Pereira Nelson A M, Laranjo Mafalda, Pina João, Oliveira Andreia S R, Ferreira João Dias, Sánchez-Sánchez Carles, Casalta-Lopes João, Gonçalves Ana Cristina, Sarmento-Ribeiro Ana Bela, Piñeiro Marta, Seixas de Melo J Sérgio, Botelho Maria Filomena, Pinho E Melo Teresa M V D
CQC and Department of Chemistry, University of Coimbra, 3004-535 Coimbra, Portugal.
Biophysics Institute, Faculty of Medicine of University of Coimbra, Azinhaga de Santa Comba, Celas, 3004-548 Coimbra, Portugal; CIMAGO-Center of Investigation in Environment, Genetics and Oncobiology, Faculty of Medicine of University of Coimbra, Azinhaga de Santa Comba, Celas, 3004-548 Coimbra, Portugal; CNC.IBILI Consortium, University of Coimbra, Azinhaga de Santa Comba, Celas, 3004-548 Coimbra, Portugal; iCBR, Coimbra Institute for Clinical and Biomedical Research, Faculty of Medicine, University of Coimbra, Azinhaga de Santa Comba, Celas, 3004-548 Coimbra, Portugal.
Eur J Med Chem. 2018 Feb 25;146:395-408. doi: 10.1016/j.ejmech.2017.12.093. Epub 2018 Jan 4.
The synthesis, photophysical behaviour and photosensitization ability of novel 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-fused 5,15-diphenylchlorins against melanoma cells are described. All studied chlorins were found to be extremely active against melanoma cell lines A375 showing IC values below 20 nM. Furthermore, a dihydroxymethyl diphenylchlorin was identified as an excellent candidate to allow modulating of different types of cell death, apoptosis vs. necrosis, by varying its concentration. This can be explored as a tool to improve the effectiveness of PDT since inflammatory response resulting from necrotic cell death after PDT can activate the antitumor immune response with implications also regarding the vascular damage. This feature combined with very low cytotoxicity against human melanoma cells in the absence of light activation and against human fibroblast HFF-1 cells makes this chlorin a candidate of choice as a photosensitizer for PDT. A comprehensive photophysical investigation including the determination of quantum yields for fluorescence, singlet oxygen sensitization and internal conversion, lifetimes and rate constants of all the excited state deactivation processes has been undertaken.
描述了新型4,5,6,7-四氢吡唑并[1,5-a]吡啶稠合的5,15-二苯基二氢卟吩对黑色素瘤细胞的合成、光物理行为和光敏化能力。发现所有研究的二氢卟吩对黑色素瘤细胞系A375具有极高的活性，其IC值低于20 nM。此外，一种二羟甲基二苯基二氢卟吩被确定为通过改变其浓度来调节不同类型细胞死亡（凋亡与坏死）的极佳候选物。这可作为一种工具来提高光动力疗法（PDT）的有效性，因为PDT后坏死性细胞死亡引起的炎症反应可激活抗肿瘤免疫反应，这也与血管损伤有关。该特性与在无光激活时对人黑色素瘤细胞以及对人成纤维细胞HFF-1细胞的极低细胞毒性相结合，使得这种二氢卟吩成为PDT光敏剂的首选候选物。已经进行了全面的光物理研究，包括测定荧光量子产率、单线态氧敏化和内转换、所有激发态失活过程的寿命和速率常数。
