Novel Short PEG Chain-Substituted Porphyrins: Synthesis, Photochemistry, and In Vitro Photodynamic Activity against Cancer Cells

Abstract

This work presents the synthesis and characterization of metal-free, zinc (II), and cobalt (II) porphyrins substituted with short PEG chains. The synthesized compounds were characterized by UV-Vis, 1H and 13C NMR spectroscopy, and MALDI-TOF mass spectrometry. The origin of the absorption bands for tested compounds in the UV-Vis range was determined using a computational model based on the electron density functional theory (DFT) and its time-dependent variant (TD-DFT). The photosensitizing activity was evaluated by measuring the ability to generate singlet oxygen (ΦΔ), which reached values up to 0.54. The photodynamic activity was tested using bladder (5637), prostate (LNCaP), and melanoma (A375) cancer cell lines. In vitro experiments clearly showed the structure–activity relationship regarding types of substituents, their positions in the phenyl ring, and the variety of central metal ions on the porphyrin core. Notably, the metal-free derivative 3 and its zinc derivative 6 exerted strong cytotoxic activity toward 5637 cells, with IC50 values of 8 and 15 nM, respectively. None of the tested compounds induced a cytotoxic effect without irradiation. In conclusion, these results highlight the potential value of the tested compounds for PDT application.

Design, Synthesis, and Anticancer Activity of Novel 3,6-Diunsaturated 2,5-Diketopiperazines

“…It was documented in previous studies that paclitaxel bound to the microtubule at the taxoid site on the luminal face of β-tubulin and maintained the stability and destroyed the dynamics of the microtubule, thus leading to mitotic catastrophe [ 33 ]. However, according to the “similarity principle” [ 34 ], our 2,5-DKPs might have the same mechanism as plinabulin or its analogs, which acted as a tubulin binder near or at the colchicine binding site located at the interfacial region of the α- and β-tubulin studied using photoaffinity labeling [ 35 , 36 ] or computational modeling [ 37 , 38 , 39 , 40 ], leading to the inhibition of tubulin polymerization and the prevention of microtubule formation, thus resulting in the apoptosis of cancer cells. The detailed mechanism will be investigated in future studies.…”

Photodynamic Therapy: From the Basics to the Current Progress of N-Heterocyclic-Bearing Dyes as Effective Photosensitizers

“…Furthermore, the investigators testified that only in the presence of GSH and hydrogen sulfide occurs the photosensitizing agent activation by the quenching group departure, stating that it has a high clinical potential in reducing the effect of cutaneous photosensitivity; Improvement of functional properties of this family of PSs: Certain functional groups can significantly contribute to refining physiological and chemical stability and biocompatibility [ 148 ]. The introduction of polyethylene glycol (PEG) moieties into porphyrin cores, for example, has been reported several times in the literature [ 149 , 150 , 151 ]. Lazewski et al [ 151 ] demonstrated that, irrespective of the coordinated metal, short-PEGylated porphyrins reveal reduced dark cytotoxicity, increased ability to produce singlet oxygen, and that the structural location where the polymer is introduced can result in the variation of the biological effects; As an interface between single-PSs and nano-PSs, Li et al [ 152 ] demonstrate that the chain conjugation of PEG-bearing porphyrins with perylene diimide units resulted, by self-assembly, in a kind of nanoparticle with attractive properties: (i) high biocompatibility; (ii) intense absorption in the visible and NIR regions; (iii) therapeutic efficiency in vitro and in vivo with reduced side effects; (iv) potential use as a theranostic agent by obtaining second near-infrared (NIR-II) fluorescence images.…”

“…Improvement of functional properties of this family of PSs: Certain functional groups can significantly contribute to refining physiological and chemical stability and biocompatibility [ 148 ]. The introduction of polyethylene glycol (PEG) moieties into porphyrin cores, for example, has been reported several times in the literature [ 149 , 150 , 151 ]. Lazewski et al [ 151 ] demonstrated that, irrespective of the coordinated metal, short-PEGylated porphyrins reveal reduced dark cytotoxicity, increased ability to produce singlet oxygen, and that the structural location where the polymer is introduced can result in the variation of the biological effects;…”

“…Furthermore, the investigators testified that only in the presence of GSH and hydrogen sulfide occurs the photosensitizing agent activation by the quenching group departure, stating that it has a high clinical potential in reducing the effect of cutaneous photosensitivity; • Improvement of functional properties of this family of PSs: Certain functional groups can significantly contribute to refining physiological and chemical stability and biocompatibility [148]. The introduction of polyethylene glycol (PEG) moieties into porphyrin cores, for example, has been reported several times in the literature [149][150][151].…”

“…Lazewski et al [151] demonstrated that, irrespective of the coordinated metal, short-PEGylated porphyrins reveal reduced dark cytotoxicity, increased ability to produce singlet oxygen, and that the structural location where the polymer is introduced can result in the variation of the biological effects;…”