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

Eva Molnar,Castelia Cristea,Monica Focsan,Eva Fischer-Fodor,Emese Gal,Luiza Gaina,Patriciu Achimas-Cadariu,Luminita Silaghi-Dumitrescu,Maria Perde-Schrepler

doi:10.3390/ijms21093178

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.

Highlights

The multiple functionalization possibilities of the highly stable planar macrocyclic porphin core combined with the huge progress recorded in the development of methodologies for synthetic organic chemistry mostly concurred with the expansion of recent literature data documenting new porphyrin derivatives with tailored chemical and optical properties
The syntheses, optical properties and electrochemical behaviors of meso-phenothiazinyl-phenyl porphyrin (MPP) dyes were first reported by our group [7] followed by the description of their metal complexation [8]
The family of meso-phenothiazinyl-phenyl-porphyrin MPP dyes was substantially extended by synthesizing the new halogen-MPP of AB3-type and the trans-A2B2 type further employed, on the one hand, as ligands in new metal-complexes, and on the other hand, as scaffolds for peripheral modification by Suzuki–Miyaura cross coupling with variousarylboronic acid derivatives

Summary

Introduction

The multiple functionalization possibilities of the highly stable planar macrocyclic porphin core combined with the huge progress recorded in the development of methodologies for synthetic organic chemistry mostly concurred with the expansion of recent literature data documenting new porphyrin derivatives with tailored chemical and optical properties. Introduction of appropriate donor/acceptor substituents and/or metal complexation contributed to the modification of structural factors, such as molecular symmetry, size and degree of conjugation of the π-electronic system, emphasizing a high impact on the optical performances of the porphyrin-based materials. Among the various heteroaromatic units attached to the porphine chromophore aiming the modulation of its photophysical properties, the introduction of an electron rich phenothiazine unit gave fruitful returns; e.g., fluorescent porphyrins emitting intense red light with high fluorescent quantum yields [1] “push−pull” porphyrin dyes for photon to energy conversion systems [2,3,4,5] as well as potential biologically active compounds [6]. The Suzuki–Miyaura cross-coupling between organoboron derivatives and organic halides in the presence of a palladium catalyst and a base became a powerful methodology for carbon–carbon bond formation [9]. This palladium-mediated cross-coupling reaction heavily benefits from the availability of: organoboron reagents (which are inert to water and oxygen, and characterized by thermal stability and low toxicity [10]); tetra-coordinated palladium-phosphine complex catalysts, such as Pd(PPh3), Pd(PPh3)2Cl2, Pd(dppf)Cl2 or Pd2(dba)3 [11]; and different bases, such as Cs2CO3 [12], K2CO3 [13], KOtBu [14], K3PO4 [15] or NEt3 [16]

Methods

Results

Conclusion