Novel Therapeutical Agents against Tumor Angiogenesis: Synthesis of Potential Inhibitors for Thymidine Phosphorylase

The aim of this project is to prepare new substances which inhibit the physiological function of thymidine phosphorylase, this being an enzyme which is responsible for the creation of new blood vessels in cancerous tumor tissue. Employing suitable inhibitors for this enzyme could permit a new form of cancer therapy which is based on "starving out" the targeted tumor. Substances which are found to be particularly effective are those which are similar to the so called "transition state" of the natural substrate for the respective enzymatic process. Consequently, compounds will be sought which structurally mimic the transition state present in thymidine phosphorylase. Such substances cannot be transformed by the enzyme because of slight differences to the natural substrate, this leading to the compound becoming "stuck" in the active site of the enzyme. In this manner, the biological function of the enzyme is retarded (enzyme inhibition). In order to determine which compound can best mimic this transition state or, in other words, is an effective inhibitor, a range of substances will be synthesized which are based on Iminosugars. Iminosugars are carbohydrates where the ring oxygen atom has been replaced by a nitrogen atom. Subsequently, these substances will be tested with respect to inhibitory properties and the most effective of them used for the structural "fine tuning" of "second generation" inhibitors. The efficiency of this approach has already been impressively demonstrated by the preparation of a number of related enzyme transition state inhibitors. The development of effective thymidine phosphorylase inhibitors is a new strategy in cancer therapy. Moreover, the use of increasingly powerful inhibitiors permits the reduction of dose without reducing therapeutic value.