Dissertation > Industrial Technology > Chemical Industry > Pharmaceutical chemical industry > General issues > Basic theory

Novel Imidazophenanthroline Derivatives: Design, Synthesis and Evaluation of Biological Activity

Author WangJunHong
Tutor WeiChunYing
School Shanxi University
Course Inorganic Chemistry
Keywords DNA Phenanthroline Antitumor drug Biological activity
CLC TQ460.1
Type Master's thesis
Year 2011
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DNA is the germ plasm of the organism, not only involved in biological activities of life, but also closely related with the tumor and hereditary diseases. In clinic, anticancer drugs destroy the structure of DNA in cancer cells, which will affect the replication and transcription of DNA and further inhibit the proliferation of cancer cells. Therefore, the design of anticancer drugs targeting DNA has drawn lots of attention presently.1,10-phenanthroline and its derivatives have remarkably biological activity. In this paper, we designed and synthesized four novel 2-(4-hydroxyphenyl) imidazo [4,5-f] 1,10-phenanthroline derivatives, and studied their in vitro antitumor activity and interactions with DNAs, and the specific results are as follows:The effect of the compounds on cancer cell viability was firstly studied by MTT assay. The results indicated that the four compounds can significantly inhibit the proliferation of HeLa and HepG2 cells, and the IC50 values are about 10-6M for HeLa and 10-5M for HepG2 cells. The results of flow cytometry test showed that the four compounds can affect the cell cycle of HeLa and HepG2 and lead to cell apoptosis.The interactions of the four compounds with DNA were studied by UV, fluorescence and CD spectroscopies. The results of UV and fluorescence spectra indicated that all compounds may interact with human telomeric G-quadruplex DNA(HTG), triplex DNA(d(T21)2/dA21) and the duplex calf thymus DNA(CT-DNA) by the intercalative mode, although there is no significant interacting with i-motif DNA. The results of CD spectra showed that the four compounds have a small perturbation on the conformation of HTG in the presence of either Na+ or K+. All compounds stabilize the base-stacking interaction of CT-DNA, but the intensity of the right-handed helicity band is decreased, suggesting the possible structural and conformational changes of CT-DNA upon interaction with compounds. FRET-melting and competitive FRET-melting assays showed that, in addition to compound D, the others can stabilize the structure of human telomeric G-quadruplex and bind G-quadruplex selectivity over duplex even at levels of 10-fold excess of duplex DNA in the presence of Na+. But in the presence of K+, all compounds can stabilize the structure of human telomeric G-quadruplex, and the ability of stablizing G-quadruplex is greater in K+ than that in Na+. However, TRAP assay indicated that the four compounds can not significantly inhibit the telomerase activity when their concentrations are less than 50μM. DNA Topo I inhibitory assay showed that the four compounds can not inhibit Topo I activity, but also not induce the structure change of plasmid DNA.

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