Synthesis of Potential Third Generation Photodynamic Therapy Sensitizers for Tumor Treatment.

Photodynamic therapy is an evolving method of cancer treatment for solid malignancies. This form of therapy depends upon the selective retention of systematically administered photosensitizers which accumulate in neoplastic tissues. Tissue destruction occurs as a result of activation of the sensitizer with visible light. The photosensitizers of choice are porphyrins which have uptake characteristics only slightly better in tumor tissues than that of normal tissues. The synthesis and study of a variety of cationic, phthalocyanine complexes (Fig.1) using a combination of organic and organometallic synthetic methods will be undertaken. These novel compounds are of interest for a number of reasons: selective uptake in tumor tissues, enhanced absorption characteristics in the red region of the spectrum where tissue penetration is best, and the ability to fine tune the absorption of these complexes to correlate to the depth of tissue of tumor locations.

Use of Transition Metal Complexes as Prodrugs (Novel dual-action/drug delivery systems)

Prodrug research matured as an offspring of pharmaceutical research during the 1970's. Since then, this approach to optimization of drug delivery has undergone considerable expansion. Prodrugs are defined as "pharmacologically inactive derivatives of a parent drug molecule that requires spontaneous or enzymatic transformation within the body in order to release the active drug, and that has improved delivery properties over the parent drug molecule." Around the same time as the start of development of prodrugs, transition complexes were found to have physiological properties. Probably the best known of these complexes is cisplatin (Fig. 2)

Figure 2. Cisplatin is a known anti tumor agent.

In all cases where transition metal complexes are used as drugs, the systems are designed so that upon ligand dissociation, cleavage or elimination, the metal is delivered as the cytotoxic species. The cytotoxicity of the metal raises the possibility of using transition metal complexes as potential prodrugs in conjunction with known anti cancer compounds. More specifically, by binding a known anti tumor agent as the dissociating ligand, we may have the capability of using a transition metal as a delivery system for anti tumor agents. Another incentive for the development of these types of systems is that upon cleavage of the pharmacologically active ligand, delivery of a cytotoxic metal species also occurs.

This research program will focus on the modification of known anti tumor agents (taxol, vinblastine,........) using organic synthetic methodologies to produce a specific binding site for the transition metal fragment. The synthesis and characterization of the modified organic moieties will be the initial step, the isolation of the transition metal-modified organic moiety complexes will follow, and the final step will be the study of these complexes as novel dual action prodrug systems. This research will involve a variety of disciplines during its course, organic synthesis, organometallic synthesis, analytical, and biological chemistry for the study of the pharmacologically activity of the novel complexes.

Probing the Structure of DNA with Square Planar Organometallic Complexes.

Rational drug design requires an understanding of drug-DNA or drug protein binding at the molecular level. Transition metal complexes are ideally suited for this role because of their spectroscopic "handles" (UV-Vis, NMR and EPR ) which are sensitive to subtle changes in the metal environment. Metal complexes may interact with DNA site specifically via (1) electrostatic interactions, (2) intercalation into the major or minor groove, (3) hydrogen-bonding with the base-pairs. A great deal of effort has focused on DNA modifications and characterization via metal mediated nucleic acid oxidations often utilizing highly reactive metal oxo intermediates.

The preparation of new metal complexes, which will cleave DNA in a highly sequence specific manner, is of interest. The synthesis of cationic, square planar, organometallic complexes of the general structure shown in figure 3 will be undertaken. These species are designed, based on known metal-DNA chemistry, with essential characteristics for this project. The cationic charge and the square planar ligand array should promote electrostatic and intercalative interactions, respectively. The chelating arylamine may be modified with a chiral auxiliary to further facilitate site selectivity. The organometallic ligand provides a highly reactive carbon-based radical, produced upon metal-carbon bond homolysis, to attack proximate nucleic acid residues via hydrogen atom abstraction. Bond homolysis may be triggered electrochemically or more ideally by photolysis.

Figure 3. General structure of Nickel square planar complexes