Metal-assisted red light-induced DNA cleavage by ternary L-methionine copper(II) complexes of planar heterocyclic bases

Ternary copper(II) complexes [Cu(L-met)B(Solv)](ClO4) (1-4), where B is a N,N-donor heterocyclic base like 2,2-bipyridine (bpy, 1), 1,10-phenanthroline (phen, 2), dipyrido[3,2-d:2',3'-f]quinoxaline (dpq, 3) and dipyrido[3,2-a:2',3'-c]phenazene (dppz, 4), are prepared and their DNA binding and photoinduced DNA cleavage activity studied (L-Hmet=L-methionine). Complex 2, structurally characterized by X-ray crystallography, shows a square pyramidal (4+1) coordination geometry in which the N,O-donor L-methionine and N,N-donor heterocyclic base bind at the basal plane and a solvent molecule is coordinated at the axial site. The complexes display a d-d band at ~600 nm in DMF and exhibit a cyclic voltammetric response due to the Cu(II)/Cu(I) couple near -0.1 V in DMF-Tris-HCl buffer. The complexes display significant binding propensity to the calf thymus DNA in the order: 4 (dppz) > 3 (dpq) > 2 (phen) » 1 (bpy). Control cleavage experiments using pUC19 supercoiled DNA and distamycin suggest major groove binding for the dppz and minor groove binding for the other complexes. Complexes 2-4 show efficient DNA cleavage activity on UV (365 nm) or red light (632.8 nm) irradiation via a mechanistic pathway involving formation of singlet oxygen as the reactive species. The DNA cleavage activity of the dpq complex 3 is found to be significantly more than its dppz and phen analogues

Evaluation of Wuchereria bancrofti GST as a Vaccine Candidate for Lymphatic Filariasis

Lymphatic parasites survive for years in a complex immune environment by adopting various strategies of immune modulation, which includes counteracting the oxidative free radical damage caused by the host. We now know that the filarial parasites secrete antioxidant enzymes. Among these, the glutathione-S-transferases (GSTs) have the potent ability to effectively neutralize cytotoxic products arising from reactive oxygen species (ROS) that attack cell membranes. Thus, GSTs have the potential to protect the parasite against host oxidative stress. GSTs of several helminthes, including schistosomes, fasciola and the filarial parasite Seteria cervi, are also involved in inducing protective immunity in the host. The schistosome 28 kDa GST has been successfully developed into a vaccine and is currently in Phase II clinical trials. Thus, GST appears to be a potential target for vaccine development. Therefore, in the present study, we cloned W. bancrofti GST, and expressed and purified the recombinant protein. Immunization and challenge experiments showed that 61% of protection could be achieved against B. malayi infections in a jird model. In vitro studies confirm that the anti-WbGST antibodies participate in the killing of B. malayi L3 through an ADCC mechanism and enzymatic activity of WbGST appears to be critical for this larvicidal function

Biochemical Characterization and Evaluation of a Brugia malayi Small Heat Shock Protein as a Vaccine against Lymphatic Filariasis

Filarial nematodes enjoy one of the longest life spans of any human pathogen due to effective immune evasion strategies developed by the parasite. Among the various immune evasion strategies exhibited by the parasite, Interleukin 10 (IL-10) productions and IL-10 mediated immune suppression has significant negative impact on the host immune system. Recently, we identified a small heat shock protein expressed by Brugia malayi (BmHsp12.6) that can bind to soluble human IL-10 receptor alpha (IL-10R) and activate IL-10 mediated effects in cell lines. In this study we show that the IL-10R binding region of BmHsp12.6 is localized to its N-terminal region. This region has significant sequence similarity to the receptor binding region of human IL-10. In vitro studies confirm that the N-terminal region of BmHsp12.6 (N-BmHsp12.6) has IL-10 like activity and the region containing the alpha crystalline domain and C-terminus of BmHsp12.6 (BmHsp12.6αc) has no IL-10 like activity. However, BmHsp12.6αc contains B cell, T cell and CTL epitopes. Members of the sHSP families are excellent vaccine candidates. Evaluation of sera samples from putatively immune endemic normal (EN) subjects showed IgG1 and IgG3 antibodies against BmHsp12.6αc and these antibodies were involved in the ADCC mediated protection. Subsequent vaccination trials with BmHsp12.6αc in a mouse model using a heterologous prime boost approach showed that 83% protection can be achieved against B. malayi L3 challenge. Results presented in this study thus show that the N-BmHsp12.6 subunit of BmHsp12.6 has immunoregulatory function, whereas, the BmHsp12.6αc subunit of BmHsp12.6 has significant vaccine potential

Wall-coated polymer brushes as catalytic support for organic reactions in continuous-flow microreactors

A microreactor platform has been realized as an enabling tool to perform synthetic organic reactions. The platform provides advantages over batch reactions, thus allowing: reactions with a potentially explosive reagent, the execution of heterogeneous catalysis by immobilizing catalysts onto the interior of a microchannel surface, and the performance of controlled formation of supramolecular nanoparticle clusters. In the first part, the regioselective ring opening of various types of aromatic and aliphatic epoxides with hazardous sodium azide to give vicinal azido alcohols, was studied in a microreactor with and without pillars in the channels. The reactions performed in microreactors with pillars displayed better conversions compared to analogous lab scale reactions. In the second part, polymer brush layers with thicknesses of a few hundred nanometers were used as a support for catalyst immobilization on the interior of microchannel walls. Polymer brushes support higher catalyst loadings as compared to monolayers. Different types of catalysts were implemented inside the microreactor. Their catalytic efficiency was studied for different reactions. In the last part, self-assembly of supramolecular nanoparticle clusters (SNPCs) has been demonstrated in a microfluidic device, by controlling the diffusive mixing of the constituting supramolecular building blocks. Microreactors are a valuable tool to study homogeneous and heterogeneous reactions in a safe and efficient way. Polymer brushes have proven to be a robust platform to immobilize various catalysts on the interior of a microchannel for performing supported catalysis. In addition, microreactors provide a unique environment for the controlled fabrication of nanomaterials compared to lab-scale equipment. So, microreactors have the potential to become a common experimental device for chemists in various disciplines

Designing molecules for PDT: red light-induced DNA cleavage on disulfide bond activation in a dicopper(II) complex

The binuclear copper(II) complex [Cu2(RSSR)2]( 1), where RSSR is a dianionic Schiff base derived from 2-(thioethyl)salicylaldimine having a disulfide bond is prepared, structurally characterized by X-ray crystallography and its photo-induced DNA cleavage activity studied. The Schiff base ligand H2RSSR is also structurally characterized. The crystal structure of 1 shows the discrete dimeric nature of the complex with each metal showing square-planar geometry with a CuN2O2 coordination (Cu...Cu, 5.011(1)Å). The tetradentate Schiff base RSSR acts as a linker of two copper centers. The sulfur atoms in the disulfide unit do not show any apparent interaction with the metal ion. Complex 1, which is cleavage inactive in the dark in the presence of reducing agents, shows significant cleavage of supercoiled pUC19 DNA on exposure to UV light of 312 nm or visible light of different wavelengths under aerobic conditions, in the absence of any additives. DNA cleavage data from control experiments reveal involvement of the disulfide unit as a photosensitizer undergoing photo-induced S-S bond cleavage on exposure to UV light and the resulting species activates molecular oxygen to form singlet oxygen (1O2) that causes DNA cleavage following a type-II process. Photo-induced DNA cleavage by 1 on red-light exposure using a CW laser of 632.8 nm or a pulsed ruby laser of 694 nm is proposed to involve sulfide radicals in a type-I process and hydroxyl radicals as the reactive species

Synthesis, crystal structure and photo-induced DNA cleavage activity of ternary copper(II) complexes of NSO-donor Schiff bases and NN-donor heterocyclic ligands

New ternary copper(II) complexes [CuL<SUP>n</SUP>B](ClO<SUB>4</SUB>) (1-3), where HL<SUP>n</SUP> is the NSO donor Schiff base derived from the condensation of 2-mercaptoethylamine hydrochloride with salicylaldehyde (HL<SUP>1</SUP>) or 2-hydroxy-3-methoxybenzaldehyde (HL<SUP>2</SUP>) and B is NN-donor heterocyclic base like 2,2'-bipyridine (bpy, 1), 1,10-phenanthroline (phen, 2) or 2,9-dimethyl-1,10-phenanthroline (dmp, 3), are prepared, structurally characterized by X-ray crystallography and their DNA cleavage activity studied. The complexes show distorted square-pyramidal (4 + 1) CuN<SUB>3</SUB>OS coordination geometry in which the NSO-donor Schiff base is bonded at the basal plane and the NN-donor heterocyclic base displays axial-equatorial mode of bonding [Cu-S distance: ~2.4 &#197;]. The one-electron paramagnetic (&#956;<SUB>eff</SUB> = ~1.9 &#956;<SUB>B</SUB>) complexes display axial EPR spectra in DMF glass at 77 K giving g||= ~2.2 (A = 162 G) and g&#8869; = ~2.0, indicating {d<SUB>x<SUP>2</SUP>-y<SUP>2</SUP></SUB>}<SUP>1</SUP> ground state. The complexes exhibit visible spectral d-d band in MeCN near 650 nm and two charge transfer bands near 400 nm. Complexes 1 and 2 display quasireversible cyclic voltammetric response in DMF-Tris buffer (1:4 v/v, pH 7.2) for the Cu(II)/Cu(I) couple at ca. -0.1 V vs. SCE. Complex 3 exhibits an irreversible reduction process forming [Cu<SUP>I</SUP>(dmp)<SUB>2</SUB>]<SUP>+</SUP>. Binding of 1-3 to calf thymus DNA shows the relative order: 2 (phen) &#8805; 3 (dmp) &gt; 1 (bpy). Complex 2 efficiently cleaves supercoiled pUC19 DNA in the presence of mercaptopropionic acid (MPA) forming hydroxyl radical or on irradiation with light of 312, 532 and 632.8 nm wavelength in a type-II process. Complexes 1 and 3 are cleavage inactive

Hydrogenation of CO2, carbonyl and imine substrates catalyzed by IrH3((PNP)-P-Ph-P-H)] complex

A series of iridium and rhodium complexes M(COD)((PNP)-P-Ph-P-H)]Cl {M = Ir (1), Rh (2)}, MH2Cl((PNP)-P-Ph-P-H)] {M = Ir (3), Rh (4)} and IrH3((PNP)-P-Ph-P-H)] (6) supported by pincer ligand HeN(CH2CH2PPh2)(2) {(PNP)-P-Ph-P-H} have been synthesized and characterized. All complexes were isolated in good yields. The iridium trihydride complex IrH3((PNP)-P-Ph-P-H)] (6) was found to be an active catalyst for the hydrogenation of CO2 in 1 M aqueous KOH solution. It also acts as a catalyst for the base-free hydrogenation of carbonyl and imine substrates in MeOH. Under similar hydrogenation conditions, 2-cyclohexen-1-one undergoes solvent assisted tandem Michael addition-reduction mediated by bifunctional Lewis-acid-catalyst IrH3((PNP)-P-Ph-P-H)] in ROH (R = Me, Et) at room temperature. The complexes 1, 3, 4, and 6 were characterized by X-ray crystallography. Extensive hydrogen bonding interactions N-H center dot center dot center dot H-Ir (2.15 angstrom), N-H center dot center dot center dot center dot Cl (2.370 angstrom) were noted in the crystal structures of these complexes. (C) 2018 Elsevier B.V. All rights reserved

Improved catalytic activity and stability using mixed sulfonic acid- and hydroxy-bearing polymer brushes in microreactors

Sulfonic acid-bearing polymer brushes were grown on the inner walls of continuous flow glass microreactors and used in the acid-catalyzed hydrolysis of benzaldehyde dimethyl acetal as a test reaction. Randomly 1:1 mixed polymer brushes of poly-3-sulfopropyl methacrylate (PSPM) and poly-2-hydroxyethyl methacrylate (PHEMA) showed a 6-fold increase of the TOF value compared to the solely PSPM-containing microreactor. This remarkable improvement is attributed to the cooperative stabilizing effect of proximal OH groups on the active sulfonic acid moieties within the brush architecture. In fact, the rational mixing of SPM with methyl methacrylate (MMA) as an OH-free comonomer caused a drop in the activity of the resulting catalytic platform. A 5-fold increase of the TON of the 1:1 PSPM–PHEMA versus the PSPM homopolymer brush systems additionally demonstrates the substantial increase in the stability of the mixed brushes catalytic platform, which could be continuously run over 7 days without significant loss of activity. The 1:1 PSPM–PHEMA mixed brush catalytic system also showed a good activity in the deprotection of 2-benzyl tetrahydropyranyl ether

Steric Protection of a Photosensitizer in a N,N-Bis[2-(2-pyridyl)ethyl]-2-phenylethylamine-copper(II) Bowl that Enhances Red Light-Induced DNA Cleavage Activity

Ternary copper(II) complexes $[Cu(py_2phe)B](ClO_4)_2$ (1-3), where $py_2phe$ is a tripodal ligand N,N-bis[2-(2-pyridyl)ethyl]-2-phenylethylamine and B is a heterocyclic base (viz., 1,10-phenanthroline (phen, 1), dipyrido[3,2-d:2',3'-f]quinoxaline (dpq, 2), or dipyrido[3,2-a:2',3'-c]phenazine (dppz, 3)), are prepared and their DNA-binding and photoinduced DNA-cleavage activities are studied. Complex 1 has been structurally characterized by single crystal X-ray crystallography. The molecular structure shows an axially elongated square-pyramidal (4 + 1) coordination geometry in which the phen ligand binds at the basal plane. The tripodal ligand $py_2phe$ displays an axial-equatorial binding mode with the amine nitrogen bonded at the axial site. A chemically significant CH-\pi interaction involving the CH moiety of the phenyl group of the tripodal ligand and the aromatic ring of phen is observed. The complexes display good binding propensity to calf thymus DNA giving a relative order of 3 (dppz) > 2 (dpq) > 1 (phen). The DNA binding constants $(K_b)$ for 1-3, determined from absorption spectral studies, are $6.2 \times 10^3$, $1.0 \times 10^4 and \hspace {2mm} 5.7 \times 10^4 M^{-1}$, respectively. The complexes show chemical nuclease activity in the presence of 3-mercaptopropionic acid as a reducing agent forming hydroxyl radicals as the cleavage active species. The photoinduced DNA-cleavage activity of the complexes has been studied using UV radiation of 365 nm and red light of 632.8 and 694 nm. The phen complex in absence of any photosensitizing moiety does not show any DNA cleavage upon photoirradiation. The dpq and dppz ligands with their photoactive quinoxaline and phenazine moieties display significant photoinduced DNA-cleavage activity. The dppz complex is more active than its dpq analogue because of the better steric protection of the DNA-bound photosensitizing dppz ligand from the solvent molecules. Control experiments reveal the formation of singlet oxygen in the light-induced DNA-cleavage reactions. The observed efficient photoinduced DNA-cleavage activity of 2 and 3 is akin to the "light switch" effect known for the tris-chelates of ruthenium(II)

DNA Cleavage on Photoexposure at the d-d Band in Ternary Copper(II) Complexes Using Red-Light Laser

Ternary copper(II) complexes $[Cu(L^1)B](ClO_4)$ (1,2) and $[Cu(L^2)B](ClO_4)$ (3, 4), where $HL^1$ and $HL^2$ are tridentate NSO- and ONO-donor Schiff bases and B is a heterocyclic base, viz. dipyrido[3,2-d:2',3'-f]quinoxaline (dpq, 1 and 3) or dipyrido[3,2-a:2',3'-c]phenazine (dppz, 2 and 4), were prepared and their DNA binding and photoinduced DNA cleavage activity studied. Complex 1, structurally characterized by single-crystal X-ray crystallography, shows an axially elongated square-pyramidal (4 + 1) coordination geometry in which the monoanionic $L^1$ binds at the equatorial plane. The NN-donor dpq ligand exhibits an axial-equatorial binding mode. The complexes display good binding propensity to calf thymus DNA, giving a relative order 2 (NSO-dppz) > 4 (ONO-dppz) > 1 (NSO-dpq) > 3 (ONO-dpq). They cleave supercoiled pUC19 DNA to its nicked circular form when treated with 3-mercaptopropionic acid (MPA) by formation of hydroxyl radicals as the cleavage active species under dark reaction conditions. The photoinduced DNA cleavage activity of the complexes was investigated using UV radiation of 365 nm and red light of 633, 647.1, and 676.4 nm (CW He-Ne and Ar-Kr mixed gas ion laser sources) in the absence of MPA. Complexes 1 and 2, having photoactive NSO-donor Schiff base and dpq/dppz ligands, show dual photosensitizing effects involving both the photoactive ligands in the ternary structure with significantly better cleavage properties when compared to those of 3 and 4, having only photoactive dpq/dppz ligands. Involvement of singlet oxygen in the light-induced DNA cleavage reactions is proposed. A significant enhancement of the red-light-induced DNA cleavage activity is observed for the dpq and dppz complexes containing the sulfur ligand when compared to their earlier reported phen (1,10-phenanthroline) analogue. Enhancement of the cleavage activity on photoexposure at the d-d band indicates the occurrence of metal-assisted photosensitization processes involving the LMCT and d-d band in the ternary structure