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The synthesis of cationic porphyrins for use in photodynamic antimicrobial chemotherapy (PACT

Hall, Claire Elizabeth


Claire Elizabeth Hall


Tim Paget


Photodynamic therapy (PDT) has been widely used in recent years for the treatment of cancers. However the growing problem of drug resistance in bacteria has led to PDT being used to treat bacterial infections in a new type of therapy called Photodynamic Antimicrobial ChemoTherapy (PACT). In PACT a drug is administered and allowed to accumulate within the target molecules prior to irradiation with red light. This produces singlet oxygen and other reactive oxygen species which target multiple areas within the cell leading to a mode of therapy that is less susceptible to the emergence of bacterial resistance.

The development of an appropriate assay for use in PACT was undertaken, looking at various parameters which might affect cell kill. These parameters included incubation time, light dose (varying fluence and fractionating), drug concentration and methods of determining cell viability. The most important factor in achieving cell kill via a PDT effect was found to be the length of time with which the drug is allowed to incubate with the cells prior to irradiation. The optimum incubation time of bacterial cells with drug prior to irradiation was found to be 5 minutes.# Cationic photosensitizers are used in PACT due to their ability to interact with the negatively charged surface of the bacterial cell wall. Several different synthesis were attempted to produce multiply cationic porphyrins.

Initially the synthesis of four tetra cationic porphyrins bearing highly fluorinated side chains was attempted. Namely these were 5,10,15,20-tetra-(4-N-(lH, 1H, 2H, 2Hperfluorohexyl)- pyridyl) porphyrin (66), 5,10,15, 20-tetra-(4-N- (1H, 1H, 2H, 2HperfluorododecyO- pyridyl) porphyrin (67), 5,10,15, 20-tetra-(4-(N-(lH, 1H, 2H, 2Hperfluorohexyl)- dimethylanilinium) porphyrin (68) and 5,10,15,20-tetra-(4-(N-lH, 1H, 2H, 2H-perfluorododecyl)-dimethylanilinium) porphyrin (69). However it was found that the alkyl iodides would not couple to the porphyrins, even under severe conditions. The purification of reactions which had partially reacted, were found to be problematic due to the porphyrins sticking to silica.

The syntheses of several different octa cationic and dendritic porphyrins were attempted with varying degrees of success.

Amines at physiological pH are cationic and therefore it was decided to attempt the synthesis of 5,10,15,20-tetra-(4-(aminomethyl)phenyl) porphyrin (70). Several different methods were used in the attempted synthesis, however all proved problematic. #It was decided to utilise parallel synthesis to produce a number of cationic photosensitizers. These were successfully synthesised and contain phosphorus, nitrogen or arsenic cations. The R groups surrounding the cations vary in 2 ways; either the aliphatic chain length varies from methyl to butyl or the aromatic vs. aliphatic character differs.

In total 11 compounds were synthesised and a further 3 were donated by Dr R Hudson to be screened in-vitro against both Gram negative and Gram positive bacteria in order to determine whether any structure activity relationships could be established.

The results of the bacterial assays for the compounds with phosphorus cations, showed that, with the exception of 5,10,15,20-tetra-(4 ((trimethylphosphomunryi)methyl) phenyl) porphyrin tetrabromide, PDT activity decreased as chain length increased. This was also found to be true in the case of the compounds with nitrogen cations, with the exception of both 5,10,15,20-tetra-(4-((trimethylamino)methyl)phenyl)porphyrin tetrabromide (92) and 5,10,15,20-tetra-(4-((triethylamino)methyl)phenyl)porphyrin tetrabromide (82), which gave no cell kill. #In general it was found that compounds with aromatic groups surrounding the cations have less activity than those with aliphatic groups. Differential activity was seen using the compounds synthesised and some idea of optimum structure derived, with 5,10,15, 20-tetra-(4-((tripropylphosphoniumyl)methyl)phenyl) porphyrin tetrabromide (90) and 5, 10,15,20-tetra-(4-((tripropylamino)methyl)phenyl) porphyrin tetrabromide (93) being the most active over a broad spectrum. Interestingly a difference was noted between the activities of S. Aureus and MRS A, possibly due to their different surface structures. Despite the limited range of compounds made, the results in this thesis show that porphyrins can be synthesised and optimized for use in PACT.


Hall, C. E. (2008). The synthesis of cationic porphyrins for use in photodynamic antimicrobial chemotherapy (PACT. (Thesis). University of Hull. Retrieved from

Thesis Type Thesis
Deposit Date Aug 17, 2012
Publicly Available Date Feb 22, 2023
Keywords Chemistry
Public URL
Additional Information Department of Chemistry, The University of Hull
Award Date Apr 1, 2008


Thesis (13.4 Mb)

Copyright Statement
© 2008 Hall, Claire Elizabeth. All rights reserved. No part of this publication may be reproduced without the written permission of the copyright holder.

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