Development of Porphyrin as a Molecular Cutter of Genes

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In this project, we designed and synthesized novel water-soluble poiphyrins based on our previous research, and intended to develop DNA-cleaving reagent specific to base sequences, through the measurement of DNA-cleaving activity against DNA having various base sequences. The activity was found to be greatly enhanced by zinc insertion into the porphyrin core, and the effect of copper insertion was also examined. The binding property of copper porphyrin with DNA was examined by absorption and resonance Raman spectroscopic technique, and the self stacking of porphyrin was found to be enhanced by the flattening of the porphyrin macrocycle. This in mind, the porphyrin was applied to the inhibition of telomerase activity, expecting to be an anti-cancer drug. Human telomere is composed of thousands of repeats of TTAGGG sequence, and quadruplex structure is produced. The binding property of the copper porphyrin with this sequence was examined, and the external stacking of the porphyrin was suggested. The copper porphyrin greatly stabilized the quadruplex structure, and the inhibition of telomerase activity was strongly suggested. We further synthesized several kinds of porphyrins having long cationic peripheries on the macrocycle. These poiphyrins stabilized the quadruplex similarly, and therefore the cationic groups were supposed to contribute greatly in the binding. In conclusion, we could synthesize porphyrin drugs which bind specifically to a sequence-dependent DNA structure, recognize the structure, and bind selectively.