Synthesis And Biological Activity Of The Cationic Porphyrin Derivative With Large Side Arm Substituents

The in vivo formation of G-quadruplex is proposed to be important with in cells.G-rich sequences with a high potential to form G-quadruplexes are found in manyimportant genomic regions. Accurate conformational detection of these genesequences is a prerequisite for elucidating their biological functions. To achieve this, aprobe that specifically recognizes G-quadruplexes in the presence of duplex andsingle-stranded DNAs must be developed. Because the size of the porphyrin core isclose to the G-quartet, porphyrin derivatives are important candidates in G-quadruplexligand studies. Previously discovered5,10,15,20-Tetrakis(N-methylpyridinium-4-yl)-21H,23H-porphyrin (TMPyP4) is a well-known G-quadruplex ligand, and the bindinginteraction between TMPyP4and G-quadruplexes has been extensively studied.However, TMPyP4has almost no selectivity for G-quadruplex against duplex DNA.One reason might be that the four side arm methylpyridine substituents are too smallto effectively prevent the intercalation of TMPyP4with duplex DNA. The recognitioncapability of this porphyrin derivative for G-quadruplexes against duplex DNA andssDNA was studied by CD, UV and fluorescent spectra. The study shows that the newcationic porphyrin derivative with large side arm substituents would be as a highlyspecific optical probe for recognizing G-quadruplexes.The following aspects were included in this thesis:1.5,10,15,20-tetra-{4-[2-(1-piperidinyl)ethoxy]phenyl} porphyrin and Thecationic porphyrin5,10,15,20-tetra-{4-[2-(1-methyl-1-piperidinyl)ethoxy]phenyl}porphyrin were designed and synthesized as new porphyrin derivative. The conditionsof the synthesis and purifications of these compounds are studied in the thesis and thestructures are identified by IR, NMR and MS, etc..2. UV-Vis absorption and fluorescence spectroscopic analysis showed thatTMPipEOPP displayed distinctively different spectroscopic characters in the presenceof G-quadruplex DNAs compared to in the presence of duplex or single-strandedDNAs, indicating that TMPipEOPP can discriminate G-quadruplex from duplex andsingle-stranded DNA obviously. Visual discrimination is also possible. SoTMPipEOPP could be developed into a highly specific G-quadruplex optical probe.and have better G-quadruplex recognizing ability than TMPyP4. 3. Job plot and Scatchard analysis suggest that a complicated bindinginteraction occurs between TMPipEOPP and G-quadruplexes. At low[G-quadruplex]/[TMPipEOPP] ratios, one G-quadruplex binds to two TMPipEOPPmolecules. One TMPipEOPP molecule stacks at one end of the G-quadruplex and theother interacts with the quadruplex through an outside-binding mode. At high[G-quadruplex]/[TMPipEOPP] ratios, two G-quadruplexes bind to one TMPipEOPPmolecule, with the TMPipEOPP molecule stacking between the ends of twoG-quadruplexes.