title: Comparative study of photodynamic properties of 13,15-N-cycloimide derivatives of chlorin p6.
abstract: Comparative study of 13,15-[N-(2-hydroxyethyl)]cycloimide chlorin p6 (2), 13,15-(N-acetoxy)cycloimide chlorin p6 (3), 13,15-(N-hydroxy)cycloimide chlorin p6 methyl ester (4) and 13,15-(N-methoxy)cycloimide chlorin p6 methyl ester (5) together with the previously investigated 13,15-[N-(3-hydroxypropyl)]cycloimide chlorin p6 (1) was performed. The dependence of the key photodynamic properties of 1-5 on the introduced substituents was analyzed. The photoinduced cell-killing activity of 4 is 100- and 280-fold higher than that of chlorin p6 and Photogem, respectively, as estimated on A549 human lung adenocarcinoma cells. The activity is reduced eight times in the order 4 > 5 > 1 > 2 > 3. The intracellular accumulation of 1-5 occurs in cytoplasm in a monomeric form bound to the lipids of cellular membranes. This form of 1, 2, 3, 4 and 5 is characterized by the high quantum yield of singlet oxygen generation, which depends on the introduced substituents, 0.66, 0.59, 0.35, 0.51 and 0.73, respectively. The photostability is two-fold less for 1 and four-fold less for 2, 3 and 5 than for 4. The rates of cellular uptake and efflux of 1-5 vary widely, thus providing the way to optimize the pharmacological properties of the photosensitizer (PS) using the respective substituents. Modifying the substituents, 1-5 were targeted to different cellular organelles. The enhanced accumulation in the Golgi apparatus and mitochondria complemented with diffuse staining of intracellular membranous structures is a property of 1-4. Compound 5 accumulates selectively in the lipid droplets and stains weakly perinuclear structures. Temperature-sensitive mechanisms of transport are responsible for the 1-4 uptake. Diffusion can play a role in the internalization of 5 but not of 1-4. Endocytosis via caveolae, clathrin-dependent and adenosine triphosphate-dependent pathways are not noticeably involved in the 1-5 internalization. Independently from their intracellular localization 1, 4 and 5 are highly efficient near-IR PS, which induce predominantly an apoptotic type of cell death under conditions providing ca 50% level of phototoxicity and necrosis at the 100% level of phototoxicity.
authors.affiliation: Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia. alexei@nmr.ru
authors.forename: Alexei
authors.initials: A
authors.lastname: Feofanov
authors.forename: George
authors.initials: G
authors.lastname: Sharonov
authors.forename: Alexei
authors.initials: A
authors.lastname: Grichine
authors.forename: Tatyana
authors.initials: T
authors.lastname: Karmakova
authors.forename: Anna
authors.initials: A
authors.lastname: Pljutinskaya
authors.forename: Victoria
authors.initials: V
authors.lastname: Lebedeva
authors.forename: Ramzes
authors.initials: R
authors.lastname: Ruziyev
authors.forename: Raisa
authors.initials: R
authors.lastname: Yakubovskaya
authors.forename: Andrei
authors.initials: A
authors.lastname: Mironov
authors.forename: Matthieu
authors.initials: M
authors.lastname: Refregier
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Maurizot
authors.forename: Paul
authors.initials: P
authors.lastname: Vigny
mesh_terms: D001692:Biological Transport; D016923:Cell Death; D045744:Cell Line, Tumor / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000494:pharmacology* / Q000633:toxicity; D011166:Porphyrins / Q000032:analysis / Q000494:pharmacology* / Q000633:toxicity; D017382:Reactive Oxygen Species / Q000378:metabolism; D012995:Solubility; D013050:Spectrometry, Fluorescence; D013194:Staining and Labeling; D013329:Structure-Activity Relationship; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013696:Temperature
chemical_list: C461439:13,15-N-(3'-hydroxypropyl)cycloimide chlorin p6; D017319:Photosensitizing Agents; D011166:Porphyrins; D017382:Reactive Oxygen Species; C072905:chlorin p6