Dalla Via Lisa, Marzaro Giovanni, Mazzoli Alessandra, Chilin Adriana, Miolo Giorgia
Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Via Marzolo 5, 35131 Padova, Italy.
Department of Chemistry, University of Perugia, via Elce di Sotto 8, 06123 Perugia, Italy.
Photochem Photobiol Sci. 2015 Nov;14(11):2074-86. doi: 10.1039/c5pp00210a.
Some 4,8-dimethyl-3-psoralenacetic acids were synthesized and studied. All the designed psoralenacetic acids bear alkyl or cycloalkyl substituents at the furan ring. These psoralenacetic acids were shown to be a novel class of psoralen derivatives characterized by an interesting photobiological profile. The carboxylic group at the 3 position, useful to confer hydrophilic properties, appears to be detrimental to the classical intercalation into DNA, likely because of repulsive interactions with the negative surface of the macromolecule. Nevertheless, the new derivatives possess a notable photoantiproliferative activity, due to a peculiar mechanism of action consisting of a decarboxylation step before exerting their photobiological activity. The most active compound 2 is able to induce a noteworthy photocytotoxic effect, with GI50 values being submicromolar on human tumor cell lines and no effect in the dark. The involvement of DNA photoaddition after UVA light-mediated decarboxylation and ROS formation is responsible for its biological activity, as demonstrated comparing the activity profile of the decarboxylated analogue. However, other biological targets seem to be involved in the photooxidative damage, such as proteins. Compound 2 could thus be considered as a prodrug, inactive without UVA light but activated upon specific irradiation, thus preventing unselective side effects and opening new perspectives on agents useful in photochemotherapy.
合成并研究了一些4,8 - 二甲基 - 3 - 补骨脂乙酸。所有设计的补骨脂乙酸在呋喃环上带有烷基或环烷基取代基。这些补骨脂乙酸被证明是一类新型的补骨脂衍生物，具有有趣的光生物学特性。3位的羧基有助于赋予亲水性，但似乎不利于经典的DNA嵌入，可能是由于与大分子负表面的排斥相互作用。然而，新衍生物具有显著的光抗增殖活性，这归因于一种特殊的作用机制，即在发挥光生物学活性之前有一个脱羧步骤。活性最高的化合物2能够诱导显著的光细胞毒性作用，在人肿瘤细胞系上的GI50值为亚微摩尔级别，且在黑暗中无作用。通过比较脱羧类似物的活性谱表明，UVA光介导的脱羧和ROS形成后DNA光加成的参与是其生物活性的原因。然而，其他生物靶点似乎也参与了光氧化损伤，如蛋白质。因此，化合物2可被视为一种前药，在没有UVA光时无活性，但在特定照射下被激活，从而防止非选择性的副作用，并为光化学疗法中有用的药物开辟了新的前景。
