Nelson A. M. Pereira

Recent Developments in the Synthesis of Dipyrromethanes. A Review

Introduction ................................................................................. 184 I. Synthesis of Dipyrromethanes ....................................................... 184 1. Dipyrromethane Synthesis via Condensation of Pyrroles with Aldehydes and Ketones .........................................................................................184 a) Synthesis of 5-Substituted Dipyrromethanes.........................................184 Preparation of 5-Aryldipyrromethanes TFA-catalyzed Condensation of Pyrrole with Aldehydes...................................................................187 Preparation of Dipyrromethane via TFA-catalyzed Condensation of Pyrrole with Aldehydes...................................................................187 Preparation of 5-Aryldipyrromethanes via BF3·Et2 O-catalyzed Condensation of Pyrrole with Aldehydes ..........................................187 Preparation of 5-(Hydroxymethyl)dipyrromethane (13) via InCl3-catalyzed Condensation of Pyrrole with Glycolaldehyde ...........190 Preparation of 5-(2-Furyl)-, 5-(3-Furyl)and of 5-(2-Selenenyl)dipyrromethanes via TFA-catalyzed Condensation of Pyrrole with Heteroaromatic Aldehydes ..............................................................192 Preparation of Dipyrromethanes via Condensation of Pyrrole with Pyridine-, Quinoline-, and 1H-Imidazole-derived Aldehydes ..............193 “On Water” Synthesis of 5-Phenyldipyrromethanes via Condensation of Pyrrole with Benzaldehyde ..........................................................197 Preparation of 5,5-Daryldipyrromethanes via BF3·Et2O-catalyzed Condensation of Pyrrole with Aromatic Ketones ...............................198 b) Synthesis of Polysubstituted Dipyrromethanes......................................199 II. Dipyrromethanes from α-Acylpyrroles.......................................... 202 Preparation of 5-Phenyldipyrromethane via TFA-catalyzed Condensation of Pyrrole with 2-(α-Hydroxy-α-phenylmethyl)pyrrole ......203 III. Dipyrromethane Synthesis via Other Approaches.......................... 205 Preparation of 5-(Trifluoromethyl)dipyrromethane from 1-Bromo1-chloro-2,2,2-trifluoroethane and Pyrrole.............................................209 Conclusion.................................................................................... 209 Acknowledgements ....................................................................... 209 References .................................................................................... 209

Synthetic porphyrins bearing β-propionate chains as photosensitizers for photodynamic therapy

Porphyrins with different numbers of β-propionate chains mimicking natural porphyrins were prepared via the 2+2 MacDonald type approach. Photodynamic activity against WiDr colon adenocarcinoma cells showed that activity is related to the number of β-propionate chains, with the derivatives with two carboxylic groups showing higher activity.

Novel 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine fused chlorins as very active photodynamic agents for melanoma cells.

The development of new stable 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-fused chlorins with high absorption properties at 650 nm, and their impressive photosensitizer ability against melanotic and amelanotic cancer cells is described. Comparison between a diester-substituted chlorin with the corresponding dihydroxymethyl derivative demonstrated that the increased hydrophilicity of the latter is crucial to ensure nanomolar activity against melanoma cells. The new photosensitizer leads to death of human melanoma cells being both apoptosis and necrosis in equal parts involved in the treatment response. The dihydroxymethyl-chlorin was particularly active against human melanocytic melanoma A375 cells, which can be viewed as a solution to overcome the resistance of melanotic melanoma to photodynamic therapy.

Platinum(II) Ring-Fused Chlorins as Near-Infrared Emitting Oxygen Sensors and Photodynamic Agents

Novel near-infrared luminescent compounds based on platinum(II) 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-fused chlorins are described. These compounds have high photostability and display light emission, in particular simultaneous fluorescence and phosphorescence emission in solution at room temperature, in the biologically relevant 700-850 nm red and near-infrared (NIR) spectral region, making them excellent materials for biological imaging. The simultaneous presence of fluorescence and phosphorescence emission at room temperature, with the phosphorescence strongly quenched by oxygen whereas fluorescence remains unaffected, allows these compounds to be used as ratiometric oxygen sensors in chemical and biological media. Both steady-state (fluorescence vs phosphorescence intensities) and dynamic (dependence of phosphorescence lifetimes upon oxygen concentration) luminescence approaches can be used. Photocytotoxicity studies against human melanocytic melanoma cells (A375) indicate that these compounds display potential as photosensitizers in photodynamic therapy.

Advances on photodynamic therapy of melanoma through novel ring-fused 5,15-diphenylchlorins

The synthesis, photophysical behaviour and photosensitization ability of novel 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-fused 5,15-diphenylchlorins against melanoma cells are described. All studied chlorins were found to be extremely active against melanoma cell lines A375 showing IC50 values below 20 nM. Furthermore, a dihydroxymethyl diphenylchlorin was identified as an excellent candidate to allow modulating of different types of cell death, apoptosis vs. necrosis, by varying its concentration. This can be explored as a tool to improve the effectiveness of PDT since inflammatory response resulting from necrotic cell death after PDT can activate the antitumor immune response with implications also regarding the vascular damage. This feature combined with very low cytotoxicity against human melanoma cells in the absence of light activation and against human fibroblast HFF-1 cells makes this chlorin a candidate of choice as a photosensitizer for PDT. A comprehensive photophysical investigation including the determination of quantum yields for fluorescence, singlet oxygen sensitization and internal conversion, lifetimes and rate constants of all the excited state deactivation processes has been undertaken.

PO-423 Novel 4,5,6,7-tetrahydropyrazolo[1,5-a] pyridine fused chlorins as very active photosensitizers against melanoma and bladder cancer cells

Introduction Photodynamic therapy (PDT) is a clinically approved therapeutic procedure, which is entering the mainstream of cancer treatments. Nowadays PDT has been successfully used in the treatment of skin cancers, but the use of PDT against melanoma can be compromised due to the natural resistance mechanism of some melanoma cancer cells. Thus, the search for new photosensitizers is a relevant research goal. Bladder cancer is also an interesting target to PDT, due to easy irradiation accessibility by cystoscopy. Material and methods A375 human melanoma cells and HT1376 human bladder cancer cells were plated. The formulation of the sensitizers consisted in a 1 mg/mL solution in DMSO and the desired concentrations being achieved by successive dilutions. The sensitizers were administered in several concentrations (from 1 nM to 10 mM) and cells were incubated for 24 hour. Controls were performed on every test. Cells were washed with PBS and new drug-free medium was added. Each plate was irradiated with a fluence rate of 7.5 mW/cm2, to reach 10 J. Evaluation by MTT assay was performed 24 hour after the photodynamic treatment in order to evaluate the cytotoxic effect. Results and discussions Our previous in vitro PDT studies demonstrated that the increase of chlorins’ hydrophilicity of leads to higher activity against A375 melanoma cells. Therefore, a series of novel 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-fused chlorins bearing dicarboxylic acid and monocarboxyic moieties were developed showing an interesting biological activity against the A375 and HT1376 cancer cells. Inhibition of the metabolic activity seems to be dependent on the concentration of the sensitizers used. With the experimental metabolic activity values, it was possible to calculate the concentration of the sensitizers that inhibits the proliferation of cultures in 50% (IC50). For this series of compounds, IC50 values ranged from mM to nM concentrations. Nevertheless, a new molecule with an IC50 value of 67,93 nM stood out. Conclusion The compounds tested were active against human melanocytic melanoma A375 cells and human bladder HT1376 cancer cells. MTT assay showed that the metabolic activity was inversely proportional to the concentration of the photosensitizer. Interestingly low IC50 values in the nanomolar range encourage further studies. Funding The Foundation for Science and Technology: POCI-01–0145-FEDER-PTDC/QEQ-MED/0262/2014; (COMPETE 2020). POCI-01–0145-FEDER-007630 and POCI-01–0145-FEDER-007440.