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In Vitro Photodynamic Activity of N‐Methylated and N‐Oxidised Tripyridyl Porphyrins with Long Alkyl Chains and Their Inhibitory Activity in Sphingolipid Metabolism
ChemMedChem ( IF 3.6 ) Pub Date : 2018-01-30 , DOI: 10.1002/cmdc.201700748 Mateo Jelovica 1 , Petra Grbčić 2 , Martina Mušković 1 , Mirela Sedić 2 , Sandra Kraljević Pavelić 2 , Martin Lončarić 3 , Nela Malatesti 1
ChemMedChem ( IF 3.6 ) Pub Date : 2018-01-30 , DOI: 10.1002/cmdc.201700748 Mateo Jelovica 1 , Petra Grbčić 2 , Martina Mušković 1 , Mirela Sedić 2 , Sandra Kraljević Pavelić 2 , Martin Lončarić 3 , Nela Malatesti 1
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A series of N‐methylated and N‐oxidised tripyridyl porphyrins were synthesised, characterised, and their PDT activity was studied with six cell lines. All the tested porphyrins with a long alkyl chain, except one, were more efficient for PDT than an N‐methylated hydrophilic porphyrin and N‐oxidised porphyrin without the long alkyl chain. Generally, N‐methylated tripyridyl porphyrins were more active than those N‐oxidised, but IC50 values for phototoxicity of two N‐oxides, named TOPyP3‐C17H33O and TOPyP3‐C17H35, were still in the nanomolar concentration range for most of the tested cell lines. However, TOPyP3‐C17H35 did not show phototoxicity on human foreskin fibroblast cells. Two methylated amphiphilic porphyrins, named TMPyP3‐C17H33 and TMPyP4‐C17H35, showed significant dark toxicity, whereas none of the oxidopyridyl porphyrins were toxic without light activation. The selected photosensitisers were shown to be apoptosis inducers, and had inhibitory effects on the clonogenic growth of HCT116 and HeLa cells. All three N‐methylated amphiphilic porphyrins significantly reduced the migratory potential of HCT116 cells. Porphyrins TMPyP3‐C17H35 and TOPyP3‐C17H35 reduced the activity of acid ceramidase, whereas TOPyP3‐C17H33O had a significant inhibitory effect on sphingosine kinase 1 activity in HeLa cells. Compounds with this dual activity were shown to be the most promising photosensitisers, with potential to treat invasive cancers.
中文翻译：
具有长烷基链的N-甲基化和N-氧化的三吡啶基卟啉的体外光动力学活性及其对鞘脂代谢的抑制活性
合成，表征了一系列N-甲基化和N-氧化的三吡啶基卟啉，并用6个细胞系研究了它们的PDT活性。除一个长链外，所有测试的具有长烷基链的卟啉均比无长烷基链的N-甲基化亲水性卟啉和N-氧化卟啉对PDT更有效。通常，N甲基化的三吡啶基卟啉比N氧化的更具活性，但两种N氧化物的光毒性的IC 50值TOPyP3-C 17 H 33 O和TOPyP3-C 17 H 35仍处于纳摩尔浓度。大多数测试细胞系的范围。但是，TOPyP3-C 17H 35对人包皮成纤维细胞没有光毒性。两种甲基化的两性卟啉分别命名为TMPyP3-C 17 H 33和TMPyP4-C 17 H 35，显示出明显的暗毒性，而没有经过光活化的氧化吡啶基卟啉均无毒。所选的光敏剂显示为凋亡诱导剂，并且对HCT116和HeLa细胞的克隆形成生长具有抑制作用。所有三种N-甲基化的两性卟啉均显着降低了HCT116细胞的迁移潜能。卟啉TMPyP3-C 17 H 35和TOPyP3-C 17 H 35降低了酸性神经酰胺酶的活性，而TOPyP3-C 17 H 33 O对HeLa细胞中的鞘氨醇激酶1活性具有明显的抑制作用。具有这种双重活性的化合物被证明是最有前途的光敏剂，具有治疗浸润性癌症的潜力。
更新日期：2018-01-30
中文翻译：
具有长烷基链的N-甲基化和N-氧化的三吡啶基卟啉的体外光动力学活性及其对鞘脂代谢的抑制活性
合成，表征了一系列N-甲基化和N-氧化的三吡啶基卟啉，并用6个细胞系研究了它们的PDT活性。除一个长链外，所有测试的具有长烷基链的卟啉均比无长烷基链的N-甲基化亲水性卟啉和N-氧化卟啉对PDT更有效。通常，N甲基化的三吡啶基卟啉比N氧化的更具活性，但两种N氧化物的光毒性的IC 50值TOPyP3-C 17 H 33 O和TOPyP3-C 17 H 35仍处于纳摩尔浓度。大多数测试细胞系的范围。但是，TOPyP3-C 17H 35对人包皮成纤维细胞没有光毒性。两种甲基化的两性卟啉分别命名为TMPyP3-C 17 H 33和TMPyP4-C 17 H 35，显示出明显的暗毒性，而没有经过光活化的氧化吡啶基卟啉均无毒。所选的光敏剂显示为凋亡诱导剂，并且对HCT116和HeLa细胞的克隆形成生长具有抑制作用。所有三种N-甲基化的两性卟啉均显着降低了HCT116细胞的迁移潜能。卟啉TMPyP3-C 17 H 35和TOPyP3-C 17 H 35降低了酸性神经酰胺酶的活性，而TOPyP3-C 17 H 33 O对HeLa细胞中的鞘氨醇激酶1活性具有明显的抑制作用。具有这种双重活性的化合物被证明是最有前途的光敏剂，具有治疗浸润性癌症的潜力。
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