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Papers by Joshy Joseph

Cheminform, 2005

For Abstract see ChemInform Abstract in Full Text.

Chemistry-a European Journal, 2003

A new series of photoactivated DNA oxidizing agents in which an acridine moiety is covalently lin... more A new series of photoactivated DNA oxidizing agents in which an acridine moiety is covalently linked to viologen by an alkylidene spacer was synthesized, and their photophysical properties and interactions with DNA, including DNA cleaving properties, were investigated. The fluorescence quantum yields of the viologen-linked acridines were found to be lower than that of the model compound 9-methylacridine (MA). The changes in free energy for the electron transfer reactions were found to be favorable, and the fluorescence quenching observed in these systems is explained by an electron transfer mechanism. Intramolecular electron transfer rate constants were calculated from the observed fluorescence quantum yields and singlet lifetime of MA and are in the range from 1.06×1010 s−1 for 1 a (n=1) to 6×108 s−1 for 1 c (n=11), that is, the rate decreases with increasing spacer length. Nanosecond laser flash photolysis of these systems in aqueous solutions showed no transient absorption, but in the presence of guanosine or calf thymus DNA, transient absorption due to the reduced viologen radical cation was observed. Studies on DNA binding demonstrated that the viologen-linked acridines bind effectively to DNA in both intercalative and electrostatic modes. Results of PM2 DNA cleavage studies indicate that, on photoexcitation, these molecules induce DNA damage that is sensitive to formamidopyrimidine DNA glycosylase. These viologen-linked acridines are quite stable in aqueous solutions and oxidize DNA efficiently and hence can be useful as photoactivated DNA-cleaving agents which function purely by the co-sensitization mechanism.

Journal of Physical Chemistry B, 2005

Novel bifunctional conjugates 1-3, with varying polymethylene spacer groups, were synthesized, an... more Novel bifunctional conjugates 1-3, with varying polymethylene spacer groups, were synthesized, and their DNA interactions have been investigated by various biophysical techniques. The absorption spectra of these systems showed bands in the regions of 300-375 and 375-475 nm, corresponding to acridine and acridinium chromophores, respectively. When compared to 1 (Phi(f) = 0.25), bifunctional derivatives 2 and 3 exhibited quantitative fluorescence yields (Phi(f) = 0.91 and 0.98) and long lifetimes (tau = 38.9 and 33.2 ns). The significant quenching of fluorescence and lifetimes observed in the case of 1 is attributed to intramolecular electron transfer from the excited state of the acridine chromophore to the acridinium moiety. DNA-binding studies through spectroscopic investigations, viscosity, and thermal denaturation temperature measurements indicate that these systems interact with DNA preferentially through intercalation of the acridinium chromophore and exhibit significant DNA association constants (K(DNA) = 10(5)-10(7) M(-1)). Compound 1 exhibits chromophore-selective electron-transfer reactions and DNA binding, wherein only the acridinium moiety of 1 interacts with DNA, whereas optical properties of the acridine chromophore remain unperturbed. Among bifunctional derivatives 2 and 3, the former undergoes DNA mono-intercalation, whereas the latter exhibits bis-intercalation; however both of them interact through mono-intercalation at higher ionic strength. Results of these investigations demonstrate that these novel water-soluble systems, which exhibit quantitative fluorescence yields, chromophore-selective electron transfer, and DNA intercalation, can have potential use as probes in biological applications.

Journal of Physical Chemistry B, 2003

Novel water soluble viologen and pyridinium linked tolylacridines 1a,b and 2a,b were synthesized ... more Novel water soluble viologen and pyridinium linked tolylacridines 1a,b and 2a,b were synthesized and their photophysical and DNA binding properties including the photoinduced electron-transfer reactions were investigated. When compared to the cases of the model tolylacridines 3a,b and the pyridinium linked derivatives 2a,b, the singlet excited states of 1a and 1b were efficiently quenched in water and methanol. Intramolecular quenching rate constants (k ET ) calculated in water are found to be 1.2 × 10 10 and 8.8 × 10 10 s -1 for 1a and 1b and 1.4 × 10 8 and 0.9 × 10 8 s -1 for 2a and 2b, respectively, suggesting thereby that the viologen moiety quenches the fluorescence of the acridine chromophore efficiently when compared to the case of the pyridinium moiety. From the intermolecular electron-transfer studies, it was observed that the singlet and triplet excited states of the acridine chromophore are capable of donating an electron to the viologen moiety. DNA binding studies indicated that the p-tolylacridine derivatives 1a and 2a exhibit strong binding to DNA with binding constants of 1.0 × 10 5 and 3.3 × 10 5 M -1 , respectively, whereas the o-tolylacridine derivatives 1b and 2b showed negligible affinity for DNA. The rate constants for the static quenching of 1a and 2a by DNA (k DNA ) are found to be 7 × 10 9 and 3 × 10 9 s -1 , respectively, indicating that 1a is an efficient DNA oxidizing agent. Nanosecond laser flash photolysis studies of these systems in aqueous solutions did not show any transients. However, in the presence of DNA, 1a gave transient absorption due to the reduced methyl viologen radical cation. These results demonstrate that the tolyl spacer group in these systems constitutes an interesting variation which controls both the electron transfer and DNA binding properties, and hence, such molecules and derivatives thereof can have potential application as probes for nucleic acids and as DNA cleaving agents.

Journal of The American Chemical Society, 2007

... Angelo Bongiorno, † Joshy Joseph, ‡ Chusheng Liu, ‡ Gary B. Schuster,* ‡ and Uzi Landman* † ;... more ... Angelo Bongiorno, † Joshy Joseph, ‡ Chusheng Liu, ‡ Gary B. Schuster,* ‡ and Uzi Landman* † ; Schools of Physics, and Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, Georgia 30332. J. Am. Chem. Soc. ... Angelov, D. Biochemistry 1997, 36, 6571−6576. ...

Journal of The American Chemical Society, 2006

The one-electron oxidation of a series of DNA oligonucleotides was examined. Each oligomer contai... more The one-electron oxidation of a series of DNA oligonucleotides was examined. Each oligomer contains a covalently linked anthraquinone (AQ) group. Irradiation of the AQ group with near-UV light results in a one-electron oxidation of the DNA that generates a radical cation (electron "hole"). The radical cation migrates through the DNA by a hopping mechanism and is trapped by reaction with water or molecular oxygen, which results in chemical reaction at particular nucleobases. This reaction is revealed as strand cleavage when the irradiated oligonucleotide is treated with piperidine. The specific oligomers examined reveal the existence of three categories of nucleobase sequences: charge shuttles, charge traps, and barriers to charge migration. The characterization of a sequence is not independent of the identity of other sequences in the oligonucleotide, and for this reason, the function of a particular sequence emerges from an analysis of the entire structure. Qualitative potential energy landscapes are introduced as a tool to assist in the rationalization and prediction of the reactions of nucleobases in oxidized DNA.

Accounts of Chemical Research, 2010

All organisms store the information necessary to maintain life in their DNA. Any process that dam... more All organisms store the information necessary to maintain life in their DNA. Any process that damages DNA, causing a loss or corruption of that information, jeopardizes the viability of the organism. One-electron oxidation is such a process. In this Account, we address three of the central features of one-electron oxidation of DNA: (i) the migration of the radical cation away from the site of its formation; (ii) the electronic and structural factors that determine the nucleobases at which irreversible reactions most readily occur; (iii) the mechanism of reaction for nucleobase radical cations. The loss of an electron (ionization) from DNA generates an electron "hole" (a radical cation), located most often on its nucleobases, that migrates reversibly through duplex DNA by hopping until it is trapped in an irreversible chemical reaction. The particular sequence of nucleobases in a DNA oligomer determines both the efficiency of hopping and the specific location and nature of the damaging chemical reaction. In aqueous solution, DNA is a polyanion because of the negative charge carried by its phosphate groups. Counterions to the phosphate groups (typically Na(+)) play an important role in facilitating both hopping and the eventual reaction of the radical cation with H(2)O. Irreversible reaction of a radical cation with H(2)O in duplex DNA occurs preferentially at the most reactive site. In normal DNA, comprising the four common DNA nucleobases G, C, A, and T, reaction occurs most commonly at a guanine, resulting in its conversion primarily to 8-oxo-7,8-dihydroguanine (8-OxoG). Both electronic and steric effects control the outcome of this process. If the DNA oligomer does not contain a suitable guanine, then reaction of the radical cation occurs at the thymine of a TT step, primarily by a tandem process. The oxidative damage of DNA is a complex process, influenced by charge transport and reactions that are controlled by a combination of enthalpic, entropic, steric, and compositional factors. These processes occur over a broad distribution of energies, times, and spatial scales. The emergence of a complete picture of DNA oxidation will require additional exploration of the structural, kinetic, and dynamic properties of DNA, but this Account offers insight into key elements of this challenge.

Bioconjugate Chemistry, 2004

A series of acridinium derivatives 1-6, wherein steric factors have been varied systematically th... more A series of acridinium derivatives 1-6, wherein steric factors have been varied systematically through substitution at the 9 position of the acridine ring, have been synthesized and their DNA interactions have been investigated by various biophysical techniques. The unsubstituted and methylacridinium derivatives 1 and 2 and the o-tolylacridinium derivative 6 exhibited high fluorescence quantum yields (Phi(f)() congruent with 1) and lifetimes (tau = 35, 34, and 25 ns, respectively), when compared with the arylacridinium derivatives 3-5. The acridinium derivatives 1 and 2 showed high DNA binding affinity (K = 7.3-7.7 x 10(5) M(-)(1)), when compared to the arylacridinium derivatives 3-5 (K = 6.9-10 x 10(4) M(-)(1)). DNA melting and viscosity studies establish that in the case of the aryl-substituted systems, the efficiency of DNA binding is in the order, phenyl > p-tolyl > m-tolyl > o-tolyl derivative. The increase in steric crowding around the acridine ring hinders the DNA binding interactions and thereby leads to negligible binding as observed in the case of 6 (o-tolyl derivative). These results indicate that a subtle variation in the substitution pattern has a profound influence on the photophysical and DNA interactions. Further, they demonstrate that pi-stacking interactions of the ligands with DNA are essential for efficient electron transfer between the DNA bases and the ligands. These water soluble and highly fluorescent molecules which differ in their DNA binding mode can act as models to study various DNA-ligand interactions.

Journal of The American Chemical Society, 2009

Thymine-thymine mispairs are barriers to long-distance radical cation migration and are high reac... more Thymine-thymine mispairs are barriers to long-distance radical cation migration and are high reactivity sites in duplex DNA oligomers. A DNA oligomer was prepared that contains only A/T base pairs, arranged into a regularly repeating series of TT steps, and a covalently linked anthraquinone photosensitizer. Its UV irradiation causes the one-electron oxidation of the DNA introducing a radical cation that reacts predominantly at the TT steps as revealed by subsequent strand cleavage. When a remote GG step is introduced into the DNA oligomer, there is little reaction at any of the TT steps and strand cleavage is detected almost exclusively at the GG step. However, when a TT step contains a thymine-thymine mispair, one electron oxidation of the oligomer results in strand cleavage at the mispair and at TT steps preceding it with little reaction at the remote GG step. Experiments in which a thymine in the mispair is replaced by uracil show that the mispair is both a highly reactive site and a barrier to radical cation hopping. These effects of the thymine-thymine mispairs may be associated with its wobble base pair structure.

Organic Letters, 2007

Thymine−Hg(II)−thymine base pairs have been incorporated in an oligonucleotide duplex to study th... more Thymine−Hg(II)−thymine base pairs have been incorporated in an oligonucleotide duplex to study their effect on DNA-mediated charge transport. The introduction of a formally charged Hg atom inside the DNA base core does not significantly alter the charge hopping and trapping properties, as discussed in this paper. Hg(II) replaces the protons normally found on thymines within the complex and acts like a "big proton" in terms of its role in DNA charge transport.

Cheminform, 2005

For Abstract see ChemInform Abstract in Full Text.

Chemistry-a European Journal, 2003

A new series of photoactivated DNA oxidizing agents in which an acridine moiety is covalently lin... more A new series of photoactivated DNA oxidizing agents in which an acridine moiety is covalently linked to viologen by an alkylidene spacer was synthesized, and their photophysical properties and interactions with DNA, including DNA cleaving properties, were investigated. The fluorescence quantum yields of the viologen-linked acridines were found to be lower than that of the model compound 9-methylacridine (MA). The changes in free energy for the electron transfer reactions were found to be favorable, and the fluorescence quenching observed in these systems is explained by an electron transfer mechanism. Intramolecular electron transfer rate constants were calculated from the observed fluorescence quantum yields and singlet lifetime of MA and are in the range from 1.06×1010 s−1 for 1 a (n=1) to 6×108 s−1 for 1 c (n=11), that is, the rate decreases with increasing spacer length. Nanosecond laser flash photolysis of these systems in aqueous solutions showed no transient absorption, but in the presence of guanosine or calf thymus DNA, transient absorption due to the reduced viologen radical cation was observed. Studies on DNA binding demonstrated that the viologen-linked acridines bind effectively to DNA in both intercalative and electrostatic modes. Results of PM2 DNA cleavage studies indicate that, on photoexcitation, these molecules induce DNA damage that is sensitive to formamidopyrimidine DNA glycosylase. These viologen-linked acridines are quite stable in aqueous solutions and oxidize DNA efficiently and hence can be useful as photoactivated DNA-cleaving agents which function purely by the co-sensitization mechanism.

Journal of Physical Chemistry B, 2005

Novel bifunctional conjugates 1-3, with varying polymethylene spacer groups, were synthesized, an... more Novel bifunctional conjugates 1-3, with varying polymethylene spacer groups, were synthesized, and their DNA interactions have been investigated by various biophysical techniques. The absorption spectra of these systems showed bands in the regions of 300-375 and 375-475 nm, corresponding to acridine and acridinium chromophores, respectively. When compared to 1 (Phi(f) = 0.25), bifunctional derivatives 2 and 3 exhibited quantitative fluorescence yields (Phi(f) = 0.91 and 0.98) and long lifetimes (tau = 38.9 and 33.2 ns). The significant quenching of fluorescence and lifetimes observed in the case of 1 is attributed to intramolecular electron transfer from the excited state of the acridine chromophore to the acridinium moiety. DNA-binding studies through spectroscopic investigations, viscosity, and thermal denaturation temperature measurements indicate that these systems interact with DNA preferentially through intercalation of the acridinium chromophore and exhibit significant DNA association constants (K(DNA) = 10(5)-10(7) M(-1)). Compound 1 exhibits chromophore-selective electron-transfer reactions and DNA binding, wherein only the acridinium moiety of 1 interacts with DNA, whereas optical properties of the acridine chromophore remain unperturbed. Among bifunctional derivatives 2 and 3, the former undergoes DNA mono-intercalation, whereas the latter exhibits bis-intercalation; however both of them interact through mono-intercalation at higher ionic strength. Results of these investigations demonstrate that these novel water-soluble systems, which exhibit quantitative fluorescence yields, chromophore-selective electron transfer, and DNA intercalation, can have potential use as probes in biological applications.

Journal of Physical Chemistry B, 2003

Novel water soluble viologen and pyridinium linked tolylacridines 1a,b and 2a,b were synthesized ... more Novel water soluble viologen and pyridinium linked tolylacridines 1a,b and 2a,b were synthesized and their photophysical and DNA binding properties including the photoinduced electron-transfer reactions were investigated. When compared to the cases of the model tolylacridines 3a,b and the pyridinium linked derivatives 2a,b, the singlet excited states of 1a and 1b were efficiently quenched in water and methanol. Intramolecular quenching rate constants (k ET ) calculated in water are found to be 1.2 × 10 10 and 8.8 × 10 10 s -1 for 1a and 1b and 1.4 × 10 8 and 0.9 × 10 8 s -1 for 2a and 2b, respectively, suggesting thereby that the viologen moiety quenches the fluorescence of the acridine chromophore efficiently when compared to the case of the pyridinium moiety. From the intermolecular electron-transfer studies, it was observed that the singlet and triplet excited states of the acridine chromophore are capable of donating an electron to the viologen moiety. DNA binding studies indicated that the p-tolylacridine derivatives 1a and 2a exhibit strong binding to DNA with binding constants of 1.0 × 10 5 and 3.3 × 10 5 M -1 , respectively, whereas the o-tolylacridine derivatives 1b and 2b showed negligible affinity for DNA. The rate constants for the static quenching of 1a and 2a by DNA (k DNA ) are found to be 7 × 10 9 and 3 × 10 9 s -1 , respectively, indicating that 1a is an efficient DNA oxidizing agent. Nanosecond laser flash photolysis studies of these systems in aqueous solutions did not show any transients. However, in the presence of DNA, 1a gave transient absorption due to the reduced methyl viologen radical cation. These results demonstrate that the tolyl spacer group in these systems constitutes an interesting variation which controls both the electron transfer and DNA binding properties, and hence, such molecules and derivatives thereof can have potential application as probes for nucleic acids and as DNA cleaving agents.

Journal of The American Chemical Society, 2007

... Angelo Bongiorno, † Joshy Joseph, ‡ Chusheng Liu, ‡ Gary B. Schuster,* ‡ and Uzi Landman* † ;... more ... Angelo Bongiorno, † Joshy Joseph, ‡ Chusheng Liu, ‡ Gary B. Schuster,* ‡ and Uzi Landman* † ; Schools of Physics, and Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, Georgia 30332. J. Am. Chem. Soc. ... Angelov, D. Biochemistry 1997, 36, 6571−6576. ...

Journal of The American Chemical Society, 2006

The one-electron oxidation of a series of DNA oligonucleotides was examined. Each oligomer contai... more The one-electron oxidation of a series of DNA oligonucleotides was examined. Each oligomer contains a covalently linked anthraquinone (AQ) group. Irradiation of the AQ group with near-UV light results in a one-electron oxidation of the DNA that generates a radical cation (electron "hole"). The radical cation migrates through the DNA by a hopping mechanism and is trapped by reaction with water or molecular oxygen, which results in chemical reaction at particular nucleobases. This reaction is revealed as strand cleavage when the irradiated oligonucleotide is treated with piperidine. The specific oligomers examined reveal the existence of three categories of nucleobase sequences: charge shuttles, charge traps, and barriers to charge migration. The characterization of a sequence is not independent of the identity of other sequences in the oligonucleotide, and for this reason, the function of a particular sequence emerges from an analysis of the entire structure. Qualitative potential energy landscapes are introduced as a tool to assist in the rationalization and prediction of the reactions of nucleobases in oxidized DNA.

Accounts of Chemical Research, 2010

All organisms store the information necessary to maintain life in their DNA. Any process that dam... more All organisms store the information necessary to maintain life in their DNA. Any process that damages DNA, causing a loss or corruption of that information, jeopardizes the viability of the organism. One-electron oxidation is such a process. In this Account, we address three of the central features of one-electron oxidation of DNA: (i) the migration of the radical cation away from the site of its formation; (ii) the electronic and structural factors that determine the nucleobases at which irreversible reactions most readily occur; (iii) the mechanism of reaction for nucleobase radical cations. The loss of an electron (ionization) from DNA generates an electron "hole" (a radical cation), located most often on its nucleobases, that migrates reversibly through duplex DNA by hopping until it is trapped in an irreversible chemical reaction. The particular sequence of nucleobases in a DNA oligomer determines both the efficiency of hopping and the specific location and nature of the damaging chemical reaction. In aqueous solution, DNA is a polyanion because of the negative charge carried by its phosphate groups. Counterions to the phosphate groups (typically Na(+)) play an important role in facilitating both hopping and the eventual reaction of the radical cation with H(2)O. Irreversible reaction of a radical cation with H(2)O in duplex DNA occurs preferentially at the most reactive site. In normal DNA, comprising the four common DNA nucleobases G, C, A, and T, reaction occurs most commonly at a guanine, resulting in its conversion primarily to 8-oxo-7,8-dihydroguanine (8-OxoG). Both electronic and steric effects control the outcome of this process. If the DNA oligomer does not contain a suitable guanine, then reaction of the radical cation occurs at the thymine of a TT step, primarily by a tandem process. The oxidative damage of DNA is a complex process, influenced by charge transport and reactions that are controlled by a combination of enthalpic, entropic, steric, and compositional factors. These processes occur over a broad distribution of energies, times, and spatial scales. The emergence of a complete picture of DNA oxidation will require additional exploration of the structural, kinetic, and dynamic properties of DNA, but this Account offers insight into key elements of this challenge.

Bioconjugate Chemistry, 2004

A series of acridinium derivatives 1-6, wherein steric factors have been varied systematically th... more A series of acridinium derivatives 1-6, wherein steric factors have been varied systematically through substitution at the 9 position of the acridine ring, have been synthesized and their DNA interactions have been investigated by various biophysical techniques. The unsubstituted and methylacridinium derivatives 1 and 2 and the o-tolylacridinium derivative 6 exhibited high fluorescence quantum yields (Phi(f)() congruent with 1) and lifetimes (tau = 35, 34, and 25 ns, respectively), when compared with the arylacridinium derivatives 3-5. The acridinium derivatives 1 and 2 showed high DNA binding affinity (K = 7.3-7.7 x 10(5) M(-)(1)), when compared to the arylacridinium derivatives 3-5 (K = 6.9-10 x 10(4) M(-)(1)). DNA melting and viscosity studies establish that in the case of the aryl-substituted systems, the efficiency of DNA binding is in the order, phenyl > p-tolyl > m-tolyl > o-tolyl derivative. The increase in steric crowding around the acridine ring hinders the DNA binding interactions and thereby leads to negligible binding as observed in the case of 6 (o-tolyl derivative). These results indicate that a subtle variation in the substitution pattern has a profound influence on the photophysical and DNA interactions. Further, they demonstrate that pi-stacking interactions of the ligands with DNA are essential for efficient electron transfer between the DNA bases and the ligands. These water soluble and highly fluorescent molecules which differ in their DNA binding mode can act as models to study various DNA-ligand interactions.

Journal of The American Chemical Society, 2009

Thymine-thymine mispairs are barriers to long-distance radical cation migration and are high reac... more Thymine-thymine mispairs are barriers to long-distance radical cation migration and are high reactivity sites in duplex DNA oligomers. A DNA oligomer was prepared that contains only A/T base pairs, arranged into a regularly repeating series of TT steps, and a covalently linked anthraquinone photosensitizer. Its UV irradiation causes the one-electron oxidation of the DNA introducing a radical cation that reacts predominantly at the TT steps as revealed by subsequent strand cleavage. When a remote GG step is introduced into the DNA oligomer, there is little reaction at any of the TT steps and strand cleavage is detected almost exclusively at the GG step. However, when a TT step contains a thymine-thymine mispair, one electron oxidation of the oligomer results in strand cleavage at the mispair and at TT steps preceding it with little reaction at the remote GG step. Experiments in which a thymine in the mispair is replaced by uracil show that the mispair is both a highly reactive site and a barrier to radical cation hopping. These effects of the thymine-thymine mispairs may be associated with its wobble base pair structure.

Organic Letters, 2007

Thymine−Hg(II)−thymine base pairs have been incorporated in an oligonucleotide duplex to study th... more Thymine−Hg(II)−thymine base pairs have been incorporated in an oligonucleotide duplex to study their effect on DNA-mediated charge transport. The introduction of a formally charged Hg atom inside the DNA base core does not significantly alter the charge hopping and trapping properties, as discussed in this paper. Hg(II) replaces the protons normally found on thymines within the complex and acts like a "big proton" in terms of its role in DNA charge transport.