Primary photoprocesses of light-activated antiviral and antitumor agents, hypericin and hypocrellin

Date
1999
Authors
Smirnov, Alexandre
Major Professor
Advisor
Jacob W. Petrich
Committee Member
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Chemistry
Abstract

The dissertation focuses on the ultrafast primary photoprocesses of the title anti-viral and anti-cancer agents, whose activity depends on light which is also accompanied by photoacidification in vesicles and living cells;By complementing the techniques of time-resolved absorption spectroscopy with those of fluorescence upconversion and applying them to hypericin, hypocrellin A and B, and their methylated analogs that are unable to execute proton transfer, it was demonstrated that intramolecular excited-state hydrogen atom transfer is a dominant primary nonradiative process;For hypocrellin A in viscous solvents such as octanol and ethylene glycol, an absorption transient of ∼10-ps duration, similar to the hypericin transient, can be detected together with another, much longer lived transient component (evident in only in pump/probe absorption spectroscopy). This long-lived 50--230 ps component exhibits a deuterium isotope effect and a strong solvent bulk viscosity dependence. Such behavior is rationalized by postulating that the excited-state tautomerization pathway, besides the proton stretch, involves at least one other reaction coordinate such as molecular skeletal motion or even conformational change. Temperature-dependant 1H-NMR and 2D ROESY studies of hypericin and hypocrellins provide strong evidence that there is only one conformational isomer/tautomer for hypericin in the ground state. On the other hand, web found three significantly populated ground-state species for hypocrellin A. These species where identified and their relative energies and interconversion barriers were determined through dynamic NMR simulations. Hypocrellin B, like hypericin, was found to be essentially homogeneous in the ground state. This is attributed to the rigidity of its structure caused by the presence of a double bond in its seven-membered ring;Time-resolved fluorescence and absorption measurements of hypericin complexed with human serum albumin (HSA) indicate that hypericin very rigidly binds to HSA by means of a specific hydrogen bonded interaction between its carbonyl oxygen and the N1-H of the tryptophan residue in the II A subdomain of HSA;Finally, the issue of absorption and emission "mirror-image" symmetry in the title polycyclic quinones, which was the key point of criticisms toward the very existence of excited-state proton transfer, is effectively addresses by appealing to the high symmetry of the aromatic core.

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