Novel Acenaphtho-heterocycle Compounds-the Relationship Between The DNA Binding Mode And The Antitumor Property

There has been substantial interest in understanding the DNA binding properties of artificial molecules in the hope of developing novel probes of DNA stucture,DNA-cleaving agent and new therapeutic drugs. Especially, the study on the binding topology between the compound and DNA not only be helpful to understand some diseases and the mechanism by which some drugs acts but also play an important role in obtaining novel antitumor lead compounds.From combination of SYBR Green-DNA melt curve, absorption titration, fluoresence titration and circular dichroism studies, the binding of a series of acenaphtho[1,2-b] pyrrole derivatives synthesized by our lab with CT DNA are analysized. Moreover, binding geometry and consequently the antitumor potency, the possible relationship between the binding mode of ligand-DNA and its antitumor property, and pharmaceutical purpose are reaseached. This thesis consists of four sections as follows:(1) Screen the DNA intercalators. Screen the DNA intercalators from the acenaphthene derivatives by means of SYBR Green-DNA melt curve and circular dichroism spectra. Through comparing the structure of the compounds, the funtional groups are analysized.(2) Elucidate the binding geometry of the DNA cleaverâ…¢-1 with DNA. The cleavege abilities are evaluated for the DNA intercalators, the result is found that compoundâ…¢-1 is a dose-dependent cleaver, which can cleave the circluar M13 mpl8 DNA into linear DNA. Then the binding geometry ofâ…¢-1 to CT DNA are researched by molecular spectroscopy, there are two different interaction mechanisms involved in the whole interaction process depending on the n (â…¢-1)/n (CT DNA). The effect of the ionic strength, pH and temperature on the binding mode is studied.(3) Analyze the relationship between the DNA intercalation geometry and the antitumor properties. The binding affinities, intercalation geometries with DNA and antitumor activities for nineâ…¢-1 analogues are investigated in detail. The compounds containing a methylpiperazine substitution (â…§-3) intercalate in a fashion that the long axis of the molecule parallel to the base-pair long axis, while the alkylamine-substituted compounds (â…¢-2,â…¢-3) locate vertically to the long axis of DNA base pairs. Further, cell-based studies show all the compounds exhibit outstanding antitumor activities against two human tumor cell lines with IC₅₀ ranging from 10^-7 to 10^-6 M^-1. Interestingly, compoundâ…§-3 which binding affinity is one of the lowest but alter DNA conformation most significantly, show much lower IC₅₀ value than other compounds. Moreover, it could induce tumor cells apoptosis, while the compoundsâ…¢-2 andâ…¢-3 could only necrotize tumor cells. It can be concluded that the geometry of the acenaphtho[1,2-b] pyrrole derivatives with DNA contribute much more to the antitumor property than binding affinity.(4) Study the interaction of the chromophore with DNA. The important role of the basic substitutions is further illustrated through combining the result of binding mode studies and antitumor studies.