Artur R. Abreu

Biodistribution and Photodynamic Efficacy of a Water‐Soluble, Stable, Halogenated Bacteriochlorin against Melanoma

The in vitro phototoxicity of a photostable, synthetic, water‐soluble, halogenated bacteriochlorin, 5,10,15,20‐tetrakis(2‐chloro‐5‐sulfophenyl)bacteriochlorin (TCPBSO3H), toward mouse melanoma (S91) cells is ∼60‐fold higher than that of the analogous porphyrin, and is associated with very weak toxicity in the dark; 90 % of S91 cells were killed in response to a light dose of 0.26 J cm−2 in the presence of [TCPBSO3H]=5 μM. In vivo toxicity toward DBA mice is very low, even at doses of 20 mg kg−1. In vivo pharmacokinetics and biodistribution of TCPBSO3H were studied in DBA mice with S91 tumors; 24 h after intraperitoneal injection of 10 mg kg−1, TCPBSO3H demonstrated preferential accumulation in S91 mouse melanoma, with tumor‐to‐normal tissue ratios of 3 and 5 for muscle and skin, respectively. Photodynamic therapy (PDT) performed under these conditions, with 90 mW cm−2 diode laser irradiation at λ 750 nm for 20 min (total light dose of 108 J cm−2), resulted in tumor regression. Tumor recurrence was observed only approximately two months after treatment, confirming the efficacy of this PDT against melanoma.

Photodynamic Therapy Efficacy Enhanced by Dynamics: The Role of Charge Transfer and Photostability in the Selection of Photosensitizers

Progress in the photodynamic therapy (PDT) of cancer should benefit from a rationale to predict the most efficient of a series of photosensitizers that strongly absorb light in the phototherapeutic window (650-800 nm) and efficiently generate reactive oxygen species (ROS = singlet oxygen and oxygen-centered radicals). We show that the ratios between the triplet photosensitizer-O2 interaction rate constant (kD) and the photosensitizer decomposition rate constant (kd), kD/kd, determine the relative photodynamic activities of photosensitizers against various cancer cells. The same efficacy trend is observed in vivo with DBA/2 mice bearing S91 melanoma tumors. The PDT efficacy intimately depends on the dynamics of photosensitizer-oxygen interactions: charge transfer to molecular oxygen with generation of both singlet oxygen and superoxide ion (high kD) must be tempered by photostability (low kd). These properties depend on the oxidation potential of the photosensitizer and are suitably combined in a new fluorinated sulfonamide bacteriochlorin, motivated by the rationale.

Synthesis of New Metalloporphyrin Triads: Efficient and Versatile Tripod Optical Sensor for the Detection of Amines

Zinc and manganese complexes of porphyrin triads have been synthesized and are shown to be efficient as highly sensitive and selective tripod optical sensors for amines at the picomolar level.

An insight into solvent-free diimide porphyrin reduction: a versatile approach for meso-aryl hydroporphyrin synthesis

This paper describes an environmentally sustainable synthetic method for the preparation of a set of meso-aryl hydroporphyrins, namely chlorins and bacteriochlorins, via reduction of porphyrins with diimide, in the total absence of solvents and bases. Thermomicroscopy studies clearly showed that the process is a typical solvent-free reaction.

Unsymmetrical porphyrins: the role of meso-substituents on their physical properties

The synthesis of one-step meso-porphyrins type AxBy containing alkyl and pyridyl groups is described. An initial assess of the amphiphilic proprieties were determined by its log Kow using fluorescence detection techniques and values from 1.42 to 2.15 were observed. The melting points of this set of porphyrins was determined and a strong effect of the number and size of the meso-alkyl chain is ascribed.

Synthesis of Ortho-alkoxy-aryl Carboxamides via Palladium-Catalyzed Aminocarbonylation

Abstract Various aryl carboxamides with alkoxy substituents at the ortho-position, applicable as direct intermediates toward novel ligands, were synthesised via aminocarbonylation of aryl-iodides (2-iodoanisole, 5-chloro-7-iodo-8-methoxy-quinoline, and 5-chloro-7-iodo-8-benzyloxy-quinoline) in the presence of in situ generated palladium(0) catalysts. Simple primary and secondary amines as well as aminoacid esters were used as N-nucleophiles. The optimization of the reaction conditions allowed the preferential formation of carboxamides or ketocarboxamides by simple or double carbon monoxide insertion, respectively. A strong dependence of the chemoselectivity on carbon monoxide pressure was observed.

Separation and atropisomer isolation of ortho-halogenated tetraarylporphyrins by HPLC: Full characterization using 1D and 2D NMR

The separation and isolation of the four atropisomers of ortho-halogenated tetraarylporphyrins by semi-preparative HPLC is described. Full characterization and assignment of all 1H and 13C resonances of 5,10,15,20-tetrakis(2-fluoro or 2-chlorophenyl)porphyrins and 5,10,15,20-tetrakis(2-fluoro or chloro-5-N-ethylsulfamoylphenyl)porphyrins by 1D and 2D NMR techniques is reported. The outcome is an unequivocal evidence of the chlorosulfonation of meso-tetra(2-haloaryl)porphyrins on the 5′-position.

Multi-spectral photoacoustic mapping of bacteriochlorins diffusing through the skin: exploring a new PAT contrast agent

A skin depth map was built reconstructing photoacoustic signals at several wavelengths of visible and infrared light. The mapping technique was used to follow the diffusion through the skin of near-infrared absorbing dyes. Such dyes can be useful for photodynamic therapy (PDT) of skin lesions and are investigated as contrast agents for photoacoustic tomography (PAT), because they strongly absorb light at wavelengths where the skin is more transparent.

Ultrafast Dynamics of Manganese(III), Manganese(II), and Free-Base Bacteriochlorin: Is There Time for Photochemistry?

Manganese(III) and manganese(II) complexes of halogenated sulfonamide tetraphenylbacteriochlorins were prepared for the first time via a transmetalation reaction and shown to be stable at room temperature. The behavior of the electronic states of the paramagnetic complexes is remarkably different from those of the metal-free bacteriochlorins or diamagnetic metallobacteriochlorins. The Mn3+ complex exhibits eight electronic transitions between different states from 300 to 1100 nm, with a very prominent band (molar absorption coefficient of ca. 50000 M-1 cm-1) at 829 nm. Ultrafast transient absorption showed the formation of an excited singquintet state that decays to a tripquintet state with a femtosecond lifetime. The tripquintet state decays in 5 ps, yielding a tripseptet state with a 570 ps lifetime. The electronic absorption of the Mn2+ complex more closely resembles those of diamagnetic metallobacteriochlorins, but the longest decay lifetime is only ca. 8 ps. The intense photoacoustic waves generated with near-infrared excitation suggest the use of these complexes in photoacoustic tomography.

Infrared absorbing dyes tailored for detection and therapy of solid tumors

We explore the use as contrast agents for photoacoustic tomography (PAT) of photosensitizers originally developed for the photodynamic therapy of cancer. We show that halogenated bacteriochlorins can enhance the sensitivity of PAT and increase the depth of the field probed by this technique.