New 6-sub-2,3-naphthalimides: Design, Synthesis, Photophysics And Biological Evaluation

The main goal of this dissertation is to contribute to the design, synthesis, photophysics and biological Evaluation of new 6-substituted 2,3-naphthalimides. This dissertation comprises of two main projects. The first project was intended to develop a new highly efficient and regio selective synthetic route for the key cyclic anhydride intermediate of 2,3-naphthalimide derivatives was presented, which is the precursor of the famous environment-sensitive fluorophore [6-N,N-Dimethylnaphthalimides(6-DMN)] and other 6-substituted naphthalimides. Starting from commercially available O-xylene, the three-step synthesis features a through process without purification of intermediates until isolation of 6-DMN precursor. The robust, chromatography-free and reproducible synthesis of precursor achieved a 54% overall yield from O-xylene. This highly efficient process was successfully completed on the gram scale in 3 days for the 6-DMN precursor.In the second project, we focused on applications of above synthesized molecules in several ways. Four new series of 6-substituted 2,3-naphthalimides have been designed and synthesized. Based on 6-Amino 2,3-naphthalimide (6-ANP) compounds, a new type of fluorophore was found to exhibit moderate to unusual large Stokes shift (297-303 nm).6-ANP derivatives display relatively low fluorescence quantum yields in high polar protic solvents such as water (ΦF～0.004,571-576 nm) and a significant unusual red shift was mainly due to (1) hydrogen bonding interaction of the excited state of the molecule with the solvents, which presumably enhance the intersystem crossing process in the system to quench fluorescence, (2) this large Stokes shift was assumed to be the consequence of a substantial change of the geometric structure from the ground state (S0) to the first excited state (S1). Compared with the other compounds studied, the fluorescence of the nitro and halo-derivatives were rather weak, probably due to the efficient intersystem crossing leading to a non-radiating triplet state.A series of 16 derivatives of 2-hydroxy-6-sub 2,3-naphthalimides was designed and efficiently synthesized as potential antitumor agents through formation of new key intermediate (6-nitro-2,3-naphthalicanhydride). All target molecules maintained hydroxyurea functional group.The cytostatic activity of these compounds was studied against A-549, HL-60, PC-3, P-388, Hela and L-1210 cell lines, and their IC50 values were found to be in the range of 10-4 to 10-6 M. The derivatives having a substitute with strong electron-donating properties at the 6-position showed enhanced inhibitory activity while compounds having an electron-withdrawing group at the same position showed lower activity. DNA binding studies showed that these derivatives behaved as DNA intercalating agents. The present work demonstrated that assembling the biological active unit of 6-sub-2,3-naphthalimides might be able to result in a novel class of lead compounds with potential antitumor activities.