Departamento de Química/Instituto de Tecnología Química UPV-CSIC, Universitat Politècnica de València, Camino de Vera s/n, 46022, València, Spain.
Unidad Mixta de Investigación UPV-Instituto de Investigación Sanitaria (IIS), La Fe, Hospital Universitari i Politècnic La Fe, Avenida de Fernando Abril Martorell 106, 46026, Valencia, Spain.
Chemistry. 2020 Dec 4;26(68):15922-15930. doi: 10.1002/chem.202001336. Epub 2020 Oct 22.
Lapatinib (LAP) is an anticancer drug, which is metabolized to the N- and O-dealkylated products (N-LAP and O-LAP, respectively). In view of the photosensitizing potential of related drugs, a complete experimental and theoretical study has been performed on LAP, N-LAP and O-LAP, both in solution and upon complexation with human serum albumin (HSA). In organic solvents, coplanar locally excited (LE) emissive states are generated; they rapidly evolve towards twisted intramolecular charge-transfer (ICT) states. By contrast, within HSA only LE states are detected. Accordingly, femtosecond transient absorption reveals a very fast switching (ca. 2 ps) from LE (λ =550 nm) to ICT states (λ =480 nm) in solution, whereas within HSA the LE species become stabilized and live much longer (up to the ns scale). Interestingly, molecular dynamics simulation studies confirm that the coplanar orientation is preferred for LAP (or to a lesser extent N-LAP) within HSA, explaining the experimental results.
拉帕替尼（LAP）是一种抗癌药物，会代谢为 N-去烷基化产物（N-LAP）和 O-去烷基化产物（O-LAP）。鉴于相关药物的光敏潜在性，对 LAP、N-LAP 和 O-LAP 进行了全面的实验和理论研究，包括在溶液中和与人血清白蛋白（HSA）结合时的研究。在有机溶剂中，生成共面局域激发（LE）发射态；它们会迅速向扭曲的分子内电荷转移（ICT）态演变。相比之下，在 HSA 中只检测到 LE 态。因此，飞秒瞬态吸收显示在溶液中，LE（λ=550nm）到 ICT（λ=480nm）的快速转换（约 2ps），而在 HSA 中，LE 物种变得稳定并存在更长时间（高达纳秒级）。有趣的是，分子动力学模拟研究证实，在 HSA 中，LAP（或在较小程度上 N-LAP）优先采用共面取向，这解释了实验结果。
