Photoprocesses of the tyrosine kinase inhibitor gefitinib: from femtoseconds to microseconds and from solution to cells

Abstract

Gefitinib (GFT) is a tyrosine kinase inhibitor currently used for the treatment of metastatic non-small cell lung cancer. Although it has been suggested that GFT can be phototoxic, there are...

Switching from ultrafast electron transfer to proton transfer in excited drug–protein complexes upon biotransformation

“…In fact, this was previously observed for 1 GFT* in toluene in the presence of increasing amounts of 3methylindole, the chromophore of the Trp residue; a k Q value of ~4.3×10 10 M -1 s -1 was determined. 12 A similar result has also been obtained here using NAc-TyrMe (Fig. S4A), with a quenching rate constant of ca.…”

“…In view of the photosensitizing potential recently demonstrated for GFT, 12 which is assumed to arise from the excited species formed upon interaction with UVA light, it seemed relevant to study the photophysical properties of GFT-MB, since this metabolite maintains the quinazoline moiety and is structurally similar to the parent drug. To this end, the species formed after excitation of GFT-MB with UVA light were first explored in organic solvents of different polarities by means of fluorescence and ultrafast transient absorption spectroscopies.…”

“…The photophysical properties of GFT interacting with HSA have been recently investigated. 12 In this case, emission from LE singlet states (LE 1 GFT*) with λ max ~390 nm is predominantly observed. However, the photobehavior of GFT-MB bound to HSA remains unexplored.…”

“…In this context, and as stated above, photoinduced electron transfer from electron donors (Tyr and/or Trp) to the excited drug might occur in GFT@HSA, which explains its low fluorescence yield. 12 By contrast, since the metabolite is a phenol, although electron transfer might also occur, as it has been observed for GFT-MB/Tyr (or Trp) mixtures in organic solvent, excited state proton transfer (ESPT) to form phenolatelike excited species might be a competitive process within the protein; these species are known to absorb and emit at wavelengths longer than phenols. [44][45][46] In this regard, not only emission from GFT-MB@HSA was shifted to longer wavelengths, but also its absorption spectrum revealed a redshifted shoulder at ca.…”

“…Actually, LE species have been proposed to be responsible for the photoinduced biological damage mediated by GFT, LAP and its metabolite N-LAP. 12,15 With this background, the aim of the present work is to compare the photobehavior of GFT with that of GFT-MB in solution and in the presence of human serum albumin (HSA) 18 using fluorescence and transient absorption spectroscopies, from the femtosecond to the microsecond time-scales. Besides, molecular dynamics (MD) simulations have been used to investigate in atomic detail the binding of this drug and its metabolite to the protein, in order to achieve a better understanding of the experimental results.…”