Photochemistry of the Phototoxic Drug Lomefloxacin: Paths Observed in the Presence of Amines or NaOH and from the Methyl Ester

Abstract

The photochemistry of the fluoroquinolone drug lomefloxacin has been examined in aqueous solution in the presence of aliphatic amines (0.01 and 0.2 M) as well as 0.01 M NaOH; a fairly efficient decomposition (Φ = 0.2 to 0.4) takes place. Under the above conditions the product distribution is the same and differs from that previously observed in neutral and acidic aqueous solution. Five products have been characterized, all of them resulting from reductive elimination of the fluorine in the 8‐position and some alteration of the piperazine side‐chain. All of the products are rationalized as resulting from the heterolytic cleavage of the C8−F bond in triplet lomefloxacin to give the corresponding triplet aryl cation. Due to the multiplicity, the C8 site has a carbene rather than a localized cation character. Under these conditions — the amino group in the 4′‐position is free — the main process is formal hydride transfer from the 3′‐position and the minor one attack of the 4′‐amino group at the C6−F bond. In accordance with this rationalization, the methyl ester of lomefloxacin exhibits a closely analogous photochemistry under neutral conditions. The cationic intermediate may be involved in the observed phototoxicity of the drug, via an oxygen‐independent path. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)

Photosensitization Reactions of Fluoroquinolones and Their Biological Consequences

“…This drug is photodegraded in the presence of aliphatic amines via reductive elimination of the fluorine in the 8-position and alteration of the piperazine side-chain. The C8 site has a carbene rather than a localized cation character (73). Again, influence of solvent polarity and proticity on the photochemical properties of NOR suggests that the phototoxicity of this drug and other FQs may strongly depend on its localization in hydrophilic or hydrophobic cell ⁄ tissue regions (74).…”

Pulse radiolysis study on several fluoroquinolones

“…The triplet states of the 6-monofluoroquinoloes defluorinate through a photosubstitution reaction of the fluorine atom by OH À , such as in enoxacin (ENX), norfloxacin (NFX), and ciprofloxacin (CPX) (Fasani et al, 1999a,b;Vermeersch et al, 1991;Mella et al, 2001). The 6,8-difluoroquinolone derivatives are defluorinated at position 8, with the formation of an aryl cation that plays an important role in their phototoxicity (Martinez et al, 1997;Fasani et al 2004;Cuquerella et al, 2006a,b;Fasani et al, 2009). …”

“…Beyond these concerns, from a strictly photochemical point of view, photochemists are interested in the photodefluorination (Fasani et al, 1997;Martinez et al, 1997;Fasani et al, 1999a,b;Albini and Monti, 2003;Cuquerella et al, 2004;Fasani et al 2004;Cuquerella et al, 2006a,b;Fasani et al, 2009) of many FQs, a very uncommon process in a wide area of fluoroaromatic photochemistry, due to the strength of the C-F bond (dissociation energy ca. 533 kJ mol À 1 ).…”

“…In recent years, the photodefluorination of some 6,8-difluoroquinolones derivatives has been studied in detail (Albini and Monti, 2003;Fasani et al 2004;Cuquerella et al, 2006a,b;Fasani et al, 2009). Apart from this reaction, other photochemical properties of FQs, such as decarboxylation, side-chain degradation, the effect of medium, and pH dependence of FQ excited states were also investigated by photochemists, and have also been reported in detail (Albini and Monti, 2003;Bilski et al, 1996;Bilski et al, 1998;Fasani et al, 1998;Sortino et al, 1998;Fasani et al, 1999a,b;Sortino et al, 1999;Bazin et al, 2000;Park et al, 2000;Sortino et al, 2000;Fasani et al, 2001;Monti and Sortino 2002;Park et al, 2002a,b;Viola et al, 2004;Lorenzo et al, 2008a,b;Lorenzo et al, 2009;Ge et al, 2010).…”