Probing DNA-Cleavage Efficiencies of Copper(II) Complexes: A Computational Perspective.

Theoretical studies on DNA-cleavage efficiencies of Cu(II) complexes 1-3 were carried out using density functional theory (DFT). The optimized Cu(II) complexes were allowed to bind to glutathiones (GSH) and ascorbic acids (VC) by the docking program so that corresponding docking structures can be obtained. To predict DNA-cleavage efficiencies, the docking structures of Cu(II) complexes with GSH and VC were further optimized by DFT. The activation energies of electrons from GSH to complexes, the redox potentials of these complexes, and binding energies of these complexes with GSH and VC were calculated. The efficiencies of complexes cleaving DNA were predicted and found to be in agreement with the experimental results. Finally, three occupied molecular orbitals of docking structures (GSH-complexes) were analyzed, and the DNA-cleavage abilities of complexes were also explained by the electron distribution on the three occupied orbitals. This work has important implications understanding the DNA-cleavage mechanism of Cu(II) complexes, which might be helpful for designing novel anticancer Cu(II) complexes for the future.

Unsaturated trinuclear iron fluoroborylene complexes.

The unsaturated trinuclear iron fluoroborylene complexes Fe3(BF)3(CO) n (n = 7, 6) have been studied using density functional theory (DFT). Relatively complicated potential energy surfaces are found with nine and eight structures within 15 kcal mol-1 of the lowest energy structures for the Fe3(BF)3(CO)7 and Fe3(BF)3(CO)6 systems, respectively. In each of these low-energy structures all three BF groups are either edge-bridging or face-bridging but never terminal groups. Some, but not all, of the low-energy structures also have edge-bridging and/or face-bridging CO groups leading to some structures with as many as five bridging groups. The relatively narrow range of Fe-Fe distances in the central Fe3 triangles of the Fe3(BF)3(CO) n (n = 7, 6) structures, mainly between 2.37 and 2.55 Å, suggests considerable delocalization in these unsaturated systems. Graphical Abstract The lowest energy Fe3(BF)3(CO)7 and Fe3(BF)3(CO)6 structures have a face-bridging µ3-BF group with the two remaining BF groups bridging edges. The lowest energy Fe3(BF)3(CO)6 structure also has one four-electron donor bridging η2-µ-CO group.

Synthesis, G-quadruplexes DNA binding, and photocytotoxicity of novel cationic expanded porphyrins.

Intensive reports allowed the conclusion that molecules with extended aromatic surfaces always do good jobs in the DNA interactions. Inspired by the previous successful researches, herein, we designed a series of cationic porphyrins with expanded planar substituents, and evaluated their binding behaviors to G-quadruplex DNA using the combination of surface-enhanced raman, circular dichroism, absorption spectroscopy and fluorescence resonance energy transfer melting assays. Asymmetrical tetracationic porphyrin with one phenyl-4-N-methyl-4-pyridyl group and three N-methyl-4-pyridyl groups exhibit the best G4-DNA binding affinities among all the designed compounds, suggesting that the bulk of the substituents should be matched to the width of the grooves they putatively lie in. Theoretical calculations applying the density functional theory have been carried out and explain the binding properties of these porphyrins reasonably. Meanwhile, these porphyrins were proved to be potential photochemotherapeutic agents since they have photocytotoxic activities against both myeloma cell (Ag8.653) and gliomas cell (U251) lines.

The inhibitory effect of helenalin on telomerase activity is attributed to the alkylation of the CYS445 residue: evidence from QM/MM simulations.

Enhanced telomerase activity is a hallmark in the majority of cancer cells. Thus, understanding the interactions between telomerase and its inhibitors is fundamentally important for the development of novel anticancer drugs without severe side effects. In this study, the covalent binding of helenalin to CYS445 of telomerase (PDB ID: 3DU6) was simulated using combined quantum chemical and molecular mechanical (QM/MM) methods. The results showed that the reaction was a reversible Michael-type addition and a hydrogen bond was formed between helenalin and the side chain of LYS416 of telomerase during the reaction procedure. The LYS416 residue is vital to telomere DNA recognition by interacting with DNA base through hydrogen bonds. The alkylation of CYS445 of telomerase by helenalin may interfere with the telomere DNA recognition at the telomerase active site, thus resulting in inhibition of the enzyme activity.

13C NMR aided design of molecularly imprinted adsorbents for selectively preparative separation of erythromycin.

Molecularly imprinted polymers (MIPs) with high binding performance and good selectivity are of interest not only in the field of analytical chemistry, but also in the bio-pharmaceutical industry because of their potential use as affinity sorbents for selectively preparative separation of drug molecules. The choice of a suitable functional monomer for the template molecule plays a key role in the performance of MIPs. Erythromycin (ERY; C37H67NO13; mol wt 733.9), produced by bio-fermentation, is a representative macrolide antibiotic with multiple polar groups. In the present study, 13C NMR spectroscopy for the first time was employed to evaluate the interactions between ERY and a set of functional monomers at the atomic level. Based on the 13C chemical shift changes in the ERY molecular structure when binding with different functional monomers, the optimal monomer of methacrylic acid (MAA) was selected and the rational binding sites were predicted. A sequence regarding the interaction force of these binding sites for MAA was proposed, and Density Functional Theory (DFT) theoretical calculation of Lewis basicity of the O/N atoms located at these sites confirmed its reliability. Molecularly imprinted sorbents (MIAs) for ERY were prepared by a suspension polymerization method using MAA as a functional monomer and ethylene glycol dimethacrylate (EGDMA) as a cross-linker. The effects of the monomer to template ratio and the solvent environment employed during the adsorption on the imprinting efficiency of MIAs were both discussed. The adsorption isotherm of ERY on MIAs was fitted by the Langmuir isotherm model. And the specific selectivity of these materials towards ERY was confirmed. The optimized MIAs as column packing materials can separate ERY from its crystal mother liquid with high recovery and good selectivity, exhibiting a promising capability for productive separation of ERY in a large scale. To the best of our knowledge, these results for the first time indicated that 13C NMR spectroscopy is a simple and effective method for the rational design of MIAs towards complex template molecules. The separation model built in this study represents a novel application of MIPs for future industrial production.

The photoinduced electron transference of porphyrin-anthraquinone dyads bridged with different lengths of links.

The photoinduced electron transference (PET) interaction in porphyrin containing donor-acceptor (D-A) molecules is of great importance in nature and a significant part of the PET research has been devoted to the study of its mechanism ("through-space" or "through-bond") in these decades. Herein we synthesized a series of covalently linked porphyrin-anthraquinone dyads (Por-C(n)-AQ) bridged with flexible alkoxy chains at different lengths (n=1, 4, 10) and investigated their intramolecular PET using a combination of electronic absorption, steady-state fluorescence and decayed luminescence spectra. The experimental results show that the PET efficiency depends on the length of the flexible linkage between the porphyrin and anthraquinone moieties. Meanwhile, theoretical calculation applying the density functional theory (DFT) was also carried out to give the frontier orbital distribution and the optimized structures of these dyads. It is found that the orientation of the dyad with high PET efficiency is disadvantageous to π-π interaction. Thus, the PET of these dyads seemingly is best compatible with a "through-bond" (superexchange) mechanism.

Major difference between the isoelectronic fluoroborylene and carbonyl ligands: triply bridging fluoroborylene ligands in Fe3(BF)3(CO)9 isoelectronic with Fe3(CO)12.

The structure of Fe(3)(BF)(3)(CO)(9) is predicted to be very different than that of any of the isoelectronic homoleptic M(3)(CO)(12) derivatives (M = Fe, Ru, Os). Thus the lowest energy Fe(3)(BF)(3)(CO)(9) structure by approximately 19 kcal/mol has mu(3)-BF groups bridging the top and bottom of the Fe(3) triangle with a third edge-bridging BF group in addition to nine terminal carbonyl groups. No analogous M(3)(CO)(12) structures are found with mu(3)-CO groups bridging the M(3) triangle. Higher energy Fe(3)(BF)(3)(CO)(9) structures with two edge-bridging mu-BF groups and one terminal BF group are also found, analogous to the experimentally known Fe(3)(CO)(12) structure. However, these structures are transition states leading to local minima with one unsymmetrical face-bridging mu(3)-BF group, one edge-bridging mu-BF group, and one terminal BF group. No Fe(3)(BF)(3)(CO)(9) structures are found with exclusively terminal BF and CO groups analogous to the known structures of M(3)(CO)(12) (M = Ru, Os). These studies suggest that the BF group has a significantly greater tendency than the CO group to bridge two or three metal atoms, probably owing to the reluctance of the fluorine of the BF ligands to be a part of a formal double or triple bond.

Prospects for making organometallic compounds with BF ligands: fluoroborylene iron carbonyls.

The fluoroborylene ligand (BF), isoelectronic with CO, was recently (2009) realized experimentally by Vidovic and Aldridge in Cp(2)Ru(2)(CO)(4)(mu-BF). In this research the related iron carbonyl fluoroborylene complexes Fe(BF)(CO)(n) (n = 4, 3), Fe(2)(BF)(CO)(8), and Fe(2)(BF)(2)(CO)(n) (n = 7, 6) are compared with the isoelectronic Fe(CO)(n+1) and Fe(2)(CO)(n+2) as well as the thiocarbonyls Fe(CS)(CO)(n) and Fe(2)(CS)(2)(CO)(n) using density functional theory. For Fe(BF)(CO)(4) the axially and equatorially substituted trigonal bipyramidal structures are predicted to be nearly degenerate as is the case for Fe(CS)(CO)(4). The lowest energy structures for Fe(BF)(CO)(3) are derived from the trigonal bipyramidal Fe(BF)(CO)(4) structures by removal of CO groups. For the binuclear derivatives Fe(2)(BF)(CO)(8) and Fe(2)(BF)(2)(CO)(n) (n = 7, 6) structures with BF bridges are preferred energetically over structures with CO bridges. However, no structures for the unsaturated Fe(2)(BF)(2)(CO)(6) are found with four-electron donor eta(2)-mu-BF groups. This differs from the corresponding Fe(2)(CS)(2)(CO)(6) where structures with eta(2)-mu-CS groups and formal Fe-Fe single bonds are preferred over structures with only two electron donor CO and CS groups and formal Fe=Fe double bonds. The lowest energy structure for Fe(2)(BF)(2)(CO)(7) is thus predicted to be similar to the well-known triply bridged Fe(2)(CO)(9) structure but with two bridging BF groups and one bridging CO group. However, the dissociation energy of Fe(2)(BF)(2)(CO)(7) into mononuclear fragments is much higher than that of Fe(2)(CO)(9). Removal of the bridging CO group from this lowest energy Fe(2)(BF)(2)(CO)(7) structure leads to the doubly BF-bridged global minimum structure for Fe(2)(BF)(2)(CO)(6).

DNA-binding and photocleavage properties of cationic porphyrin-anthraquinone hybrids with different lengths of links.

Four cationic porphyrin-anthraquinone (Por-AQ) hybrids differing in lengths of flexible alkyl linkage, 5-[4-(1-N-anthraquinonon-yl)-L-oxophenyl]-10,15,20-tris(N-methylpyridinium-4-yl)porphyrin triiodide, (L = acetyl, pentanoyl, octanoyl, undecanoyl, designed as [AQATMPyP]I3, [AQPTMPyP]I3, [AQOTMPyP]I3 and [AQUTMPyP]I3, respectively, see Fig. 1), were synthesized and their interactions with DNA were investigated. The results of spectroscopic, denaturation and viscosity measurements suggest that [AQATMPyP]I3 binds to DNA through non-intercalative mode while the other three hybrids with longer links bind via bis-intercalative mode. Ethidium bromide (EB) competition experiment was carried out to determine the binding constants (Kb) of these compounds for CT DNA, and [AQPTMPyP]I3 shows the largest Kb among these hybrids. The photocleavage mechanism and wavelength-dependent cleaving abilities of these hybrids to pBR322 plasmid DNA were also comparably investigated.

Binding to DNA purine base and structure-activity relationship of a series of structurally related Ru(II) antitumor complexes: a theoretical study.

The thermodynamics of the binding of a series of structurally related Ru(II) antitumor complexes, that is, alpha-[Ru(azpy)2Cl2] 1, beta-[Ru(azpy)2Cl2] 2, alpha-[Ru(azpy)(bpy)Cl2] 3, and cis-[Ru(bpy)2Cl2] 4 to DNA purine bases (gunine, adenine at N7 site) has been studied by using the DFT method. The binding of imine form of 9-methyladenine (9-MeAde) to the Ru(II) moiety in a didentate fashion via its N6 and N7 atoms was also considered. The geometrical structures of the DNA model base adducts were obtained at the B3LYP/(LanL2DZ + 6-31G(d)) level in vacuo. The following exact single-point energy calculations were performed at the B3LYP/(LanL2DZ(f)+6-311+G(2d, 2p)) level both in vacuo and in aqueous solution using the COSMO model. The bond dissociation enthalpies and free energies, reaction enthalpies and free energies both in the gas phase and in aqueous solution for all considered Ru(II)-DNA model base adducts were obtained from the computations. The calculated bond dissociation enthalpies and free energies allow us to build a binding affinity order for the considered Ru(II)-DNA model base adducts. The theoretical results show that the guanine N7 is a preferred site for this series of complexes and support such an experimental fact that alpha-[Ru(azpy)(bpy)(9-EtGua)H2O](2+) (3-(9-EtGua)) is isomerized to alpha'-[Ru(azpy)(bpy)(9-EtGua)H2O](2+) (3'-(9-EtGua)). On the basis of structural and thermodynamical characteristics, the possible structure-activity relationship was obtained, and the distinct difference in cytotoxicities of this series of structurally related antitumor complexes was explained theoretically.

Tricationic pyridium porphyrins appending different peripheral substituents: experimental and DFT studies on their interactions with DNA.

Four tricationic pyridium porphyrins appending hydroxyphenyl, methoxyphenyl, propionoxyphenyl or carboxyphenyl group at meso-20-position of porphyrin core have been synthesized and their abilities to bind and cleave DNA have been investigated. Using a combination of absorption, fluorescence, circular dichroism (CD) spectra, thermal DNA denaturation as well as viscosity measurements, their binding modes and intrinsic binding constants (K(b)) to calf DNA (CT DNA) were comparatively studied and also compared with those of 5,10,15,20-tetrakis(1-methylpyridinium-4-yl)porphyrin (TMPyP). The results suggest that the K(b) values of these porphyrins are greatly influenced by the number of positive charges and steric hindrance. Theoretical calculations applying the density functional theory (DFT) have been carried out and explain their DNA-binding properties reasonably. The efficiency of DNA photocleavage by these porphyrins shows high dependence on the values of K(b).

Experimental and DFT studies on DNA binding and photocleavage of two cationic porphyrins. Effects of the introduction of a carboxyphenyl into pyridinium porphyrin.

The DNA-binding affinities and DNA photocleavage abilities of cationic porphyrin, 5-(4-carboxyphenyl)-10,15,20-tris(4-methylpyridiniumyl)porphyrin (CTMPyP), and its reference compound meso-tetrakis(N-methyl-4-pyridiniumyl)porphyrin (H2TMPyP) have been investigated. The DNA-binding behaviors of the two compounds in NaH2PO4 buffer were compared systematically by using absorption, fluorescence and circular dichroism (CD) spectra, thermal denaturation as well as viscosity measurements. The experimental results show that CTMPyP binds to DNA in an outside binding mode, while H2TMPyP in an intercalative mode. Photocleavage experiments reveal that both two compounds employ 1O2-mediated mechanism in cleaving DNA and H2TMPyP can cleave DNA more efficiently than CTMPyP. Theoretical calculations were carried out with the density functional theory (DFT), and the calculated results indicate that the character and energies of some frontier orbitals of CTMPyP are quite different from those of H2TMPyP. These theoretical results can be used to explain their different DNA-binding modes and affinities to a certain extent.

DNA binding and photocleavage properties of a novel cationic porphyrin-anthraquinone hybrid.

A novel cationic porphyrin-anthraquinone (Por-AQ) hybrid has been synthesized and characterized. Using the combination of absorption titration, fluorescence spectra, circular dichroism (CD) as well as viscosity measurements, the binding properties of the hybrid to calf thymus (CT) DNA have been investigated compared with its parent porphyrin. The experimental results show that at low [Por]/[DNA] ratios, the parent porphyrin binds to DNA in an intercalative mode while the hybrid binds in a combined mode of outside binding (for porphyrin moiety) and partial intercalation (for anthraquinone). Ethidium bromide (EB) competition experiment determined the binding affinity constants (K(app)) of the compounds for CT DNA. Theoretical calculational results applying the density functional theory (DFT) can explain the different DNA binding behaviors reasonably. (1)O(2) was suggested to be the reactive species responsible for the DNA photocleavage of porphyrin moieties in both two compounds. The wavelength-depending cleavage activities of the compounds were also investigated.

A combined computational and experimental study on DNA-photocleavage of Ru(II) polypyridyl complexes [Ru(bpy)2(L)]2+ (L = pip, o-mopip and p-mopip).

A combined computational and experimental study on DNA-photocleavage by Ru(II) polypyridyl complexes [Ru(bpy)2(L)]2+ 1-3 (bpy = 2,2-bipyridine; L: pip = 2-phenylimidazo[4,5-f]1,10-phenanthroline, o-mopip = 2-(2-methoxyphenyl)imidazo[4,5-f]1,10-phenanthroline and p-mopip = 2-(4-methoxyphenyl)imidazo[4,5-f]1,10-phenanthroline) has been carried out. The DNA-photocleavage behavior of these complexes was comparably measured by the gel electrophoresis experiments. The experimental results show that they can induce considerable DNA-photocleavage, and have different DNA-photocleavage efficiencies (phi) following the order phi (1) < phi (2) < phi (3). In order to understand their DNA-photocleavage mechanism and trend, the theoretical studies on the geometric and electronic structures of these complexes in the ground state (S0), the first singlet excited state (S1) and triplet excited states (T1), have been carried out using the density functional theory (DFT/TD-DFT), Hartree-Fock (HF) and configuration interaction singles (CIS) methods. In particular, the reduction potentials (E*red) of the excited complexes in aqueous solution, which seem to be closely responsible for the DNA-photocleavage behavior, were calculated to be 0.966 V (vs. SCE) for complex , 1.024 V (vs. SCE) for complex and 1.030 V (vs. SCE) for complex , respectively. Such computational results show that the reduction potentials of the excited complexes reach the theoretical range for oxidizing some DNA-bases, and follow the order E*red (1) < E*red (2) < E*red (3). Therefore, here, in addition to the general theoretical explanation of their DNA-photocleavage mechanism according to our recent report, a further explanation on the trend of their DNA-photocleavage efficiencies, i.e., phi (1) < phi (2) < phi (3), was reasonably carried out, on the basis of the calculated electrochemical properties in the excited states as well as general photochemical insights.

Theoretical studies on the excited states, DNA photocleavage, and spectral properties of complex [Ru(phen)(2)(6-OH-dppz)](2+).

The structures and related properties of the complex [Ru(phen)2(6-OH-dppz)]2+ (phen = 1,10-phenanthroline; dppz = dipyrido [3,2-a:2',3'-c]phenazine) in the ground state (S0), the first singlet excited state (S1), and the first triplet excited state (T1) have been studied using density functional theory (DFT), time-dependent (TD) DFT, Hartree-Fock (HF), and configuration interaction singles (CIS) methods. Three electronic absorption-spectral bands (1MLCT, 1LL, and 1LL) lying in the range of 250-550 nm in vacuo and in aqueous solution were theoretically calculated, simulated, and assigned with TDDFT method. In particular, the theoretical results show the following: (1) The positive charges of central Ru atom in the excited states (S1 and T1) are greatly increased relative to those in the ground state (S0), and thus the Ru atom in the excited states can be regarded as Ru(III). (2) The positive charges on the main ligand (6-OH-dppz) in the excited states are considerably reduced, and thus the interaction between the main ligand (intercalative ligand) and DNA base pairs is considerably weakened. (3) The geometric structures in excited states are also distorted, resulting in obvious increase in the coordination bond length. It is advantageous to the complex forming a high oxidizing center (i.e., Ru(III) ion). On the basis of these results, a theoretical explanation on photoinduced oxidation reduction mechanism of DNA photocleavage by [Ru(phen)2(6-OH-dppz)](2+) has been presented.

Density functional theory/time-dependent DFT studies on the structures, trend in DNA-binding affinities, and spectral properties of complexes [Ru(bpy)2(p-R-pip)]2+ (R = -OH, -CH3, -H, -NO2).

Studies on the electronic structures and trend in DNA-binding affinities of a series of Ru(II) complexes [Ru(bpy)2(p-R-pip)]2+ (bpy = 2,2-bipyridine; pip = 2-phenylimidazo[4,5-f] [1,10]-phenanthroline; R = -OH, -CH3, -H, -NO2) 1-4 have been carried out, using the density functional theory (DFT) at the B3LYP/LanL2DZ level. The electronic absorption spectra of these complexes were also investigated using time-dependent DFT (TDDFT) at the B3LYP//LanL2DZ/6-31G level. The computational results show that the substituents on the parent ligand (pip) have a significant effect on the electronic structures of the complexes, in particular, on the energies of the lowest unoccupied molecular orbital (LUMO) and near some unoccupied molecular orbitals (LUMO+x, x = 1-4). With the increase in electron-withdrawing ability of the substituent in this series, the LUMO+x (x = 0-4) energies of the complexes are substantially reduced in order, for example, epsilon(LUMO)(1) approximately epsilon(LUMO)(2) > epsilon(LUMO)(3) > epsilon(LUMO)(4), whereas the pi-component populations of the LUMO+x (x = 0-4) are not substantially different. Combining the consideration of the bigger steric hindrance of complex 2, the trend in DNA-binding affinities (K(b)) of the complexes, that is, K(b)(2) < K(b)(1) < K(b)(3) < K(b)(4) can be reasonably explained. In addition, the experimental singlet metal-to-ligand charge transfer ((1)MLCT) spectra of these complexes can be well simulated and discussed by the TDDFT calculations.

Density functional theory studies on the Raman and IR spectra of meso-tetraphenylporphyrin diacid.

The vibrational spectra of meso-tetraphenylporphyrin diacid (H4TPP2+) have been studied with the density functional theory. Raman and IR spectra of H4TPP2+ and its N-deuterated analogue (D4TPP2+) are measured and compared with the computational results. Complete assignments of observed IR and Raman bands were proposed on the bases of calculation results. The DFT calculations reproduce 140 observed fundamentals with the RMS 8.6 cm-1. The computational as well as the experimental results reveal that the saddle-distortion of porphyrin macrocycle for the diacid leads to a significant effect on its vibrational spectra. Especially, several out-of-plane skeletal modes, which were either unobserved or very weak in the Raman spectra of CuTPP and H2TPP, are activated in the Raman spectra of the diacids. In addition, enhancement for the Raman bands of phenyl CC stretching modes were observed and attributed to the conjugation effect of pi-systems of the phenyl and the porphyrinato macrocycles.