Reaction Dynamics of Excited 2-(3-Benzoylphenyl)propionic Acid (Ketoprofen) with Histidine

Abstract

Photoreaction dynamics of 2-(3-benzoylphenyl)propionic acid (ketoprofen, KP), one of nonsteroidal anti-inflammatory drugs, with histidine in a phosphate buffer solution (pH 7.4) was investigated with the laser flash photolysis. The deprotonated form of KP (KP(-)) was decarboxylated via UV laser excitation to form a carbanion. It was found that histidine accelerates the protonation reaction of the carbanion to 3-ethylbenzophenone ketyl biradical (3-EBPH) for the first time. The experimental results of the photoreaction of KP with alanine as well as the photoreaction of KP with 4-methylimidazole (a part of the side chain of histidine) in methanol, clearly showed that the protonated form of histidine is a key species for the protonation reaction of the carbanion. These series of the initial reactions should result in the occurrence of photosensitization in vivo. The reaction mechanism was discussed in detail.

Photoreaction of Ketoprofen with Tryptophan and Tyrosine in Phosphate Buffer Solution

“…In the phosphate buffer solution of pH 7.4, almost all KP exists in the deprotonated form of KP (KP − ) because of its acidity (p K a = 4.7). According to the previous report , an intense band around 600 nm appearing immediately after the laser irradiation was due to KP carbanion, and the band around 525 nm at 1.7 μs after the laser was assigned to EBPH. The same spectra were obtained with Tyr.…”

“… *Reference ; †For amino acids and dipeptides, correction of the concentration should be required because actual quencher for carbanion was the protonated form to the side chain of basic amino acids and dipeptides ; ‡Reference ; §Reference ; ∥Reference ; ¶This work. …”

“…Several proton‐donating sites for these compounds are considered. As for basic amino acids and dipeptides including a histidine moiety in the phosphate buffer solution at pH 7.4, the protonated side chain is the donating site not the protonated N ‐terminal because alanine and glycine have no effect on the lifetime of the carbanion . Therefore, on phenol compounds such as Tyr, DOPA, 4‐MP, the phenolic OH group is concluded to be the proton‐donating site.…”

“…An experimental setup of the transient absorption spectrum measurement has been reported elsewhere . Briefly, a XeCl excimer laser (Lamda Physik COMPex 102; 308 nm, 200 mJ, 20 ns pulse duration) was used as an excitation light and a Xe flash lamp (Ushio UXL‒300DO; 300 W) was used as a monitoring light source.…”

Effect of Basic Amino Acids on Photoreaction of Ketoprofen in Phosphate Buffer Solution

“…In previous articles, we examined photoreaction of KP with triethylamine in methanol (18) and histidine (His) in phosphate buffer solution (Fig. 2; 19). It was found that the lifetime of carbanion became shorter and the yield of EBPH larger under the presence of His for the first time.…”