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.

Novel pH-Independent Amphiphilic Chlorophyll a Derivatives with Oligoethyleneglycol Substituents as a Hydrophilic Part: Synthesis and Hydrophilicity Estimation

“…Pyropheophorbide a (3). Methyl pyropheophorbide a (2) (61 mg, 0.11 mmol) was dissolved in acetone (4 ml), concentrated hydrochloric acid (0.5 mL, HCl 30-33 %) was added to the resulting solution and left for 20 hours in the darkness at room temperature.…”

“…It is known that chlorophyll a derivatives are intensively investigated as photosensitizers (PS) for photodynamic therapy (PDT) in various fields of medicine (oncology, [1][2][3][4][5][6] otolaryngology, [7,8] ophthalmology, [9,10] surgery, [11] treatment of fungal diseases [12] ). Some of them have been already used in clinical practice.…”

“…Some of them have been already used in clinical practice. [1][2][3] The formation of amphiphilic properties of chlorin PS molecule enhances photodynamic action through more effective interaction of PS with cell membranes, that increases the efficiency of PDT in many cases. [13,14] Taking into account that the porphyrin macrocycle is hydrophobic the hydrophilic moieties introduction to the macrocycle periphery is of great interest.…”

“…[15][16][17][18] And the influence of the structure of these compounds on the hydrophilicity was not studied systematically. Here we report the synthesis of several phorbines (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21) and chlorins (22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32) with di-, tri-, tetra-, penta-and hexaethylene glycol substituents using methyl pheophorbide a (1) and its derivatives (2)(3)(4)(5) as an initial material (Scheme 1). The influence of the oligoethylene glycol chain length, its position at the macrocycle periphery and the structure of macrocycle on the hydrophilicity of compounds obtained was estimated using their mobility on the reverse phase HPLC data.…”

Chlorin p6 Cycloimides: Syntheses, Properties and Possible Fields of Application

“…Этим способом впервые был получен незамещенный по атому азота циклоимид 20, а также циклоимиды, содержащие у азота остатки алифатических спиртов, эфиров аминокислот и ациламинов (Схема 4 Chlorin p 6 Cycloimides Изучена фотодинамическая активность in vitro и in vivo N-(3-гидроксипропил)циклоимида хлорина p 6 25а. [25][26][27][28] Исследования на мышах с подкожной лимфомой P338 показали, что наибольший фотодинамический эффект достигается при введении фотосенсибилизатора в дозе 4 мкмоль/кг и облучении через 1.5 часа после инъекции. При более коротком интервале между инъекцией хлорина 25а и облучением (15 мин) и дозе 1 мкмоль/кг наблюдалась эффективная сосудисто-направленная ФДТ.…”