29th Annual Meeting of the American Society of Photobiology

Downtown Marriot

Chicago, Il.

A model for the stereoselectivity of photochemical hydrogen abstraction from lipids by chiral drugs

Abstract-
In previous work, it has been shown that non-steroidal anti-inflammatory 2-arylpropionic acids containing the benzophenone chromophore are able to initiate lipid peroxidation ultimately resulting in cell membrane damage. These drugs contain an asymmetric center in their structure, which could in principle influence photochemical reactions with target biomolecules. Since a certain degree of stereoselectivity in photochemical processes (i. e. electron transfer) has been found in some model systems, phototoxicity might be a stereoselective process. In order to study hydrogen abstraction by excited n,* carbonyl triplets from simple 1,4-dienic systems mimicking polyunsaturated fatty acids, we have prepared model bichromophoric structures coupling (S)-ketoprofen with the pure S and R enantiomers of 1,2-dimethyl-2,5-cyclohexadien-1-methenol, a chiral non-conjugated diene containing double allylic hydrogens. Laser flash photolysis of both samples produced two different transient species assigned to a short-lived biradical (arising after intramolecular hydrogen abstraction) and the corresponding long-lived ketyl radical formed by the intermolecular process. Intramolecular hydrogen abstraction was found to be more efficient in the case of the SR stereoisomer. This observation is consistent with the results obtained upon photolysis of the samples and analysis of the crude irradiation mixture: two cyclic photoproducts were formed upon intramolecular hydrogen abstraction by the benzophenone triplets from the cyclohexadiene moiety followed by radical coupling. It is noteworthy that photodegradation of the SR isomer, and thus intramolecular hydrogen abstraction rate, was faster than that found for the SS isomer. Parallel experiments showed that the intramolecular process is not affected by the presence of oxygen while the intermolecular reaction (using benzophenone and the parent cyclohexadiene derivative) is quenched under the same conditions. These results suggest that lipid peroxidation by chiral drugs might be a stereoselective process.

Keywords: phototoxicity, hydrogen abstraction, ketoprofen