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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<<trans-BPyB(SPh)P (structures are shown below).Cobalt complexes of the water-soluble porphyrins Tet(MPy)P and Tet(SPh)P have been reported in the literature in the investigation of several chemical and biological systems. However, questions remain in the literature regarding the synthesis and characterization of these compounds, especially concerning the oxidation state of the cobalt. The chemistry related to the synthesis of these complexes is further investigated, and synthetic methods for the specific oxidation states of cobalt are developed. New cobalt (II) and/or (III) complexes of the water-soluble porphyrins T(MPy)PhP,T(MPy)(NPh)P, cis-B(MPy)B(NPh)P, PyT(SPh)P, (APh)T(SPh)P and cis-(NPh)PyB(SPh)P (structures of these free bases are shown above) are synthesized and characterized. The pKa values of the coordinated aquo ligands of four diaquocobalt(III)complexes of water-soluble porphyrins in aqueous solutions are measured using proton NMR spectroscopy. The aggregation of cobalt(II) complexes of water-soluble porphyrinin aqueous solutions is observed by Ill NMR spectra for the first time. The accumulation of the porphyrin free-bases in HT-29 cells has been found to be closely related to the chemical structures, especially to sign, number and distribution of charges. Generally, porphyrins with lower charge accumulate more than ones with higher charge; porphyrins with positive charge accumulate more than those with the same negative charge; and the trans-isomer accumulates more than the cisisomer. The porphyrin free-bases are found to be essentially non-toxic toward Chinese hamster ovary (CHO) cells. The cobalt(III) complexes of cationic porphyrins exhibit some selective toxicity toward hypmdc CHO cells, a property for which the compounds are designed, although the toxicities in hypoxic conditions are too small for use in bioreductive drugs. The porphyrins and metalloporphyrins have not shown high radiosensitization toward CHO cells under hypoxic conditions, and have not shown photosensitization toward HT-29 cells at wavelengths of 630 ± 10 run, although some weak effects are found. More biological studies (e.g., tumor accumulation studies in vivo) are needed before final evaluations of these drugs are made. Potential uses of the synthesized porphyrins in other aspects of cancer treatments and diagnosis should also be considered in future work.

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