BRIEF DESCRIPTION OF SCIENTIFIC CONTRIBUTIONS
The major research activities of our group in the area of chemistry include,
There is a widespread interest in studying the interaction of small molecules with DNA and also in compounds that cleave DNA in unique and controllable ways. In this context and with a view to develop simple molecules that can bind to DNA and cleave DNA only in the presence of light, our group has synthesized novel bifunctional acridine, bisacridine and pyrene conjugates and have examined their photophysical and DNA binding and cleaving properties. These investigations reveal that the synthesized derivatives exhibit high affinity for DNA with association constants in the range 105-107 M-1. Studies have also suggested that the spacer length and nature of the binding group play a major role in controlling the photophysical, DNA binding and cleaving properties and these systems constitute a potential group of novel DNA cleaving agents that function purely through the electron transfer mechanism. We have also investigated the photodimerization and repair of thymidine dimers in peptide nucleic acids (PNAs), which are DNA mimics with normal bases connected to a pseudopeptide chain. It has been observed that the enzyme photolyase uniquely recognizes the thymine dimer in the DNA strand of a DNA/PNA hybrid duplex and irradiation of such a complex lead to the repair of the thymine dimers efficiently. In the process, we have developed a simple and highly sensitive chemical assay for the analysis and location of thymine dimers in DNA.
Recently, our group has been involved in developing novel molecular probes for selective recognition of biologically important molecules such as nucleotides, DNA, amino acids and proteins. In this context, we have synthesized acridine based systems wherein the 9th position of the acridine ring was functionalized with the bulky substituents. Of these systems, the ortho-tolyl acridinium system showed selective interactions with single strand DNA (ssDNA) as compared to double strand DNA (dsDNA) leading to the development of a fluorimetric assay for the quantification of ssDNA under physiological conditions. Our group has also synthesized a series of novel functionalized cyclophanes for biomolecular recognition. Among the various cyclophanes synthesized, the viologen bridged cyclophanes exhibited selective interactions with nucleotides such as ATP and GTP through the synergistic effects of p-p stacking and electrostatic interactions inside the rigid cavity. Further, the versatility of this probe was demonstrated in buffer and blood serum by a fluorescence indicator displacement assay employing a highly fluorescent indicator, 8-hydroxy-1,3,6-pyrene sulfonate (HPTS). Our results indicate that the non-fluorescent complex formed by this cyclophane with HPTS acts a sensitive “turn-on” fluorescent probe for efficient detection of GTP and ATP through an indicator displacement mechanism. We have also developed a novel water-soluble imidazolium bridged symmetrical cyclophane, which, interestingly, exhibited sequence-selective interactions with DNA. The uniqueness of this system is that it can be used for the quantification of DNA through a turn on excimer emission intensity in buffer and under gel electrophoresis conditions.
We have also investigated the photochemistry of several multichromophoric organic systems such as dibenzobarrelenes, naphthobarrelenes, dibenzopentalenofurans, epoxides, and benzoylaziridines. It has been shown that the photolysis of the substituted dibenzobarrlenes yields the corresponding dibenzosemibullvalenes through a triplet state mediated di-p-methane rearrangement, while the dibenzocyclooctatetraenes are isolated as major products under direct irradiation conditions. The photochemistry of the substituted benzoylaziridines, on the other hand, gave products arising through the ring opening via C-C bond cleavage leading to azomethine ylides, intramolecular hydrogen abstraction and C-N bond cleavage products. Recently, we have also been successful in developing novel photochromic materials based on disubstituted dibenzobarrelenes. The importance of these systems is that they exhibit photochromism in the solid state as well as in solution and uniquely through the formation of long-lived triplet biradical intermediates. The results of these investigations indicate that these multichromophoric compounds exhibit novel photochromic behavior as well as undergo interesting photorearrangements that lead to the synthesis of a variety of biologically important polycyclic ring systems.
Photodynamic therapy (PDT) is fast developing as a viable treatment for both cancerous and non-cancerous diseases. It involves the inactivation of living cells by the combined action of light and a photosensitizer. In this context, we have synthesized a series of squaraines, croconaines, porphyrins and aza-BODIPY dyes and have investigated their detailed photophysical and in vitro and in vivo photobiological properties to evaluate their potential use as sensitizers in PDT. These dyes exhibited favorable absorption and fluorescence properties as well as high triplet excited state yields and were found to interact with molecular oxygen resulting in the generation of cytotoxic singlet oxygen in good yields. As expected of a good sensitizer, these systems were found to be non-toxic in the dark while exhibited high photocytotoxicity in mammalian cells and bacterial strains. On excitation with visible light and at sub-micro and nanomolar concentrations, these dyes exhibited efficient cytotoxicity by reducing the cloning efficiency of mammalian cells and bacterial colonies to less than 1%. It is noteworthy that these dyes were non-mutagenic and induced very few micronuclei both in the presence and absence of visible light irradiation. Further to improve the cellular uptake and pharmacokinetics, sugar and cholesterol moieties were incorporated into these dyes. These studies clearly indicate that the synthesized systems based on squaraine, croconaine, porphyrin and aza-BODIPY chromophores form a new generation sensitizers that can have applications in photodynamic therapy of cancer, age related macular degeneration and related diseases.
The major research activities of our group in the area of chemistry include,
- Design of probes for biomolecular recognition and DNA cleaving agents,
- Photochemistry of multichromophoric organic systems and
- Development of novel sensitizers for photodynamic therapeutical applications.
There is a widespread interest in studying the interaction of small molecules with DNA and also in compounds that cleave DNA in unique and controllable ways. In this context and with a view to develop simple molecules that can bind to DNA and cleave DNA only in the presence of light, our group has synthesized novel bifunctional acridine, bisacridine and pyrene conjugates and have examined their photophysical and DNA binding and cleaving properties. These investigations reveal that the synthesized derivatives exhibit high affinity for DNA with association constants in the range 105-107 M-1. Studies have also suggested that the spacer length and nature of the binding group play a major role in controlling the photophysical, DNA binding and cleaving properties and these systems constitute a potential group of novel DNA cleaving agents that function purely through the electron transfer mechanism. We have also investigated the photodimerization and repair of thymidine dimers in peptide nucleic acids (PNAs), which are DNA mimics with normal bases connected to a pseudopeptide chain. It has been observed that the enzyme photolyase uniquely recognizes the thymine dimer in the DNA strand of a DNA/PNA hybrid duplex and irradiation of such a complex lead to the repair of the thymine dimers efficiently. In the process, we have developed a simple and highly sensitive chemical assay for the analysis and location of thymine dimers in DNA.
Recently, our group has been involved in developing novel molecular probes for selective recognition of biologically important molecules such as nucleotides, DNA, amino acids and proteins. In this context, we have synthesized acridine based systems wherein the 9th position of the acridine ring was functionalized with the bulky substituents. Of these systems, the ortho-tolyl acridinium system showed selective interactions with single strand DNA (ssDNA) as compared to double strand DNA (dsDNA) leading to the development of a fluorimetric assay for the quantification of ssDNA under physiological conditions. Our group has also synthesized a series of novel functionalized cyclophanes for biomolecular recognition. Among the various cyclophanes synthesized, the viologen bridged cyclophanes exhibited selective interactions with nucleotides such as ATP and GTP through the synergistic effects of p-p stacking and electrostatic interactions inside the rigid cavity. Further, the versatility of this probe was demonstrated in buffer and blood serum by a fluorescence indicator displacement assay employing a highly fluorescent indicator, 8-hydroxy-1,3,6-pyrene sulfonate (HPTS). Our results indicate that the non-fluorescent complex formed by this cyclophane with HPTS acts a sensitive “turn-on” fluorescent probe for efficient detection of GTP and ATP through an indicator displacement mechanism. We have also developed a novel water-soluble imidazolium bridged symmetrical cyclophane, which, interestingly, exhibited sequence-selective interactions with DNA. The uniqueness of this system is that it can be used for the quantification of DNA through a turn on excimer emission intensity in buffer and under gel electrophoresis conditions.
We have also investigated the photochemistry of several multichromophoric organic systems such as dibenzobarrelenes, naphthobarrelenes, dibenzopentalenofurans, epoxides, and benzoylaziridines. It has been shown that the photolysis of the substituted dibenzobarrlenes yields the corresponding dibenzosemibullvalenes through a triplet state mediated di-p-methane rearrangement, while the dibenzocyclooctatetraenes are isolated as major products under direct irradiation conditions. The photochemistry of the substituted benzoylaziridines, on the other hand, gave products arising through the ring opening via C-C bond cleavage leading to azomethine ylides, intramolecular hydrogen abstraction and C-N bond cleavage products. Recently, we have also been successful in developing novel photochromic materials based on disubstituted dibenzobarrelenes. The importance of these systems is that they exhibit photochromism in the solid state as well as in solution and uniquely through the formation of long-lived triplet biradical intermediates. The results of these investigations indicate that these multichromophoric compounds exhibit novel photochromic behavior as well as undergo interesting photorearrangements that lead to the synthesis of a variety of biologically important polycyclic ring systems.
Photodynamic therapy (PDT) is fast developing as a viable treatment for both cancerous and non-cancerous diseases. It involves the inactivation of living cells by the combined action of light and a photosensitizer. In this context, we have synthesized a series of squaraines, croconaines, porphyrins and aza-BODIPY dyes and have investigated their detailed photophysical and in vitro and in vivo photobiological properties to evaluate their potential use as sensitizers in PDT. These dyes exhibited favorable absorption and fluorescence properties as well as high triplet excited state yields and were found to interact with molecular oxygen resulting in the generation of cytotoxic singlet oxygen in good yields. As expected of a good sensitizer, these systems were found to be non-toxic in the dark while exhibited high photocytotoxicity in mammalian cells and bacterial strains. On excitation with visible light and at sub-micro and nanomolar concentrations, these dyes exhibited efficient cytotoxicity by reducing the cloning efficiency of mammalian cells and bacterial colonies to less than 1%. It is noteworthy that these dyes were non-mutagenic and induced very few micronuclei both in the presence and absence of visible light irradiation. Further to improve the cellular uptake and pharmacokinetics, sugar and cholesterol moieties were incorporated into these dyes. These studies clearly indicate that the synthesized systems based on squaraine, croconaine, porphyrin and aza-BODIPY chromophores form a new generation sensitizers that can have applications in photodynamic therapy of cancer, age related macular degeneration and related diseases.