Simi K. Pushpan

Porphyrins in photodynamic therapy - a search for ideal photosensitizers

The utility of light as a therapeutic agent can be traced back over thousands of years when it was used in Ancient Egypt, India and China to treat a variety of skin diseases like psoriasis, vitiligo, rickets, cancer and psychosis. The isolation of porphyrins and their inherent tumor localizing properties coupled with its ability to generate reactive singlet oxygen when activated by light of particular wavelength which in turn results in cytotoxicity led to the emergence of a new modality namely, photodynamic therapy (PDT) as a therapeutic tool. The higher degree of selectivity offered by this modality and fewer side effects when compared to chemotherapy and radiotherapy has prompted the researchers around the globe to generate new photosensitizers. Porphyrins and expanded porphyrins are one class of molecules under intense investigation due to their photosensitizing ability for PDT application. Expanded porphyrins result from the expansion of the phi electron conjugation by increasing the number of heterocyclic rings or bridging carbons of the existing porphyrin framework. These chromophores show strong absorptions in the red region (650-800 nm) compared to that of normal 18phi porphyrins. The strong absorption of light by a water soluble nontoxic photosensitizing molecule in the therapeutic window resulting in maximum penetration of light into the tissues coupled with high singlet oxygen production will conceptualize an ideal photosensitizer. This review highlights various porphyrinoid sensitizers reported till date and their photosensitizing ability both in vitro and in vivo studies. Furthermore, the urgent need for developing ideal photosensitizer for PDT will also be highlighted.

NOVEL HETEROATOM CONTAINING RUBYRINS

Synthesis of rubyrins containing two or three heteroatoms (O, S, Se) in the core is accomplished using modified diols and tetrapyrromethanes. Substitution of heteroatoms leads to significant reductions in HOMO-LUMO gap and easier oxidations and reductions reflecting the changes in electronic structure of the rubyrin skeleton.

Synthesis of meso-substituted core modified expanded porphyrins; Effect of acid catalysts on the cyclization

[3+2] condensation between modified tripyrromethane and bithiophene or bifurandiol leads to the formation of 18π, 22π, 26π macrocycles under Lewis acid conditions while only 22π macrocycle is formed under protic acid conditions.

Aromatic core-modified expanded porphyrinoids with meso-aryl substitutents

Porphyrins are the most widespread of all prosthetic groups found in Nature. The ubiquity of their functions in Nature led researchers around the globe to focus their attention on these highly colored macrocycles. The interdisciplinary interest generated by porphyrins resulted in the syntheses of modified porphyrins, which can be put to a variety of uses in medicine and industry. A brief overview of the synthetic methodologies resulting in the formation of aromatic meso-aryl-substituted core-modified aromatic heterocyclic ring-inserted expanded porphyrinoids like sapphyrins, smaragdyrins, rubyrins, hexaphyrins, heptaphyrins, and octaphyrins reported to date are discussed in this article.

ONE POT SYNTHESIS OF CORE MODIFIED EXPANDED PORPHYRINS

Abstract Reaction of various diols with pyrrole in TFA CH 2 Cl 2 leads to formation of core modified expanded porphyrins.

In Vitro and In Vivo Investigations on the Photodynamic Activity of Core-modified Expanded Porphyrin—Ammonium Salt of 5,10,15,20-tetrakis-(meso-p-sulfonato phenyl)-25,27,29-trithia Sapphyrin¶,†

Abstract The core modification of expanded porphyrins has been proved to have better photochemical properties, which are favorable for photodynamic therapy (PDT) applications. In this context, this study was aimed to investigate the in vitro and in vivo photodynamic activity of one such core-modified expanded porphyrin, namely, ammonium salt of 5,10,15,20-tetrakis-(meso-p-sulfonato phenyl)-25,27,29-trithia sapphyrin. For the in vitro studies, human erythrocytes were used as a membrane semimodel system to investigate the partitioning ability and drug-uptake characteristics. The partition studies on the membrane semimodel system revealed that maximum partitioning occurs at 12 µgm/mL concentration, and from the drug-uptake studies it is observed that maximum amount of the sensitizer is bound to the erythrocyte membranes during a 45 min incubation period. Photohemolysis studies at different concentrations of the sensitizer and exposure time showed maximum damage at 5 µgm/mL and 30 min exposure time. In vivo studies were performed on 7,12-dimethylbenz-(a)nthracene–induced superficial squamous cell carcinoma on mouse skin. The sensitizer at a concentration of 2.5% in 2.0% dimethyl sulfoxide was applied topically on the tumor spot. After 1 h incubation the tumor spot was exposed to laser irradiation from Nd–YAG laser at its second harmonic wavelength of 532 nm. The photodynamic efficacy was estimated by tumor volume measurements at regular intervals after the treatment. One month after PDT exposure a 3.9-fold decrease in the tumor volume was observed with respect to the tumor volume before treatment. The treatment efficacy was further confirmed by histological and fluorescence spectroscopic evaluations of the tissue biopsy sample from the treated area. The results of our study suggest that the ammonium salt of 5,10,15,20-tetrakis-(meso-p-sulfonato phenyl)-25,27,29-trithia sapphyrin may find possible applications in the new modality of cancer treatment.

Inverted porphyrins and expanded porphyrins: An overview

Porphyrins and metallopophyrins have attracted the attention of chemists for the past 100 years or more owing to their widespread involvement in biology. More recently, synthetic porphyrins and porphyrin-like macrocycles have attracted the attention of researchers due to their diverse applications as sensitizers for photodynamic therapy, MRI contrasting agents, and complexing agents for larger metal ions and also for their anion binding abilities. The number of π-electrons in the porphyrin ring can be increased either by increasing the numberof conjugated double bonds between the pyrrole rings or by increasing the number of heterocyclic rings. Thus, 22π sapphyrins, 26π rubyrins, 30π heptaphyrins, 34π octaphyrins and higher cyclic polypyrrole analogues containing 40π, 48π, 64π, 80π and 96π systems have recently been reported in the literature. These macrocycles show rich structural diversity where normal and different kinds of inverted structures have been identified. In this review, an attempt has been made to collect the literature of the inverted porphyrins and expanded porphyrins reported until December 2001. Since themeso aryl expanded porphyrins have tendency to form both inverted and non-inverted structures more emphasis has been given tomeso aryl expanded porphyrins.

meso-Aryl sapphyrins with heteroatoms; synthesis, characterization, spectral and electrochemical properties

The synthesis, characterization and spectral properties of six new meso-aryl core modified sapphyrins are described. An efficient approach involving an acid catalyzed condensation of bithiophene diol 1 and modified tripyrranes 2a–2e allows preparation of the desired meso-aryl sapphyrins in 16–36% yield. The product distribution and the isolated yield were found to be dependent on the nature of the acid catalyst (Lewis acid or protic acid) and its concentration. Protic acid catalyst exclusively gave the expected sapphyrins while two additional products, an 18π tetraphenylporphyrin and a 26π modified rubyrin, were isolated under Lewis acid catalysis. An analysis of proton NMR and absorption spectral data suggests that in free base sapphyrins, the heterocyclic ring opposite to the bithiophene unit is inverted as in N-5 meso-aryl sapphyrin and the degree of inversion is dependent on the nature of the heterocyclic ring. The energy optimized structure calculated from the semi-empirical method substantiates such a conclusion. Protonation of sapphyrins generates respective mono- and dications and the heterocyclic ring retains an inverted structure in contrast to normal N-5 sapphyrins. The triplet excited lifetimes for free base and protonated derivatives are similar both under argon saturated and air equilibrated conditions, indicating that the triplet state quenching by oxygen is minimal. Cyclic voltammetric studies reveal easier reductions and harder oxidations relative to meso-aryl porphyrins and the Δredox observed for 3d suggests significant reduction of the HOMO–LUMO energy gap consistent with the large red shift observed for the Soret band.

Heptaphyrins: Expanded porphyrins with seven heterocyclic rings

Expanded porphyrins containing seven pyrrole/heterocyclic rings linked in a cyclic fashion are termed heptaphyrins. The number ofπ-electrons in heptaphyrins depends on the number ofmeso carbon bridges used to link the heterocyclic rings, accordingly heptaphyrins with 28π-electrons and 30π-electrons are reported to date. Both condensation reactions of the appropriate precursors and acid-catalysed oxidative coupling reactions have been utilized to synthesise the heptaphyrins. The 30π heptaphyrins exhibit rich structural diversity where some of the heterocyclic rings in the macrocycle undergo a 180° ring flipping. An overview of the synthetic methods employed for the synthesis of heptaphyrins, their spectroscopic properties, structural behaviour and aromatic properties are highlighted in this paper.

Dynamic behavior and strategy for the complete 1H and 13C assignments for meso-aryl expanded heptaphyrins

The detailed 1H and 13C NMR analysis of 5,10,19,24-tetramesityl-33,35,36,38,39-pentathiaheptaphyrin (1) and 5,10,19,24-tetraphenyl-35,36-dioxa-33,38,39-trithiaheptaphyrin (2) in the native and protonated state were carried out using two-dimensional NMR techniques. The analysis suggests that the earlier reported structure containing inverted terminal thiophene of trithiophene should be corrected as the inverted thiophene and furan of bithiophene and bifuran instead of trithiophene system of 1 and 2, respectively. Temperature dependent and titration studies suggest that 1 is less flexible in the native state then 2 due to presence of the mesityl group despite having disorder due to the presence of the heavier sulphur atom. This was consequently proven by the NMR information obtained in 5,10,19,24-tetramesityl-35,36-dioxa-33,38,39-trithiaheptaphyrin (3). Whereas in its protonated state, 2 was found to be less flexible than 1 due to presence of intramolecular hydrogen bonding involving N-H---O between the pyrrole NH and oxygen of the furan of bifuran system. A systematic NMR strategy has been generated in order to provide complete a structure determination of expanded porphyrins along with their dynamic behavior.