Towards G-quadruplex recognition by porphyrins and porphyrazines
This thesis describes the development and synthesis of porphyrins and porphyrazines, with the potential to bind selectively to G-quadruplex DNA. The original idea was to generate Dynamic Combinatorial Libraries composed of porphyrinic building blocks equipped with thiol groups. Unfortunately, the ma...
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University of Cambridge
2006
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| Online Access: | http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.599484 |
| Summary: | This thesis describes the development and synthesis of porphyrins and porphyrazines, with the potential to bind selectively to G-quadruplex DNA. The original idea was to generate Dynamic Combinatorial Libraries composed of porphyrinic building blocks equipped with thiol groups. Unfortunately, the majority of the porphyrine building blocks that were developed turned out to be insoluble under physiological conditions and hence this approach had to be abandoned. Four pyridinium type porphyrins systematically lacking <i>meso</i> substituents were synthesised and their binding with G-Quadruplex was assessed by Surface Plasmon Resonance. It was concluded that two <i>meso</i> substituents <i>trans</i> orientated to each other were sufficient to give good binding. The same <i>trans</i> porphyrin was shown to be able to select and induce the formation of the anti-parallel G-quadruplex conformation in a K<sup>+</sup> free buffer. The high stoichiometries of bound porphyrin to quadruplex DNA observed in previous experiments led to the development of two cationic strapped porphyrins. One of the molecules did not show any specific binding affinities with the DNA, while the other one was not capable of preventing high binding stoichiometries probably due to self aggregation. The effect of metal centres composed of Zinc(II) and Manganese(III) in the porphyrin core has been also assessed. The binding behaviour of the zinc porphyrins was shown to be similar to the corresponding free bases, while the manganese ones showed a dramatic decrease of their binding abilities. Two known porphyrazines have been discovered to be a new class of strong G-quadruplex binders. They have demonstrated high selectivity towards quadruplex over duplex DNA and the ability to induce the formation of the anti-parallel G-quadruplex conformation in a K<sup>+</sup> free buffer. One of the porphyrazines has been assessed for <i>in vitro </i>cell cytotoxicity presenting very promising results. |
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