Joshy Joseph

Oxidation of DNA: Damage to Nucleobases

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.

Carbazole-Linked Near-Infrared Aza-BODIPY Dyes as Triplet Sensitizers and Photoacoustic Contrast Agents for Deep-Tissue Imaging

Four new N-ethylcarbazole-linked aza-boron-dipyrromethene (aza-BODIPY) dyes (8u2009a,b and 9u2009a,b) were synthesized and characterized. The presence of the N-ethylcarbazole moiety shifts their absorption and fluorescence spectra to the near-infrared region, λ≈650-730u2005nm, of the electromagnetic spectrum. These dyes possess strong molar absorptivity in the range of 3-4×104 u2009m-1 u2009cm-1 with low fluorescence quantum yields. The triplet excited state and singlet oxygen generation of these dyes were enhanced upon iodination at the core position. The core-iodinated dyes 9u2009a,b showed excellent triplet quantum yields of about 90 and 75u2009%, with singlet oxygen generation efficiency of about 70 and 60u2009% relative to that of the parent dyes. Derivatives 8u2009a,b showed dual absorption profiles, in contrast to dyes 9u2009a,b, which had the characteristic absorption band of aza-BODIPY dyes. DFT calculations revealed that the electron density was spread over the iodine and dipyrromethene plane of 9u2009a,b, whereas in 8u2009a,b the electron density was distributed on the carbazole group and dipyrromethene plane of aza-BODIPY. The uniqueness of these aza-BODIPY systems is that they exhibit efficient triplet-state quantum yields, high singlet oxygen generation yields, and good photostability. Furthermore, the photoacoustic (PA) characteristics of these aza-BODIPY dyes was explored, and efficient PA signals for 8u2009a were observed relative to blood serum with in vitro deep-tissue imaging, thereby confirming its use as a promising PA contrast agent.

Oxidative Thymine Mutation in DNA: Water-Wire-Mediated Proton-Coupled Electron Transfer

One-electron oxidation of A/T-rich DNA leads to mutations at thymine. Experimental investigation of DNA containing methyl-deuterated thymine reveals a large isotope effect establishing that cleavage of this carbon-hydrogen bond is involved in the rate-determining step of the reaction. First-principles quantum calculations reveal that the radical cation (electron hole) generated by DNA oxidation, initially located on adenines, localizes on thymine as the proton is lost from the methyl group, demonstrating the role of proton-coupled electron transfer (PCET) in thymine oxidation. Proton transport by structural diffusion along a segmented water-wire culminates in proton solvation in the hydration environment, serving as an entropic reservoir that inhibits reversal of the PCET process. These findings provide insight into mutations in A/T-rich DNA such as replication fork stalling that is implicated in early stage carcinogenesis.

Oxidatively Damaged Nucleobases in Duplex DNA Oligomers: Reaction at Thymine−Thymine Mispairs

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.

Cross-Linkable Fluorene-Diphenylamine Derivatives for Electrochromic Applications

Multicolor electrochromic systems based on heat cross-linkable arylamine-substituted fluorene derivatives, FD and FDOMe, are reported. These derivatives with pendant vinyl groups have been synthesized by the Buchwald-Hartwig amination reaction and were well-characterized using various analytical and spectroscopic techniques such as NMR, ESI-MS, and single-crystal X-ray diffraction analysis. FD and FDOMe exhibited thermally activated cross-linking above their melting temperatures, which was confirmed through absorption, differential scanning calorimetry (DSC), FT-IR, and wide-angle X-ray diffraction (WAXD) techniques. Cross-linked FD films (FD-X) on ITO showed two reversible redox peaks at 0.74 and 0.91 V (versus Ag/AgCl) that correspond to the formation of radical cations and dications, respectively. The corresponding redox peaks were observed at 0.6 and 0.8 V for cross-linked FDOMe films (FDOMe-X). Spectroelectrochemical studies of the electrochromic films on ITO revealed multicolor electrochromism of FD-X (colorless-yellow-dark cyan) and FDOMe-X (colorless-brick red-blue) with a color contrast of ∼44% at 485 nm for FD-X and ∼63% at 500 nm for FDOMe-X and good switching stability between the neutral and oxidized states (>300 cycles) with low switching voltages (<0.9 V for the first oxidation and <1.3 V for the second oxidation). Furthermore, fabrication of electrochromic devices using FD-X and FDOMe-X on FTO substrate with PMMA-based solid electrolyte was demonstrated, where the devices exhibited reasonably low switching time between the redox states (<30 s) with good optical contrast.

Photoisomerisation of dibenzobarrelenes—a facile route to polycyclic synthons

Triplet state mediated di-pi-methane rearrangements of dibenzobarrelenes give a variety of interesting synthons, formed as primary and secondary photoproducts. These synthons could find use for the synthesis of complex synthetic targets. This tutorial review highlights the photoisomerisation of some bridgehead substituted dibenzobarrelenes and the products derived from them. Selected examples of photoisomerisations proceeding through a tri-pi-methane pathway are also included.

Amino Acid-Porphyrin Conjugates: Synthesis and Study of their Photophysical and Metal Ion Recognition Properties

Synthesis, photophysical and metal ion recognition properties of a series of amino acid‐linked free‐base and Zn‐porphyrin derivatives (5–9) are reported. These porphyrin derivatives showed favorable photophysical properties including high molar extinction coefficients (>1 × 105 m−1 cm−1 for the Soret band), quantum yields of triplet excited states (63–94%) and singlet oxygen generation efficiencies (59–91%). Particularly, the Zn‐porphyrin derivatives, 6 and 9 showed higher molar extinction coefficients, decreased fluorescence quantum yields, and higher triplet and singlet oxygen quantum yields compared to the corresponding free‐base porphyrin derivatives. Further, the study of their interactions with various metal ions indicated that the proline‐conjugated Zn‐porphyrins (6 and 9) showed high selectivity toward Cu2+ ions and signaled the recognition through changes in fluorescence intensity. Our results provide insights on the role of nature of amino acid and metallation in the design of the porphyrin systems for application as probes and sensitizers.

Design and synthesis of solution processable green fluorescent D–π–A dyads for OLED applications

New solution processable organic donor–π–acceptor dyads 1 and 2 having electron donating phenoxazine and electron accepting oxadiazole groups have been synthesized. Intramolecular electron communication between the donor and acceptor moieties of these dyads was tuned through changing the substitution pattern at the phenylene linker. The photophysical properties of these dyads have been studied in the solution and film states. These dyads showed green fluorescence and exhibited a positive solvatochromism in the emission spectra, which indicates more polar excited states owing to an efficient charge migration from the donor phenoxazine to the acceptor oxadiazole moiety. The electrochemical, morphological and thermal properties were investigated through cyclic voltammetry, thermogravimetric and atomic force microscopy (AFM) analyses. To understand the electronic structure and band gap of these dyads, density functional theory (DFT) calculations have been performed. Furthermore, we have fabricated the solution processed un-doped electroluminescence devices based on these dyads, which exhibited efficient green emission with Commission Internationale de l’Eclairage (CIE) coordinates of (0.26, 0.49) and (0.27, 0.47) for 1 and 2, respectively, with a luminance maximum of ca. 1751 cd m−2 for the dyad 1, thereby demonstrating its use in organic light emitting diodes (OLEDS).

Selective recognition of cyanide ions by amphiphilic porphyrins in aqueous medium

Herein, we report the synthesis of two amphiphilic porphyrins having pyridinium moieties and their anion recognition properties in aqueous medium. The study of their interactions with various anions reveals that these porphyrins exhibit unique and selective interactions with CN- ions when compared to the other anions. The addition of CN- ions to an aqueous solution of the butyl porphyrin resulted in a hypochromicity of ca. 78% at 419 nm with a concomitant band formation at 449 nm in the absorption spectrum. Similarly, we observed ca. 82% quenching in the emission intensity by the addition of 12.5 M of CN- ions in the fluorescence spectrum of the porphyrin mediated through aggregation. The limit of detection of CN- ions was found to be ca. 49 ppb and the nature of interactions has been studied through various microscopic and spectroscopic techniques. These studies have confirmed 1,4-addition of CN- ions to the pyridinium moiety of the porphyrin system, which led to the aggregation induced self-assembly resulting in the sensitive detection of CN- ions through changes in absorbance and fluorescence intensity in aqueous medium.

Fullerene Cluster Assisted Self‐Assembly of Short DNA Strands into Semiconducting Nanowires

Programmable, hierarchical assembly of DNA nanostructures with precise organisation of functional components have been demonstrated previously with tiled assembly and DNA origami. However, building organised nanostructures with random oligonucleotide strands remains as an elusive problem. Herein, a simple and general strategy, in which nanoclusters of a fullerene derivative act as stapler motifs in bringing ordered nanoscale assembly of short oligonucleotide duplexes into micrometre-sized nanowires, is described. In this approach, the fullerene derivative, by virtue of its amphiphilic structure and unique hydrophobic-hydrophilic balance, pre-assembles to form 3-5u2005nm sized clusters in a mixture of DMSO-phosphate buffer, which further assists the assembly of DNA strands. The optimum cluster size, availability of DNA anchoring motifs and the nature of the DNA strands controls the structure of these nanomaterials. Furthermore, horizontal conductivity measurements through conductive AFM confirmed the charge transport properties of these nanowires. The current strategy could be employed to organise random DNA duplexes and tiles into functional nanostructures, and hence, open up new avenues in DNA nanotechnology.