DNA Targeted Heterocycle-fused Naphthalene Derivatives: Design, Synthesis And Biological Evaluation

Series of DNA targeted antitumor prodrugs consist of flat,rigid and large conjugated aromatic structure were synthesized and characterized.Also novel thio-heterocyclic compounds with N-oxide were primarily synthesized.11 new derivatives of Benzo[c,d]indol-2(H)-one have been synthesized,while whose solid geometric optimization have been calculated and relegated at 6-31G basis set level with the method of B3LYP of density functional theory.Their DNA bonding properties were evaluated through UV-Vis spectra,Fluorescence spectra and CD spectra combined with viscosity measurement.The result showed that this 11 compounds can efficiently intercalate base pairs of CT DNA,while AC3's bonding constant is K_b=1.65×10⁵mol^-1·L.DNA photo-damaging assay were taken with pBR322 plasmid.All the compounds are efficient to cleave super-coiled DNA,while AC1-6 can photo-cleave super-coiled DNA into linear fragments.The results of cleavage assays under different conditions indicate that the mechanism of the cleavage is hydrolyzation.The inhibitory test against 7721,MCF-7,Hela and BGC-823 cell lines in vitro showed that this compounds exhibited high antitumor activities, IC₅₀ value of compound AC6 against MCF-7 cell reached 3nM.9H-thioxanthen-9-one derivatives S1-S5 have been designed and synthesized,whose structure were validated by ¹HNMR,TOF MS,IR.They have larger plane structure and import more effective atom S.Their spectra properties,DNA intercalative,DNA photo-damaging and antitumor activities were evaluated.UV and CD titration illustrated their strong interaction with calf thymus DNA.Through the tendency we claim the bonding mode is partial intercalation. Agarose gel electrophoresis experiment proved their high photo-cleave efficacy against pBR322 plasmid DNA.The antitumor activities test of these compounds exhibited efficient activities against 7721,MCF-7,Hela and BGC-823 cell lines.IC₅₀ of compound S5 against Hela cell reached 10^-8M.Series of novel precursor characterized N-oxide structure and hetero-aromatic system were designed and synthesized,which could be developed into new-style bioreductive cytotoxin against tumor.For the key step of the synthesis has many by-reactions which induces complexity of the products,we studied the relevant mechanisms and optimized the reaction conditions in order to improve the conversion rate.