Tamarit Lorena, El Ouardi Meryem, Lence Emilio, Andreu Inmaculada, González-Bello Concepción, Vayá Ignacio, Miranda Miguel A
Departamento de Química/Instituto de Tecnología Química UPV-CSIC, Universitat Politècnica de València Camino de Vera s/n 46022 València Spain
Instituto de Investigación Sanitaria La Fe, Hospital Universitari i Politècnic La Fe Avenida de Fernando Abril Martorell 106 46026 Valencia Spain.
Chem Sci. 2022 Aug 2;13(33):9644-9654. doi: 10.1039/d2sc03257k. eCollection 2022 Aug 24.
Photosensitization by drugs is directly related with the excited species and the photoinduced processes arising from interaction with UVA light. In this context, the ability of gefitinib (GFT), a tyrosine kinase inhibitor (TKI) used for the treatment of a variety of cancers, to induce phototoxicity and photooxidation of proteins has recently been demonstrated. In principle, photodamage can be generated not only by a given drug but also by its photoactive metabolites that maintain the relevant chromophore. In the present work, a complete study of -desmorpholinopropyl gefitinib (GFT-MB) has been performed by means of fluorescence and ultrafast transient absorption spectroscopies, in addition to molecular dynamics (MD) simulations. The photobehavior of the GFT-MB metabolite in solution is similar to that of GFT. However, when the drug or its metabolite are in a constrained environment, . within a protein, their behavior and the photoinduced processes that arise from their interaction with UVA light are completely different. For GFT in complex with human serum albumin (HSA), locally excited (LE) singlet states are mainly formed; these species undergo photoinduced electron transfer with Tyr and Trp. By contrast, since GFT-MB is a phenol, excited state proton transfer (ESPT) to form phenolate-like excited species might become an alternative deactivation pathway. As a matter of fact, the protein-bound metabolite exhibits higher fluorescence yields and longer emission wavelengths and lifetimes than GFT@HSA. Ultrafast transient absorption measurements support direct ESPT deprotonation of LE states (rather than ICT), to form phenolate-like species. This is explained by MD simulations, which reveal a close interaction between the phenolic OH group of GFT-MB and Val116 within site 3 (subdomain IB) of HSA. The reported findings are relevant to understand the photosensitizing properties of TKIs and the role of biotransformation in this type of adverse side effects.
药物的光敏化与激发态物种以及与UVA光相互作用产生的光诱导过程直接相关。在这种情况下，吉非替尼（GFT）是一种用于治疗多种癌症的酪氨酸激酶抑制剂（TKI），其诱导蛋白质光毒性和光氧化的能力最近已得到证实。原则上，光损伤不仅可以由特定药物产生，还可以由保持相关发色团的光活性代谢物产生。在本工作中，除了分子动力学（MD）模拟外，还通过荧光和超快瞬态吸收光谱对去吗啉代丙基吉非替尼（GFT-MB）进行了全面研究。GFT-MB代谢物在溶液中的光行为与GFT相似。然而，当药物或其代谢物处于受限环境中时，即在蛋白质内部，它们的行为以及与UVA光相互作用产生的光诱导过程则完全不同。对于与人类血清白蛋白（HSA）结合的GFT，主要形成局部激发（LE）单重态；这些物种与酪氨酸和色氨酸发生光诱导电子转移。相比之下，由于GFT-MB是一种酚类，激发态质子转移（ESPT）形成酚盐样激发物种可能成为另一种失活途径。事实上，与蛋白质结合的代谢物比GFT@HSA表现出更高的荧光产率、更长的发射波长和寿命。超快瞬态吸收测量支持LE态的直接ESPT去质子化（而非ICT），以形成酚盐样物种。MD模拟对此进行了解释，其揭示了GFT-MB的酚羟基与HSA第3位点（亚结构域IB）内的Val116之间的紧密相互作用。所报道的发现对于理解TKIs的光敏特性以及生物转化在这类不良副作用中的作用具有重要意义。
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