Modeling the photochemistry of the reference phototoxic drug lomefloxacin by steady-state and time-resolved experiments, and DFT and post-HF calculations.
The irradiation in water of 1-ethyl-6,8-difluoro-7(3-methylpiperazino)3-quinolone-2-carboxylic acid (lomefloxacin), a bactericidal agent whose use is limited by its serious phototoxicity (and photomutagenicity in the mouse), leads to formation of the aryl cation in position eight that inserts into the 1-ethyl chain. Trapping of the cation was examined and it was found that chloride and bromide straightforwardly add in position eight, but with iodide and with pyrrole the 1-(2-iodoethyl) and the 1-[2-(2-pyrrolyl)ethyl] derivatives are formed. Flash photolysis reveals the triplet of lomefloxacin, a short-lived species (lambda max=370 nm, tau=40 ns) that generates the triplet cation (lambda max=480 nm, tau approximately 120 ns). The last intermediate is quenched both by halides and by pyrrole. DFT and post-HF methods have shown that the triplet is the lowest state of the cation (Delta G(ST)=13.3 kcal mol(-1)) and intersystem crossing (ISC) to the singlet has no role because a less endothermic process occurs, that is, intramolecular hydrogen abstraction from the N-ethyl chain (9.2 kcal mol(-1)) that finally leads to cyclization. The halides form weak complexes with the triplet cation (kq from 4.9 x 10(8) for Cl(-) to 7.0 x 10(9) m(-1) s(-1) for I-). With Cl(-) and Br(-) ISC occurs in the complex along with C8--X bond formation. However, this latter process is slow with bulky iodide and with neutral pyrrole, and in these cases moderately endothermic electron transfer (ca. 7 kcal mol(-1)) yielding the 8-quinolinyl radical occurs. Hydrogen exchange leads to a new radical on the 1-ethyl chain and to the observed products. These findings suggest that the mutagenic activity of the DNA-intercalated drug involves attack of the photogenerated cation to the heterocyclic bases.
Freccero
Mauro
M
Department of Organic Chemistry, University of Pavia, Via Taramelli 10, 27100 Pavia, Italy. mauro.freccero@unipv.it
Fasani
Elisa
E
Mella
Mariella
M
Manet
Ilse
I
Monti
Sandra
S
Albini
Angelo
A
D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000528:radiation effects; D003198:Computer Simulation; D017484:Dermatitis, Phototoxic; D024841:Fluoroquinolones / Q000737:chemistry* / Q000528:radiation effects*; D008956:Models, Chemical; D008958:Models, Molecular; D015394:Molecular Structure; D009153:Mutagens / Q000737:chemistry / Q000528:radiation effects; D010777:Photochemistry; D011789:Quantum Theory; D014466:Ultraviolet Rays
D000900:Anti-Bacterial Agents; D024841:Fluoroquinolones; D009153:Mutagens; C053091:lomefloxacin