Dark and Photoinduced Cytotoxic Activity of the New Chlorophyll-a Derivatives with Oligoethylene Glycol Substituents on the Periphery of Their Macrocycles

Abstract

In the present work, we investigated the dark and photoinduced cytotoxic activity of the new chlorophyll-a derivatives which contain the substituents of oligoethylene glycol on the periphery of their macrocycles. These compounds were tested using human cell lines to estimate their potential as photosensitizers for photodynamic therapy of cancer. It was shown that all the tested compounds have expressed photoinduced cytotoxic activity in vitro. Detailed study of the biological activity of one of the most perspective compound in this series—pyropheophorbide-a 17-diethylene glycol ester (Compound 21) was performed. This new compound is characterized by lower dark cytotoxicity and higher photoinduced cytotoxicity than previously described in a similar compound (DH-I-180-3) and clinically used PhotolonTM. Using fluorescent microscopy, it was shown that Compound 21 quickly penetrates the cells. Analysis of caspase-3 activity indicated an apoptosis induction 40 min after exposure to red light (λ = 660 nm). The induction of DNA damages and apoptosis was shown using Comet assay. The results of expression analysis of the stress-response genes indicate an activation of the genes which control the cell cycle and detoxification of the free radicals after an exposure of HeLa cells to Compound 21 and to red light. High photodynamic activity of this compound and the ability to oxidize biomolecules was demonstrated on nuclear-free mice erythrocytes. In addition, it was shown that Compound 21 is effectively activated with low energy 700 nm light, which can penetrate deep into the tissue. Thus, Compound 21 is a prospective substance for development of the new drugs for photodynamic therapy of cancer.

Copper Сomplexes of Сhlorin Derivatives of Chlorophyll a as Potential Photosensitizers for Medical Purposes

“…The photosensitizing efficiencies of metal-free chlorins, virtually coincides with the data reported earlier. [21,30,31] IC 50 in the cells incubated in the dark exceeds IC 50 in illuminated samples by two or more orders of magnitude. The photodamaging effect of complexes (Cu-1-Cu-3) is somewhat weaker, however, the ability of these compounds to exert a photosensitizing cell killing is manifested quite clearly.…”

“…The dark and photoinduced toxic activity of chlorins was investigated as described in refs. [21,30,31]…”

“…The IC 50 values used for estimation of the dark and photoinduced toxicity in experiments on HeLa cells (Table 1) were determined similarly to refs. [21,30,31] The metal-free chlorins (1-3) as well as their copper complexes (Cu-1-Cu-3) showed distinct photosensitizing effect. The photosensitizing efficiencies of metal-free chlorins, virtually coincides with the data reported earlier.…”

Synthesis and Cytotoxic Activity of Transition Metal Porphyrinates with a Fragment of Diethylene Glycol on the Periphery of the Macrocycle

“…[7][8][9][10][11][12] В то же время, внедрение фрагмента олигоэтиленгликоля, а также его положение в хлориновом макроцикле может оказывать влияние на темновую цитотоксичность соединения. [13] В связи с этим в настоящей работе синтезированы новые порфиринаты переходных металлов (меди, цинка и никеля) с фрагментом диэтиленгликоля (ДЭГ) на периферии макроцикла (Cu-1, Cu-3, Ni-1, Ni-3, Zn-1, Zn-3, Схема 1) и исследована темновая цитотоксическая активность вновь и ранее синтезированных комплексов (Cu-2, Ni-2, Zn-2) в сравнении с соответствующими безметальными хлоринами (1-3) на линиях опухолевых клеток HeLa с целью выявления перспективных темновых противоопухолевых цитостатиков.…”

Synthesis and In Vitro Anti‐Tumor, Anti‐Mycobacterial and Anti‐HIV Activities of Diethylene‐Glycol‐Tethered Bis‐Isatin Derivatives

“…In recent years, the bis‐nuclear compounds have been attracted great interests in the drug development since they usually exhibited some unique properties such as enhanced biological activities compared with the corresponding mono‐nuclear analogs . Bis‐isatin derivatives demonstrated promising anti‐cancer, anti‐viral and anti‐TB activities,, and the structure‐activity relationship (SAR) revealed that the linker between the two isatin moieties played a pivotal role in exert their biological activities . Diethylene glycol fragment has the potential to exert diverse noncovalent interactions, which may facilitate the bind with active site, and some diethylene glycol tethered derivatives possess considerable biological activities ,.…”