In Vitro Photodynamic Activity of N-Methylated and N-Oxidised Tripyridyl Porphyrins with Long Alkyl Chains and Their Inhibitory Activity in Sphingolipid Metabolism.

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-C17 H33 O and TOPyP3-C17 H35 , were still in the nanomolar concentration range for most of the tested cell lines. However, TOPyP3-C17 H35 did not show phototoxicity on human foreskin fibroblast cells. Two methylated amphiphilic porphyrins, named TMPyP3-C17 H33 and TMPyP4-C17 H35, 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-C17 H35 and TOPyP3-C17 H35 reduced the activity of acid ceramidase, whereas TOPyP3-C17 H33 O 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.