Tavarekere K. Chandrashekar

Structural Diversity in Expanded Porphyrins

Inspired by the chemistry of porphyrins, in the last decade, a new research area where porphyrin analogues such as expanded, isomeric, and contracted porphyrins have been synthesized, and their chemistry has been exploited extensively. Expanded porphyrins are macrocyclic compounds where pyrrole or heterocyclic rings are connected to each other through meso carbon bridges. Depending on the number of pyrrole rings in conjugation or the number of double bonds linking the four pyrrole rings expanded porphyrins containing up to 64 pi electrons are reported in the literature. The interest in these systems lies in their potential applications as anion binding agents, as photosensitizers for photodynamic therapy (PDT), in antisensing applications, as MRI contrasting agents, and more recently, as material for nonlinear optical application. Expanded porphyrins containing more than four pyrrole or heterocyclic rings, such as sapphyrin (five pyrrole), rubyrin (six pyrrole), heptaphyrin (seven pyrrole), and octaphyrin (eight pyrrole), are reported in the literature. Furthermore, substituents on expanded porphyrins can be attached either at the meso carbons or at beta-pyrrole positions. beta-substituted expanded porphyrins generally adopt normal structure where all the pyrrole nitrogens point inward in the cavity 1, while the meso-substituted expanded porphyrins exhibit normal 2, inverted 3, fused 4, confused 5, and figure eight 6 conformations. The conformation of expanded porphyrin is dependent on the nature of the linkage of the heterocyclic rings, the nature and the number of the heteroatoms present in the cavity, and the state of protonation. It is possible to change one conformation to another by varying temperature or by simple chemical modification, such as protonation by acids. An understanding of the structure-function correlation in expanded porphyrins is an important step for designing these molecules for their potential applications. In this context, even though several meso aryl expanded porphyrins are reported in literature, there is no comprehensive understanding of structural diversity exhibited by them. In this Account, an attempt has been made to provide a systematic understanding of the conditions and circumstances that lead to various conformations and structures. Specifically, the structural diversities exhibited by five pyrrolic macrocycles to ten pyrrolic macrocycles are covered in this Account. In pentapyrrolic systems, sapphyrins, N-fused, and N-confused pentaphyrins are described. It has been shown that the positions of the heteroatom affect the conformation and in turn the aromaticity. In hexapyrrolic systems, rubyrins and hexaphyrins are covered. The conformation of core-modified rubyrins was found to be dependent on the number and nature of the heteroatom present inside the core. Further, in the hexapyrrolic systems, an increase in the number of meso carbons from four (rubyrin) to six (hexaphyrin) increases the conformational flexibility, where different types of conformations are observed upon going from free base to protonated form. Heptapyrrolic and octapyrrolic expanded porphyrins also exhibit rich structural diversity. Octaphyrins are known to exhibit figure eight conformation, where the macrocycle experiences a twist at the meso carbon, losing aromatic character. By suitable chemical modification, it is possible to avoid the twist, and planar 34 pi core-modified octaphyrins have been reported that show aromatic character and obey the (4 n + 2) Hückel rule. The structural diversity exhibited by nine pyrrolic macrocycles (nonaphyrins) and ten pyrrolic macrocycles (decaphyrins) are also described.

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.

Smaragdyrins: Emeralds of Expanded Porphyrin Family

Porphyrins are tetrapyrrolic 18 π electron conjugated macrocycles with wide applications that range from materials to medicine. Expanded porphyrins, synthetic analogues of porphyrins that contain more than 18 π electrons in the conjugated pathway, have an increased number of pyrroles or other heterocyles or multiple meso-carbon bridges. The expanded porphyrins have attracted tremendous attention because of unique features such as anion binding or transport that are not present in porphyrins. Expanded porphyrins exhibit wide applications that include their use in the coordination of large metal ions, as contrasting agents in magnetic resonance imaging (MRI), as sensitizers for photodynamic therapy (PDT) and as materials for nonlinear optical (NLO) studies. Pentaphyrin 1, sapphyrin 2, and smaragdyrin 3 are expanded porphyrins that include five pyrroles or heterocyclic rings. They differ from each other in the number of bridging carbons and direct bonds that connect the five heterocyclic rings. Sapphyrins were the first stable expanded porphyrins reported in the literature and remain one of the most extensively studied macrocycles. The strategies used to synthesize sapphyrins are well established, and these macrocycles are versatile anion binding agents. They possess rich porphyrin-like coordination chemistry and have been used in diverse applications. This Account reviews developments in smaragdyrin chemistry. Although smaragdyrins were discovered at the same time as sapphyrins, the chemistry of smaragdyrins remained underdeveloped because of synthetic difficulties and their comparative instability. Earlier efforts resulted in the isolation of stable β-substituted smaragdyrins and meso-aryl isosmaragdyrins. Recently, researchers have synthesized stable meso-aryl smaragdyrins by [3 + 2] oxidative coupling reactions. These results have stimulated renewed research interest in the exploration of these compounds for anion and cation binding, energy transfer, fluorescent sensors, and their NLO properties. Recently reported results on smaragdyrin macrocycles have set the stage for further synthetic studies to produce stable meso-aryl smaragdyrins with different inner cores to study their properties and potential for various applications.

meso-Tetrakis(p-sulfonatophenyl)N-Confused Porphyrin Tetrasodium Salt: A Potential Sensitizer for Photodynamic Therapy

A water-soluble derivative of N-confused porphyrin (NCP) was synthesized, and the photodynamic therapeutic (PDT) application was investigated by photophysical and in vitro studies. High singlet oxygen quantum yield in water at longer wavelength and promising IC(50) values in a panel of cancer cell lines ensure the potential candidacy of the sensitizer as a PDT drug. Reactive oxygen species (ROS) generation on PDT in MDA-MB 231 cells and the apoptotic pathway of cell death was illustrated using different techniques.

Sapphyrin Supramolecules through C−H⋅⋅⋅S and C−H⋅⋅⋅Se Hydrogen Bonds—First Structural Characterization of meso- Arylsapphyrins Bearing Heteroatoms

An unprecedented coupling reaction of heteroatom-containing tripyrranes leads to the formation of core-modified sapphyrins 1 and 2, which self-assemble in the solid state to form supramolecular ladders. Weak C-H⋅⋅⋅S and C-H⋅⋅⋅Se hydrogen-bonding interactions in addition to C-H⋅⋅⋅N hydrogen bonds are responsible for the observed structures.

In vitro demonstration of apoptosis mediated photodynamic activity and NIR nucleus imaging through a novel porphyrin.

We synthesized a novel water-soluble porphyrin THPP and its metalated derivative Zn-THPP having excellent triplet excited state quantum yields and singlet oxygen generation efficiency. When compared to U.S. Food and Drug Administration approved and clinically used sensitizer Photofrin, THPP showed ca. 2-3-fold higher in vitro photodynamic activity in different cell lines under identical conditions. The mechanism of the biological activity of these porphyrin systems has been evaluated through a variety of techniques: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, comet assay, poly(ADP-ribose)polymerase (PARP) cleavage, CM-H(2)DCFDA assay, DNA fragmentation, flow cytometric analysis, fluorescence, and confocal microscopy, which confirm the apoptotic cell death through predominantly reactive oxygen species (ROS). Moreover, THPP showed rapid cellular uptake and are localized in the nucleus of the cells as compared to Hoechst dye and Photofrin, thereby demonstrating its use as an efficient sensitizer in photodynamic therapy and live cell NIR nucleus imaging applications.

Spectroscopic and electrochemical studies on oxaporphyrins and oxathiaporphyrins

The synthesis and characterization of oxaporphyrins (OTPP and O2TPP) containing one and two furan rings in place of pyrrole and a mixed oxathiaporphyrin (OSTPP) is reported. Spectroscopic and electrochemical studies reveal that oxaporphyrins exhibit optical and emission characteristics closer to the parent H2TPP, while their electrochemical behaviour parallels that reported for mono and dithiaporphyrins. However the characteristics of the mixed oxathia derivative resemble that of monothiaporphyrin. Protonation studies reveal weaker resonance interaction between the β-hydrogens and meso-phenyl substituents in sharp contrast to thiaporphyrins. The reduction potentials for OSTPP and O2TPP indicate stabilization and destabilization of their LUMOs relative to the parent H2TPP in the ground and excited states, respectively.

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.

Core Modified meso‐Aryl Corrole: First Examples of CuII, NiII, CoII and RhI Complexes

A variety of metal complexes of 5,10,15-triphenyl-21-monooxa-corrole 4 have been investigated. This monooxa corrole, where one of the pyrrole ring is replaced by a furan moiety, is synthesized by the alpha-alpha coupling reaction of 16-oxa tripyrrane and dipyrromethane. The single crystal X-ray structure of 4 indicates only small deviation of the inner-core heteroatoms from planarity and this macrocycle arrange themselves into a columnar structure. Insertion of metals further flattens the corrole framework. Specifically, oxacorrole 4 binds to Nil(II), Cu(II), and Co(II) with the participation of all heteroatoms in the coordination. However, Rh(I) ion binds to only one imino and one amino nitrogen of the macrocycle. The bond angles at the metal center in the Ni(II) and Rh(I) complexes reveal square planar geometry completed by two CO molecules for Rh(I). The EPR spectra of the paramagnetic that Cu(II) and Col(II) complexes display significant decreases in the metal hyperfine couplings compared with the corresponding porphyrin complexes. The presence of superhyperfine coupling in the Cu(II) complex suggests delocalization of unpaired electron density into the ligand orbitals. Electrochemical studies reveal easier oxidations and harder reductions relative to the corresponding porphyrin derivatives while, the metallated derivatives did not show their characteristic metal reductions due to the high energy of their LUMO.

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.