Synthesis And Biological Activity Of Cationic Porphyrins Targeting G-quadruplex DNA

Telomerase is active in 85-90% of cancer cells, but not in most normal somatic cells. Therefore, telomerase may be a significant component for the cancer cells forming and becomes a new target of the caner treatment. In the presence of cations such as K+,Na+, the 3' single-stranded end of telomeric DNA can fold into a G-quadruplex DNA structure, inhibiting the activity of telomerase and inducing that the cells enter a replicative senescence state. Small molecules that target G-quadruplex DNA have become potential telomerase inhibitors and been a hot research topic. Some of them can induce and stabilize the G-quadruplex DNA structure, providing a new and broad treatment for cancer.Cationic porphyrins have a size similar to that of the G-tetrad and become one of the most potential inhibitors. In this thesis, four cationic porphyrins A, B, C, D were synthesized. Using UV/vis absorption, fluorescence and circular dichroism (CD) spectroscopy, we studied the interaction between the porphyrins and G-quadruplex DNA in K+-containing solution. The results showed that:1. After interacting with G-quadruplex DNA in the normal titration method, all of the porphyrins showed that the redshift was less than 8 nm and the hypochromicity (△H) was between 10% and 35%. The interaction rations of porphyrins to DNA(r) were 1:1 according to the fluorescence spectroscopy. The CD spectroscopy reflected that the structure of G-quadruplex DNA did not change during the measurement. Referencing the whole spectroscopy, the mode of outside binding was conjectured between the porphyrins and G-quadruplex DNA.2. The melting temperature (Tm) of compound A was measured to evaluate it stability with G-quadruplex DNA. At 293nm and r=1, the Tm value of DNA was increased by 12.11℃. However, at 265nm, we detected that the parallel structure was formed firstly, and then infolded.3. When annealing the quadruplex DNA in the presence of the porphyrins, the CD spectra suggested that the porphyrin can shift antiparallel quadruplex structure towards a parallel quadruplex structure. According to the induce CD spectra, the mode of end-stacking binding was conjectured between the porphyrins and G-quadruplex DNA. In a word, all of the four porphyrins can intereact with G-quadruplex DNA. Eespecially compound A may have potential stability with G-quadruplex DNA.