Synthesis, evaluation and mechanistic studies of halogenated psoralen and acridine photosensitizers

A series of psoralen and acridine photosensitizers have been designed and synthesized with the aim to inactivate viruses targeting viral nucleic acids by the production of radical intermediates.; A Stern-Volmer-like mathematical equation for data treatment in determining the binding constants of these DNA-intercalating sensitizers with DNA by ethidium fluorescence displacement method. This new method allows us to measure the binding constants of a DNA intercalator more easily and accurately. The fluorescence of these photosensitizers are quenched efficiently by calf thymus DNA and GMP. The photophysical properties of psoralen derivatives are interpreted in terms of conjugating ability, heavy atom effect, and excited state quenching processes. The existence of linear solvation energy relationships of the maximum wavelength of UV-Vis absorption and fluorescence of 8-methoxypsoralen (8-MOP) with Taft's combined solvatochromic parameters, {dollar}pi*{dollar}+c{dollar}alpha{dollar} support that psoralen compounds both in ground state and in excited state form hydrogen bounds with protic solvent molecules.; Halogenated psoralen and acridine photosensitizers are more effective in photocleaving the supercoiled pBR322 DNA than their non-halogenated counterparts. The DNA photocleavage results of all sensitizers tested are oxygen independent. In the case of psoralen derivatives, DNA unwinding and cleaving processes are successfully differentiated by gel electrophoresis for the first time. In contrast to DNA photocleavage, the viral inactivation of {dollar}lambda{dollar} phage sensitized by acridine derivatives are strongly oxygen dependent. The results demonstrated the difficulty of extrapolating DNA model studies to understanding viral inactivation. On the other hand, the absence of oxygen effect on the results of {dollar}lambda{dollar} phage viral inactivation by psoralen derivatives indicate these sensitizers target viral DNA. Furthermore, several psoralen sensitizers studied demonstrated to be more powerful agents in inactivating {dollar}lambda{dollar} phage than 4{dollar}prime{dollar}-aminomethyl-4,5{dollar}prime{dollar},8-trimethylpsoralen (AMT), the best psoralen photosensitizer reported.; Finally, preliminary mechanistic studies substantiate that psoralen derivatives react upon photolysis with DNA via the hypothesized single electron transfer mechanism. Based on the results obtained in this project, a detailed mechanism for the reaction of psoralen drugs with DNA has been proposed. As a conclusion, DNA strand scission, in addition to photocycloaddition reactions, contributes to the biological effectiveness of psoralen drugs.