Relationship between Intracellular Concentration of S-Adenosylhomocysteine and Inhibition of Vaccinia Virus Replication and Inhibition of Murine L-929 Cell Growth

9-(trans-2',trans-3'-Dihydroxycyclopent-4'-enyl)-adenine (compound 1) and -3-deazaadenine (compound 2), which are specific inhibitors of S-adenosylhomocysteine (AdoHcy) hydrolase, were reported earlier by our laboratory (M. Hasobe, J. G. McKee, D. R. Borcherding, and R. T. Borchardt, Antimicrob. Agents Chemother. 31:1849-1851, 1987) to have anti-vaccinia virus activity with reduced murine L-929 cell toxicity compared with the prototype compound neplanocin A. In this study, we showed that the antiviral and cytotoxic effects of compounds 1 and 2 can be related to intracellular concentrations of AdoHey, which are elevated in cells treated with these inhibitors of AdoHcy hydrolase. For example, concentrations of analogs 1 and 2 that produce 50% inhibition of vaccinia virus replication caused only slight elevations in intracellular levels of AdoHcy (from 50 [controls] to 100 to 125 [drug-treated cells] pmol/mg of protein) and elevations in the ratios of AdoHcy/S-adenosylmethionine (from 0.05 to 0.1 [controls] to 0.15 to 0.19 [drug-treated cells]). In contrast to the extreme susceptibility of virus replication to slight elevations in intracellular AdoHcy, cell viability was quite tolerant to higher levels of this metabolite. For example, concentrations of analogs 1 and 2 that produced 50% inhibition of L-929 cell replication caused significant increases in intracellular levels of AdoHcy (to 825 to 950 pmol/mg of protein) and elevations in AdoHcy/S-adenosylmethionine ratios (approximately 1.3). These data make it possible to assign a therapeutic index of 7 to 8 to these compounds on the basis of the comparison of intracellular levels of AdoHcy that caused 50% inhibition of vaccinia virus replication with those that caused 50% inhibition of L-929 cell replication.This work was supported by a Public Health Service grant from the National Institutes of Health (GM-29332) and a grant from Glaxo, Inc

9-(trans-2',trans-3'-Dihydroxycyclopent-4'-Enyl)-Adenine and -3-Deazaadenine: Analogs of Neplanocin A Which Retain Potent Antiviral Activity but Exhibit Reduced Cytotoxicity

Two synthetic analogs of neplanocin A, which were shown in a separate study to be inhibitors of S-adenosylhomocysteine hydrolase and devoid of substrate activity with adenosine kinase, were found in this study to inhibit vaccinia virus replication in murine L929 cells but to have reduced cytotoxicity compared with that of the parent compound. These results confirm that S-adenosylhomocysteine hydrolase is the molecular target which mediates the antiviral effects of neplanocin A and that transformation by cellular adenosine kinase mediates its cytotoxic properties.This work was supported by Public Health Service research grant GM-29332 from the National Institutes of Health

Interaction of metal phthalocyanines with carbon zigzag and armchair nanotubes with different diameters

Quantum-chemical calculations of the association of metal free, cobalt, copper and zinc phthalocyanines (MPc) with carbon zigzag and armchair nanotubes (CNTs) with diameters in the range of 7–14 Å were carried out by the DFT method with the use of BH van der Waals density functional and DZP atomic basis set. It was shown that interaction energy between the phthalocyanine molecules and the CNTs, as a whole, increases with an increase of the diameter of carbon nanotubes. However, in the case of CNT(n,0) the energy reaches its maximal value at n = 16 or 17 depending on the central metal atom and phthalocyanine orientation on the carbon nanotubes surface. Up to diameter of 10.5 Å of the CNTs, stronger binding of the considered MPc macrocyclic molecules is observed with carbon armchair nanotubes. However, in the case of higher diameters the phthalocyanines are associated more strongly with the zigzag CNTs

Historical Perspectives in the Development of Antiviral Agents Against Poxviruses

The poxvirus vaccinia virus (VV) served as the model virus for which the first antivirals, the thiosemicarbazones, were identified. This dates back to 1950; and, although there is at present no single antiviral drug specifically licensed for the chemotherapy or -prophylaxis of poxvirus infections, numerous candidate compounds have been described over the past 50 years. These compounds include interferon and inducers thereof (i.e., polyacrylic acid), 5-substituted 2’-deoxyuridines (i.e., idoxuridine), IMP dehydrogenase inhibitors, S-adenosylhomocysteine hydrolase inhibitors, acyclic nucleoside phosphonates (such as cidofovir) and alkoxyalkyl prodrugs thereof (such as CMX001), viral egress inhibitors (such as tecovirimat), and cellular kinase inhibitors (such as imatinib)

Design and synthesis of a series of truncated neplanocin fleximers

In an effort to study the effects of flexibility on enzyme recognition and activity, we have developed several different series of flexible nucleoside analogues in which the purine base is split into its respective imidazole and pyrimidine components. The focus of this particular study was to synthesize the truncated neplanocin A fleximers to investigate their potential anti-protozoan activities by inhibition of S-adenosylhomocysteine hydrolase (SAHase). The three fleximers tested displayed poor anti-trypanocidal activities, with EC50 values around 200 μM. Further studies of the corresponding ribose fleximers, most closely related to the natural nucleoside substrates, revealed low affinity for the known T. brucei nucleoside transporters P1 and P2, which may be the reason for the lack of trypanocidal activity observed

Zinc Phthalocyanine−Graphene Hybrid Material for Energy Conversion: Synthesis, Characterization, Photophysics and Photoelectrochemical Cell Preparation

Graphene exfoliation upon tip sonication in o-­‐DCB was accomplished. Then, covalent grafting of (2-­‐ aminoethoxy)(tri-­‐tert-­‐butyl) zinc phthalocyanine (ZnPc), to exfoliated graphene sheets was achieved. The newly formed ZnPc-­‐graphene hybrid material was found soluble in common organic solvents without any precipitation for several weeks. Application of diverse spectroscopic techniques verified the successful formation of ZnPc-­‐graphene hybrid materi-­‐ al, while thermogravimetric analysis revealed the amount of ZnPc loading onto graphene. Microscopy analysis based on AFM and TEM was applied to probe the morphological characteristics and to investigate the exfoliation of graphene sheets. Efficient fluorescence quenching of ZnPc in the ZnPc-­‐graphene hybrid material suggested that photoinduced events occur from the photoexcited ZnPc to exfoliated graphene. The dynamics of the photoinduced electron transfer was evaluated by femtosecond transient absorption spectroscopy, thus, revealing the formation of transient species such as ZnPc+ yielding the charge-­‐separated state ZnPc•+–graphene•–. Finally, the ZnPc-­‐graphene hybrid material was integrated into a photoactive electrode of an optical transparent electrode (OTE) cast with nanostructured SnO2 films (OTE/SnO2), which exhibited sta le and reproducible photocurrent responses and the incident photon-­‐to-­‐current conversion efficien-­‐ cy was determine

Near-Unity Singlet Fission on a Quantum Dot Initiated by Resonant Energy Transfer

The conversion of a high-energy photon into two excitons using singlet fission (SF) has stimulated a variety of studies in fields from fundamental physics to device applications. However, efficient SF has only been achieved in limited systems, such as solid crystals and covalent dimers. Here, we established a novel system by assembling 4-(6,13-bis(2-(triisopropylsilyl)ethynyl)pentacen-2-yl)benzoic acid (Pc) chromophores on nanosized CdTe quantum dots (QDs). A near-unity SF (198 ± 5.7%) initiated by interfacial resonant energy transfer from CdTe to surface Pc was obtained. The unique arrangement of Pc determined by the surface atomic configuration of QDs is the key factor realizing unity SF. The triplet-triplet annihilation was remarkably suppressed due to the rapid dissociation of triplet pairs, leading to long-lived free triplets. In addition, the low light-harvesting ability of Pc in the visible region was promoted by the efficient energy transfer (99 ± 5.8%) from the QDs to Pc. The synergistically enhanced light-harvesting ability, high triplet yield, and long-lived triplet lifetime of the SF system on nanointerfaces could pave the way for an unmatched advantage of SF.acceptedVersionPeer reviewe

Efficient photocatalytic proton-coupled electron-transfer reduction of O2 using a saddle-distorted porphyrin as a photocatalyst

Photocatalytic O2 reduction reactions proceeded to produce H2O2 using a diprotonated saddle-distorted dodecaphenylporphyrin as a photocatalyst. The quantum yield (12%), the turnover number (3000 for 6 h), and the turnover frequency (500 h−1) are achieved in photocatalytic systems based on free-base porphyrins for the first time. The photocatalytic reaction mechanism has been revealed by ns-laser flash photolysis and kinetic analysis

Structure-based model for light-harvesting properties of nucleic acid nanostructures

Programmed self-assembly of DNA enables the rational design of megadalton-scale macromolecular assemblies with sub-nanometer scale precision. These assemblies can be programmed to serve as structural scaffolds for secondary chromophore molecules with light-harvesting properties. Like in natural systems, the local and global spatial organization of these synthetic scaffolded chromophore systems plays a crucial role in their emergent excitonic and optical properties. Previously, we introduced a computational model to predict the large-scale 3D solution structure and flexibility of nucleic acid nanostructures programmed using the principle of scaffolded DNA origami. Here, we use Förster resonance energy transfer theory to simulate the temporal dynamics of dye excitation and energy transfer accounting both for overall DNA nanostructure architecture as well as atomic-level DNA and dye chemical structure and composition. Results are used to calculate emergent optical properties including effective absorption cross-section, absorption and emission spectra and total power transferred to a biomimetic reaction center in an existing seven-helix double stranded DNA-based antenna. This structure-based computational framework enables the efficient in silico evaluation of nucleic acid nanostructures for diverse light-harvesting and photonic applications.United States. Office of Naval Research (ONR N000141210621)United States. Army Research Office (ARO MURI W911NF1210420

Synthesis of Novel Porphyrin and its Complexes Covalently Linked to Multi-Walled Carbon Nanotubes and Study of their Spectroscopy

Novel covalent porphyrin and its complexes (Co2+, Zn2+) functionalized multi-walled carbon nanotubes (MWNTs) have been successfully synthesized by the reaction of the carboxyl on the surface of MWNTs which was synthesized to use carbon radicals generated by the thermal decomposition of azodiisobutyronitrile (AIBN) with 5-p-hydroxyphenyl-10,15,20-triphenyl-porphyrin and its complexes (Co2+, Zn2+). Three resulting nanohybrids were characterized by spectroscopy (FT-IR, Raman, and UV-vis), TGA, and TEM. The quality of porphyrin attached to the MWNTs was determined from thermogravimeric analysis (TGA) of the MWNTs, which showed a weight loss of about 60%. The Raman and absorption spectroscopy data showed that the electronic properties of modified MWNTs were mostly retained, without damaging their one-dimensional electronic properties. From fluorescence measurements, it was observed that the porphyrin and its complexes (Co2+, Zn2+) were nearly quenched by MWNTs, indicating that this covalently modified mode facilitated the effective energy or electron transfer between the excited porphyrin moiety and the extended π-system of MWNTs