Anaerobic DNA cleavage in red light by dicopper(II) complexes on disulfide bond activation

Binuclear complexes [Cu(μ-RSSR)]2 (1) and [M2(μ-PDS)(H2O)]2 (M = Cu(II), 2; Fe(II), 3), where H2RSSR is a reduced Schiff base derived from 2-(thioethyl)salicylaldimine having a disulphide moiety and H2PDS is derived from dimerization of D-penicillamine, have been prepared, structurally characterized, and their photo-induced DNA cleavage activity studied. The crystal structure of 1 shows the complex as a discrete binuclear species with each metal in a CuN2O2 square-planar geometry (Cu...Cu, 6.420 Å). The tetradentate RSSR2- acts as a bridging ligand. The sulphur atoms in the disulphide unit do not interact with the metal ions. Complexes 1-3 do not show any DNA cleavage activity in darkness. The copper(II) complexes exhibit chemical nuclease activity in the presence of 3-mercaptopropionic acid. Cleavage of supercoiled DNA has been observed in UV-A light of 365 nm for 1 and red light of 647.1 nm for both 1 and 2 in air. Mechanistic data reveal the involvement of the disulphide unit as photosensitizer generating hydroxyl radicals (•OH) as the reactive species. Photo-induced DNA cleavage in red light seems to involve sulphide radicals in a type-I process and hydroxyl radicals. The dicopper(II) complexes show significant anaerobic photo-induced DNA cleavage activity in red light under argon following type-I pathway without involving any reactive oxygen species

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

Synthesis, crystal structure and magnetic properties of a polymeric copper(II) schiff-base complex having binuclear units covalently linked by isonicotinate ligands

The polynuclear copper(II) complex [{Cu2L(O2CC5H4N)}·C2H5OH]x (1), where H3L is a 1:2 Schiff base derived from 1,3-diaminopropan-2-ol and salicylaldehyde, has been prepared and structurally characterized. The structure consists of a one-dimensional zigzag chain in which the binuclear [Cu2L]+ units are covalently linked by isonicotinate ligands to give a syndiotactic arrangement of the copper ions protruding outside the chain. In the basic unit, the copper(II) centres are bridged by an alkoxo and a carboxylato ligand, giving a Cu···Cu distance of 3.492(3) Å and a Cu-O-Cu angle of 130.9(2)° . While one copper centre has a square-planar geometry, the other copper is squarepyramidal with the pyridine nitrogen being the axial ligand. The visible electronic spectrum of 1 shows a broad d-d band at 615 nm. The complex shows a rhombic X-band EPR spectral pattern in the polycrystalline phase at 77 K. Magnetic susceptibility measurements in the temperature range 22 to 295 K demonstrate the antiferromagnetic behaviour of 1. A theoretical fit to the magnetic data is based on a model assuming 1 as an equimolar mixture of copper atoms belonging to an antiferromagnetically coupled one-dimensional Heisenberg chain with the other copper atoms outside the chain behaving like paramagnetic centres

Oxovanadium(IV)-based near-IR PDT agents: design to biological evaluation

An oxovanadium(IV) complex of dipyridophenazine, as a potent metal-based PDT agent, shows efficient DNA photocleavage activity at near-IR region and high photocytotoxicity in both UV-A and visible light in HeLa cells

Nonlinear Langevin dynamics via holography

In this work, we consider non-linear corrections to the Langevin effective theory of a heavy quark moving through a strongly coupled CFT plasma. In AdS/CFT, this system can be identified with that of a string stretched between the boundary and the horizon of an asymptotically AdS black-brane solution. We compute the Feynman-Vernon influence phase for the heavy quark by evaluating the Nambu-Goto action on a doubled string configuration. This configuration is the linearised solution of the string motion in the doubled black-brane geometry which has been proposed as the holographic dual of a thermal Schwinger-Keldysh contour of the CFT. Our expression for the influence phase passes non-trivial consistency conditions arising from the underlying unitarity and thermality of the bath. The local effective theory obeys the recently proposed non-linear fluctuation dissipation theorem relating the non-Gaussianity of thermal noise to the thermal jitter in the damping constant. This furnishes a non-trivial check for the validity of these relations derived in the weak coupling regime.Comment: 31 pages + appendices. Minor revision added on integrating out ghost fields in the path integra

Copper complexes as chemical nucleases

Redox active mononuclear and binuclear copper(II) complexes have been prepared and structurally characterized. The complexes have planar N-donor heterocyclic bases like 1,10-phenanthroline (phen), dipyridoquinoxaline (dpq) and dipyridophenazine (dppz) ligands that are suitable for intercalation to B-DNA. Complexes studied for nuclease activity have the formulations [Cu(dpq)2(H2O)] (ClO4)2.H2O (1), [CuL(H2O)2(μ-ox)](ClO4)2 (L = bpy,2; phen,3; dpq,4; and dppz,5) and [Cu(L)(salgly)] (L = bpy,6; phen,7; dpq,8; and dppz,9), where salgly is a tridentate Schiff base obtained from the condensation of glycine and salicylaldehyde. The dpq complexes are efficient DNA binding and cleavage active species. The dppz complexes show good binding ability but poor nuclease activity. The cleavage activity of thebis-dpq complex is significantly higher than thebis-phen complex of copper(II). The nuclease activity is found to be dependent on the intercalating nature of the complex and on the redox potential of the copper(II)/copper(I) couple. The ancillary ligand plays a significant role in binding and cleavage activity

Impact of metal on the DNA photocleavage activity and cytotoxicity of ferrocenyl terpyridine 3d metal complexes

Ferrocenyl terpyridine 3d metal complexes and their analogues, viz. [M(Fc-tpy)2](ClO4)2 (1-4), [Zn(Ph-tpy)2](ClO4)2 (5) and [Zn(Fc-dpa)2]X2 (X = ClO4, 6; PF6, 6a), where M = Fe(II) in 1, Co(II) in 2, Cu(II) in 3 and Zn(II) in 4, Fc-tpy is 4'-ferrocenyl-2,2':6',2''-terpyridine, Ph-tpy is 4'-phenyl-2,2':6',2''-terpyridine and Fc-dpa is ferrocenyl-N,N-dipicolylmethanamine, are prepared and their DNA binding and photocleavage activity in visible light studied. Complexes 2, 4, 5 and 6a that are structurally characterized by X-ray crystallography show distorted octahedral geometry with the terpyridyl ligands binding to the metal in a meridional fashion, with Fc-dpa in 6a showing a facial binding mode. The Fc-tpy complexes display a charge transfer band in the visible region. The ferrocenyl (Fc) complexes show a quasi-reversible Fc+-Fc redox couple within 0.48 to 0.66 V vs. SCE in DMF-0.1 M TBAP. The DNA binding constants of the complexes are 104 M-1. Thermal denaturation and viscometric data suggest DNA surface binding through electrostatic interaction by the positively charged complexes. Barring the Cu(II) complex 3, the complexes do not show any chemical nuclease activity in the presence of glutathione. Complexes 1-4 exhibit significant plasmid DNA photocleavage activity in visible light via a photoredox pathway. Complex 5, without the Fc moiety, does not show any DNA photocleavage activity. The Zn(II) complex 4 shows a significant PDT effect in HeLa cancer cells giving an IC50 value of 7.5 µ M in visible light, while being less toxic in the dark (IC50 = 49 µ M)

Metal-assisted red light-induced efficient DNA cleavage by dipyridoquinoxaline-copper(II) complex

Complete cleavage of double stranded pUC19 DNA by the complex [Cu(dpq)2(H2O)](ClO4)2 (dpq, dipyridoquinoxaline) has been observed on irradiation at 694 nm from a pulsed ruby laser, assisted by the metal d-band transition as well as the quinoxaline triplet states in the absence of any external additives

Vitamin-B6 Schiff base dioxovanadium(V) complex for targeted visible light-induced anticancer activity

A dioxovanadium(V) complex of vitamin-B6 Schiff base [VO2L] (1) (where H2L·HCl is 3-hydroxy-5-(hydroxymethyl)-4-(((2-hydroxyphenyl)imino)methyl)-2-methylpyridin-1-ium chloride) has been prepared and structurally characterized. Its photo-induced cytotoxicity and mechanism of cell death has been studied. Single crystal X-ray structure shows five-coordinate square-pyramidal geometry of the complex having the dianionic O,N,O-donor tridentate vitamin-B6 Schiff base and two cis-oriented oxo ligands bound to V(V). DFT study shows the HOMO located on the amino-phenolic moiety, while the LUMO is on the protonated aromatic unit, i.e., the pyridiniumphenolate moiety. Vitamin-B6 transporting membrane carrier (VTC) pathway seems to be responsible for the higher cellular uptake and activity of the complex into the cervical HeLa and breast cancer MCF-7 cells in preference to the normal embryonic fibroblast 3T3 cells. The complex exhibits reactive oxygen species (ROS) mediated apoptotic photocytotoxicity in visible light of 400–700 nm in the cancer cells (IC50: ~16 μM), while being essentially non-toxic in the dark. Alkaline Comet assay shows damage of the nuclear DNA.

Photocleavage of DNA by copper(II) complexes

The chemistry of ternary and binary copper(II) complexes showing efficient visible lightinduced DNA cleavage activity is summarized in this article. The role of the metal in photo-induced DNA cleavage reactions is explored by designing complex molecules having a variety of ligands. Ternary copper(II) complexes with amino acid like L-methionone or L-lysine and phenanthroline base are efficient photocleavers of DNA. Complexes of formulation $[Cu(L^n)(phen)](ClO_4)$ with NSO-donor Schiff base $(HL^n)$ and NN-donor heterocyclic base 1,10-phenanthroline (phen) show significant cleavage of supercoiled (SC) DNA on exposure to red light at \approx 700 nm. The d–d and CT electronic bands of the copper(II) complexes play important roles in DNA cleavage reactions. The mechanistic pathways are found to be dependent on the types of ligands present in the copper(II) complexes and the photo-excitation energy. While UV exposure generally proceeds via a type-II process forming singlet oxygen as the reactive species, red-light exposure leads to DNA cleavage following different mechanistic pathways, viz. type-I, type-II and photo-redox pathways. Ternary copper(II) complexes with phen as DNA binder and Schiff base with a thiomethyl group as photosensitizer, cleave SC DNA to its nicked circular (NC) form in a type-II process in red-light. The binary complex $[Cu(dpq)_2(H_2O)](ClO_4)_2$ (dpq, dipyridoquinoxaline) cleaves DNA by photo-redox pathway at 694 nm. The binuclear complex $[Cu^{II} _2(RSSR)_2]$, where $H_2RSSR$ is a Schiff base derived from 2-(thioethyl)salicylaldimine, cleaves SC DNA at 632.8nm (CW He–Ne laser) and 694 nm (ruby laser) involving sulphide (type-I process) and hydroxyl radicals (photo-redox pathway) as the reactive species