Novel Acenaphtho-heterocycle And Derivatives: Synthesis, Spectra And Application As DNA-Target Molecules

8-Oxo-8H-acenaphtho[l,2-b]pyrrole-9-carbonitrile, a flat and highly electron-deficient heteroaromatic compound, was used as precursor to synthesize a series of amino, hydroxyl and dodecylsulfanyl mono-substituted derivatives at 3-position through nucleophilic aromatic substitution of hydrogen (NASH) reaction. 6-Amino substituted derivatives were obtained as the isomers of 3-substituted products. It can be concluded from unusual characteristics for NASH reactivity of the precursor that there were two active sites for NASH reaction in one molecule;two hydrogen atoms in one aromatic conjugation system could be replaced simultaneously;NASH reaction with different nucleophiles (nitrogen, hydroxy group, sulfur) could be happened also.8-Oxo-8//-acenaphtho[l,2-b]pyrrole-9-carboxylic acid esters with improved solubility were obtained from 8-oxo-8H-acenaphtho[l,2-b]pyrrole-9-carbonitrile, and the highly electron-deficient feature was kept in these novel precursors. So a series of 3-substituted derivatives of the ester precursors were synthesized by NASH reaction with amines.Compared with that of the carbonitrile precursor with primary amine substituents at 3-position, the maximum wavelength for the derivatives of ester precursors were red-shifted about 17-20 nm and 14-17 nm in UV-Vis absorption and emission spectra, respectively, and fluorescence quantum yields were decreased. There existed significant difference in UV-Vis and emission spectra between the derivatives with 3-alicyclic secondary amine substituents and those with 3-primary amine substituents. The maximum wavelength of UV-vis and the fluorescence quantum yield were mainly depended on the polarity of solvents and a large Stokes shift (60-90 nm) was obtained, which could be attributed to the excited-state intramolecular charge transfer (ICT).Interaction with DNA and antitumor abilities for 8-oxo-8H-acenaphtho[l,2-b]pyrrole-9-carbonitrile(carboxylic acid ester) and their derivatives were evaluated by agarose gel electrophoresis, UV-Vis absorption and fluorescence spectrum, DNA melt curves, circulardichroism (CD) spectroscopy, cytotoxicity experience etc. The results demonstrated that the compounds with N-dialkyl group and N-methyl-piperazinyl side chain could bind strongly with CT DNA and the binding constants are in the order of 105-106. Under the irradiation of long wavelength light (A. > 400 nm), compound 1-1 could be used to cleave Ml3 mpl8 single strand circular DNA by generating singlet oxygen, the lowest effective concentration is 50 uM. There were two different interaction mechanisms (intercalation and stacking on surface) involved in the interaction process of compound 1-1 with CT DNA. The inhibitory test against HeLa, A549 and P388 cell lines in vitro showed that the compounds with N-dialkyl group and N-methyl-piperazinyl side chain exhibited higher activity and the IC50 values are in the range of 10" -10" M. Moreover, those compounds without N-dialkyl group basic side chain showed moderate antitumor activity unexpectedly, especially for compound 1-9 with thiomorpholinyl substituent, the IC50 value against HeLa cell is 1.7><1O"5 M. Isotope incorporation experiment of compound 1-9 showed that it disturbed the synthesis of DNA and RNA.