Mitochondria‐Targeted Anticancer Activity of BODIPY‐Appended Iron(III) Catecholates in Red Light

Abstract

Iron(III) catecholates of dipicolylamine (dpa) bases having appended Benzyl (in bzdpa) or BODIPY (borondipyrromethene) moiety (in L1 and L2), viz. [Fe(Bzdpa)(cat)Cl] (1), [Fe(L1)(cat)Cl] (2) and [Fe(L2)(cat)Cl] (3), were prepared and characterized (H2cat=catechol). The iron(III) complexes with a ligand‐to‐metal charge transfer (LMCT) band within 600–800 nm were studied for their photocytotoxicity in visible (400–700 nm) and red (600–720 nm) light. Complex 2 with a BODIPY fluorophore in L1 gave IC50 values of 2.2±0.5 and 15.0±0.7 μM in visible and red light, respectively, in HeLa cells. Complex 3 with a diiodo‐BODIPY moiety showed excellent PDT activity giving respective IC50 values of 0.8±0.2 and 12.6±1.1 μM. They are less toxic in dark (IC50: ≥85 μM). A similar activity was observed in MCF‐7 cancer cells. The BODIPY complexes showed significant mitochondrial localization. Annexin FITC assay showed apoptotic cell death involving reactive oxygen species (ROS). Photo‐generation of ROS was evidenced from dichlorofluorescein diacetate (DCFDA) assay. Mechanistic studies on DNA photocleavage reactions showed the presence of two types of ROS. Singlet oxygen formation from BODIPY was evidenced from the 1,3‐diphenylisobenzofuran (DPBF) experiments. Hydroxyl radical was generated on red light photo‐activation of the LMCT band within photodynamic therapy (PDT) spectral window.

Iron(III) Complexes of Vitamin B6 Schiff Base with Boron‐Dipyrromethene Pendants for Lysosome‐Selective Photocytotoxicity

“…Combining the abovementioned strategies for targeting cancer versus non‐cancerous cells, and with the knowledge that boron‐dipyrromethene (BODIPY)‐based photosensitizers prefer mitochondrial localization,, we have designed and synthesized new ternary iron(III) complexes of formulation [Fe(L 1–3 )(L 4,5 )](NO 3 ) ( 1–4 ), where L 1 is benzyl‐bis[(pyridin‐2‐yl)methyl]methanamine (bzdpa in 1 ), L 2 is noniodinated BODIPY‐appended dipicolylamine ligand (in 2 , 3 ), L 3 is a diiodinated BODIPY analogue (in 4 ), L 4 is a vitamin B 6 Schiff base, namely 3‐hydroxy‐5‐(hydroxymethyl)‐4‐{[(2‐hydroxyphenyl)imino] methyl}‐2‐methylpyridine (in 1 , 3 , and 4 ), and L 5 is 2‐[(2‐hydroxyphenylimino)‐methyl]phenol (in 2 ) as a nonpyridoxal Schiff base (Figure ). While the vitamin B 6 unit is expected to facilitate the uptake of the complex selectively into the cancer cells over the non‐cancerous cells, the BODIPY‐appended NNN ‐donor dipicolylamine (dpa) ligand in the ternary structure in complex 4 is expected to generate singlet oxygen, causing light‐induced cell death by the type‐II pathway that is known for Photofrin®.…”

Photochemotherapy of Infrared Active BODIPY-Appended Iron(III) Catecholates for in Vivo Tumor Growth Inhibition

“…26 The photocytotoxicity of complex 2 in MCF-7 and HeLa cancer cells under infrared light irradiation has prompted us to study its anticancer potential in vitro and in vivo in BT474luc cancer cell line. 24 The anticancer activity of complex 2 was studied by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay (Figure S1, Supporting Information). The half-maximal inhibitory concentration (IC 50 ) for complex 2 was 6 μM in BT474luc cancer cells in infrared light of 600–720 nm with relatively lower dark cytotoxicity (18 μM).…”

“…27 The results on BT474luc cells are in accordance to our earlier findings using HeLa and MCF-7 cells. 24…”

“…Following the literature reports, the ligands and complexes were prepared. 24 UV–visible and emission spectra were obtained from Bruker Alpha and PerkinElmer Spectrum 750 spectrophotometers and a HORIBA Jobin Yvon IBH TCSPC fluorimeter (fitted with FluoroHub software analysis). The experiments conducted under infrared light irradiation were carried out with an infrared light photoreactor, Waldmann PDT 1200 L, and standard protocols.…”

Synthesis, Characterization, and Biological Evaluation of Red-Absorbing Fe(II) Polypyridine Complexes

“…To tackle metal, it is anticipated to have a reduced metal-induced cellular toxicity [34,35] in comparison to other metal-based complexes. Chakravarty and co-workers have already reported several Fe(III)-based complexes with a dipyrido[3,2-d:2 ,3 -f]quinoxaline [35][36][37] or a dipicolylamine [34,[38][39][40][41][42][43][44][45] moiety as effective PSs. As an impressive example, the Fe(III) complexes 1 was prepared with a dipicolylamine ligand combined with an anthracenyl moiety, which is able to intercalate in the DNA, and a catechol ligand, which promotes an intense ligand-to-metal charge-transfer band in the near IR window (Figure 1).…”