one compound (ABPP) is reported; studies in two different crystal forms. In demonstrating both antiviral and high interferon inducing activity it is possible that this compound could be useful against cancer and also viral infections.

Thermalized polarization dynamics of a discrete optical-waveguide system with four-wave mixing

Statistical mechanics of two coupled vector fields is studied in the tight-binding model that describes propagation of polarized light in discrete waveguides in the presence of the four-wave mixing. The energy and power conservation laws enable the formulation of the equilibrium properties of the polarization state in terms of the Gibbs measure with positive temperature. The transition line T=∞ is established beyond which the discrete vector solitons are created. Also in the limit of the large nonlinearity an analytical expression for the distribution of Stokes parameters is obtained, which is found to be dependent only on the statistical properties of the initial polarization state and not on the strength of nonlinearity. The evolution of the system to the final equilibrium state is shown to pass through the intermediate stage when the energy exchange between the waveguides is still negligible. The distribution of the Stokes parameters in this regime has a complex multimodal structure strongly dependent on the nonlinear coupling coefficients and the initial conditions.