摘要:

Fluoroquinolones (FQs) are a class of compounds widely used as broad-spectrum antimicrobial agents.1They develop their pharmacological actionviaspecific inhibition of sub-unit A of the bacterial gyrase, an enzyme that controls DNA shape.2In the last few years these molecules have received growing attention from interdisciplinary areas of the scientific community due to both practical purposes and fundamental aspects. Actually, despite the important step forward in infective therapy represented by FQs, a serious drawback for their use is their phototoxic and photocarcinogenic activity.3,4Beyond these concerns, from a strictly photochemical point of view, the interest of photochemists in this class of molecules has been captured by the fact the many of them undergo photodefluorination,5a very uncommon process in the wide arena of fluoroaromatic photochemistry, due to the strength of the C–F bond (dissociation energyca.523 kJ mol−1). In this regard, only rare examples have been reported.6–8The photodefluorination process was suggested to have a decisive role in the entire photosensitization process involving biological substrates.3,5,9,10However, only in recent years have detailed studies addressing the characterization of both stable and transient species involved in the photodegradation of some of these derivatives appeared in the literature.11–19As stated above, FQs inhibit the bacterial gyrase. Although the exact mechanism of this action is still unclear, there is evidence that FQs interact directly with DNA in synergy with the gyrase enzyme.20–22Therefore, DNA is thought to be one of the main cellular targets responsible for the aforementioned drug-photoinduced disorders.The picture emerging from these considerations suggests that in order to gain a deeper and more appropriate understanding of the molecular basis of such adverse reactions photoinduced by FQs, it is of fundamental importance to elucidate the binding features and photochemical behavior of complexes between FQs and DNA. Nevertheless, only a limited number of contributions addressed to this topic have been reported up to now.23Binding efficiency, association mode and photoreactivity of these complexes represent key factors that can play dominant roles in determining both the amount and mechanism of the observed noxious side-photoeffects. With this in mind we have focused our attention on the binding properties of lomefloxacin (LOM) and enoxacin (ENX) to calf thymus DNA (ct-DNA), as well as to the photoreactivity of these FQ-DNA complexes at neutral pH.LOM and ENX are two FQs well known for being able to induce remarkable photocarcinogenic and phototoxic reactions3,4,9,24and are characterized by efficient photodefluorination pathways.11–15LOM is not only much more phototoxic, photomutagenic and photocarcinogenic than other FQs3,4,25,26but also one of the most photodegradable.11–14Although photodefluorination is the sole photoreaction occurring for these two compounds,11LOM and ENX are characterized by different photodefluorination mechanisms. In fact, the loss of fluoride is mediated by a singlet state in the case of LOM whereas a triplet photoreactivity has been ascertained for ENX.13,15Furthermore, recent steady-state and time-resolved spectroscopic investigations have pointed out an unusually active role of the phosphate buffer in modulating both the efficiency and nature of FQ photodecomposition through static and dynamic quenching processes of the lowest excited states.12,19This unexpected role of the inorganic salt spurred us to perform this work at two different phosphate buffer concentrations in order to better correlate DNA affinity and photoreactivity for both FQs.

ISSN:1144-0546    

DOI:10.1039/b107652n

出版商:RSC    

年代:2001

数据来源: RSC