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UBC Theses and Dissertations

Porphyrin chemistry pertaining to the design of anticancer agents Meng, Grant G.


A limitation of radiotherapy is the lack of selectivity (in term of cell killing) toward tumor cells, especially toward hypoxic tumor cells. Porphyrin drugs used in photodynatnic therapy (PDT) have good selectivity (in term of drug accumulation) toward tumors, but the therapy has a limitation due to poor penetration of light through tissues. The initial objective of this thesis work was to design, synthesize and test for potential porphyrin radiosensitizers with improved tumor selectivity. The rationale was that the radio sensitization abilities of the porphyrins might be improved by introduction of certain functional groups (including nitro groups and metal ions), while retaining or improving (by balancing lipophilicity and hydrophilicity) selective properties of porphyrins. Such a drug would first selectively accumulate in tumors, then sensitize the effects of X-rays, which penetrate tissues well, to kill cells, thus overcoming some of the limitations of both radiotherapy and PDT. If such compounds can be synthesized, they may also be used in other aspects in cancer treatments and diagnosis, including PDT, chemotherapy, boron neutron capture therapy, and magnetic resonance imaging diagnosis. The potential of such compounds to be bioreductive drugs by targeting the hypoxic cells in tumors is also of interest in this project. This thesis work focuses mainly on the synthesis and characterization of some designed porphyrins and metalloporphyrins. Some preliminary in vitro studies of these compounds are also presented. A method of combining pyrrole condensation with aldehydes and subsequent modification is developed and used to synthesize a large variety of porphyrins. Among 40porphyrins synthesized, 22 are new and 15 are water-soluble. A new class of porphyrins with three different meso substituents is synthesized (e.g., cis-(NPh)PyB(SPh)P, the structure of which is shown below). Substituents which are presumed to improve the properties of radiosensitization (NO2), DNA association (NH2, pyridyl), and water-solubility (methylpyridinium and sulfonatophenyl) are introduced into the porphyrin structures. The Ili NMR spectra of these porphyrins are presented with each of the signals assigned. The aggregation of the porphyrin free-bases in aqueous solutions is reported. All the water-soluble porphyrin free-bases aggregate in aqueous solutions, but to different degrees. Different models for the aggregation are suggested, including a new "slide-over" model for the aggregation of trisionic porphyrins. Equilibrium constants (K) for an assumed monomer dimer process for 6 porphyrins have been calculated, and the Kvalues for anionic porphyrins are in the order: Tet(SPh)P < PyT(SPh)P (APh)T(SPh)P

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