Novel Phenothiazine-Bridged Porphyrin-(Hetero)aryl dyads: Synthesis, Optical Properties, In Vitro Cytotoxicity and Staining of Human Ovarian Tumor Cell Lines

Abstract

We report here the synthetic procedure applied for the preparation of new AB3-type and trans-A2B2 type meso-halogenophenothiazinyl-phenyl-porphyrin derivatives, their metal core complexation and their peripheral modification using Suzuki–Miyaura cross coupling reactions with various (hetero)aryl (phenothiazinyl, 7-formyl-phenothiazinyl, (9-carbazolyl)-phenyl and 4-formyl-phenyl, phenyl) boronic acid derivatives. The meso-phenothiazinyl-phenyl-porphyrin (MPP) dyes family was thus extended by a series of novel phenothiazine-bridged porphyrin-(hetero)aryl dyads characterized by UV–Vis absorption/emission properties typical to the porphyrin chromophore, slightly modulated by increasing the size of peripheral substituents. Three phenothiazine-bridged porphyrin-heteroaryl dyads with fluorescence emission above 655 nm were selected as fluorophores in red spectral region for applications in cellular staining of human ovarian tumors. In vitro experiments of cell metabolic activity displayed a moderate toxicity on human ovarian tumor cell lines (OVCAR-3, cisplatin-sensitive A2780 and cisplatin-resistant A2780cis respectively). Visualization of the stained living cells was performed both by fluorescence microscopy imaging and by fluorescence lifetime imaging under two photon excitation (TPE-FLIM), confirming their cellular uptake and the capability of staining the cell nucleus.

Ethyne Functionalized Meso-Phenothiazinyl-Phenyl-Porphyrins: Synthesis and Optical Properties of Free Base Versus Protonated Species

“…A series of new MPP comprising peripheral ethynyl units (ethynyl-MPP) was successfully prepared by one-pot Adler–Longo mixt. mixed condensation reaction of pyrrole with ethynyl functionalized (hetero)aryl-carbaldehydes (7-ethynyl-10-methyl-10 H -phenothiazin-3-carbaldehyde [ 33 ] or 4-ethynyl-benzaldehyde) and (hetero)aryl-carbaldehydes (7-bromo-10-methyl-10 H -phenothiazin-3-carbaldehyde [ 34 ] or 4-bromo-benzaldehyde); mixtures of A 3 B- ( 2a , 2b , 2c , 2d ) and trans -A 2 B 2 -type ( 3a , 3b , 3c , 3d ) ethynyl-MPP dyes were thus obtained in a 2:1 molar ratio ( Scheme 1 ). Trans disubstituted isomers were selectively obtained as major rection products pointing towards a steric control induced by the folded structure of phenothiazine-carbaldehyde [ 31 ].…”

“…The phenothiazine fluorophore displayed greenish daylight fluorescence characterized by large Stokes shifts but low fluorescence quantum yields (e.g., phenothiazine-carbaldehyde acetals λ em 506 nm, Φ fl < 0.01) [ 35 ], while meso -tetraphenothiazinyl-porphyrin exhibited electronic spectral characteristics typical to the porphyrin fluorophore with a red shift of the emission maxima (λ em = 669 nm, Φ fl = 0.05 [ 34 ]) comparative to TPP (λ em 652 nm Φ fl = 0.11). Functionalization of the meso positions of the porphyrin with ethynyl groups resulted in a significant bathochromic shift of the fluorescence peak maxima and higher fluorescence quantum yields (e.g., 5,15- bis(arylethynyl)-10,20-diphenyl-porphyrine λ em = 695 nm, Φ fl = 0.20 [ 23 ]).…”

“…7-Bromo-10-methyl-10H-phenothiazin-3-carbaldehyde 7 was prepared according to previously reported procedures [ 34 ].…”

Advances in the Chemistry of Porphyrins and Related Macrocycles

“…This class of compounds is especially versatile, being engaged in a wide multitude of today’s core applications ranging from biology to medicine and material science. The Special Issue entitled “Advances in the Chemistry of Porphyrins and Related Macrocycles“ collects featured research papers providing an overview of the recent developments and advances related to some topic aspects of porphyrin and porphyrinoid chemistry, including biological and biomedical applications [ 1 , 2 , 3 , 4 , 5 , 6 , 7 ], photophysics [ 8 ], supramolecular chemistry [ 9 ], and sensing materials [ 10 , 11 , 12 ]. The Special Issue welcomed the submission of original full research articles [ 1 , 3 , 4 , 6 , 7 , 8 , 9 , 10 , 11 ], as well as some review articles [ 2 , 5 , 12 ] aiming to provide a comprehensive foundation on some of the above-mentioned research field, highlighting the current state of knowledge.…”

“…The Special Issue entitled “Advances in the Chemistry of Porphyrins and Related Macrocycles“ collects featured research papers providing an overview of the recent developments and advances related to some topic aspects of porphyrin and porphyrinoid chemistry, including biological and biomedical applications [ 1 , 2 , 3 , 4 , 5 , 6 , 7 ], photophysics [ 8 ], supramolecular chemistry [ 9 ], and sensing materials [ 10 , 11 , 12 ]. The Special Issue welcomed the submission of original full research articles [ 1 , 3 , 4 , 6 , 7 , 8 , 9 , 10 , 11 ], as well as some review articles [ 2 , 5 , 12 ] aiming to provide a comprehensive foundation on some of the above-mentioned research field, highlighting the current state of knowledge. Several researchers from many research institutions, by virtue of their qualified scientific expertise, have contributed to the success of this Special Issue, and their scientific contributions are summarized here.…”