A molecular insight into the phototoxic reactions observed with vemurafenib, a first-line drug against metastatic melanoma

作者：Morliere P^*; Bosca F; Silva A M S; Teixeira A; Galmiche A; Maziere J C; Nourry V; Ferreira J; Santus R; Filipe P

来源：Photochemical and Photobiological Sciences, 2015, 14(11): 2119-2127.

DOI：10.1039/c5pp00231a

The electronic properties of vemurafenib (VB) provide a rational basis for understanding its strong UVA-induced phototoxicity. Thus, solvation of hydrophobic VB by hydrogen bonding solvents controls its photophysical, photochemical and photosensitizing properties. Addition of phosphate buffered saline (PBS) to methanol (MeOH) induces a bathochromic shift of the VB absorbance spectrum and a fluorescence emission (lambda(max) = 450 nm, quantum yield (phi) = 0.011). Phosphorescence (lambda(max) = 461 nm) is observed at 77 K in MeOH. 308 nm laser flash spectroscopy demonstrates that the lifetimes (tau) and quantum yields of the VB triplet state (T-3(1)*) in deaerated MeOH (tau(MeOH) = 0.41 mu s, lambda(max) similar to 380 nm), MeOH-PBS and HSA solutions markedly depend on the microenvironment. A long-lived radical (half-life > 200 mu s) is also formed. The T-3(1)* state is quenched by O-2 and electron donors (Cys and 2'-deoxyguanosine) at a rate constant > 1 x 10(9) M-1 s(-1). UVA-irradiation of VB in air-saturated MeOH or MeOH-PBS solutions produces a UVA-absorbing photoproduct (phi similar to 5 x 10(-4)). VB photosensitizes Trp destruction by type I (radical formation) and type II (singlet oxygen (O-1(2)) formation) photodynamic reactions (phi = 0.005). Singlet oxygen production is further demonstrated by the VB-photosensitized His oxidation (phi(MeOH) = 0.006).

• 出版日期2015