Theoretical studies on DNA-photocleavage efficiencies of Ru(II) polypyridyl complexes.

Theoretical studies on the DNA-photocleavage efficiencies of Ru(II) polypyridyl complexes 1-4 have been carried out using density functional theory (DFT). First, an evaluation of the computational accuracy of the redox potentials for [Ru(bpy)(3)](2+) in the ground state and the excited state was tested by different computational methods. Secondly, the redox potentials of complexes 1-4 in the excited state were accurately computed. Finally, the trend in the DNA-photocleavage efficiencies (φ) of complexes 1-4, i.e., φ(4) > φ(3) > φ(2) > φ(1), were reasonably explained by the excited-state reduction potentials and the electron-transfer activation energies. In particular, the DNA-photocleavage efficiencies of two new Ru(II) complexes 3 and 4 were predicted.

Theoretical studies on DNA-photocleavage efficiencies and mechanisms of Ru(II) polypyridyl complexes.

Theoretical studies on the DNA-photocleavage efficiencies and mechanisms of Ru(II) complexes [Ru(bpy)(2)(L)](2+) (bpy = 2,2'-bipyridine; L: dppz = dipyrido[3,2-a:2',3'-c]phenazine; mitatp = 5-methoxy-isatino[1,2-b]-1,4,8,9-tetraazatriphenylene; nitatp = 5-nitro-isatino [1,2-b]-1,4,8,9-tetraazatriphenylene) 1-3 were carried out using density functional theory (DFT). First, the accuracies of redox potentials computed for [Ru(bpy)(3)](2+) in the ground state and the excited state by different computational methods were tested, and then the redox potentials of complexes 1-3 in their excited states were computed accurately. Secondly, the trend in the DNA-photocleavage efficiencies (ϕ) of complexes 1-3 [i.e., ϕ(2) > ϕ(3) > ϕ(1)] was reasonably well explained by their excited-state reduction potentials and their electron-transfer activation energies. Finally, the photoinduced oxidation-reduction mechanism utilized by these complexes was explored, and the DNA-photocleavage process was explained rationally.

Theoretical studies on the related properties of Co(III) polypyridyl complexes interacting with DNA.

Theoretical studies on the related properties of Co(III) polypyridyl complexes [Co(phen)(2)L](3+) (L: dppz = dipyrido[3,2-a:2',3'-c]phenazine; phen = 1,10-phenanthroline; dione = 1,10-phenanthroline-5,6-diketone) 1-3 interacting with DNA, including the DNA-binding, DNA-photocleavage and spectral properties, have been carried out. First, the full geometry-optimizations of these three complexes in their ground states were carried out in aqueous solution. The optimized structures of these three complexes were docked into DNA-base-pairs using the Dock6.0 program. Secondly, the binding modes of complexes 1-3 were revealed in detail and the trend in DNA-binding affinities was reasonably explained. Thirdly, the electronic absorption and emission spectra of docking model of the optimal complex 1 were calculated and simulated. The experimental intense absorption and emission bands of Co(Ш) complex 1 in the presence of DNA were explained in detail, in particular, the reason why the emission spectra of complex 1 in the presence of DNA are greatly stronger than those in the absence of DNA was theoretically elucidated. Finally, the DNA-photocleavage essential of complexes was explored and the DNA photocleavage efficiencies (φ), i.e., φ(1)>φ(2)>φ(3), was also reasonably explained.

Binding conformations and QSAR of CA-4 analogs as tubulin inhibitors.

A theoretical study on the binding conformations and the quantitative structure-activity relationship (QSAR) of combretastatin A4 (CA-4) analogs as inhibitors toward tubulin has been carried out using docking analysis and comparative molecular field analysis (CoMFA). The appropriate binding orientations and conformations of these compounds interacting with tubulin were revealed by the docking study; and a 3D-QSAR model showing significant statistical quality and satisfactory predictive ability was established, in which the correlation coefficient (R(2)) and cross-validation coefficient (q(2)) were 0.955 and 0.66, respectively. The same model was further applied to predict the pIC(50) values for 16 congeneric compounds as external test set, and the predictive correlation coefficient R(2)(pred) reached 0.883. Other tests on additional validations further confirmed the satisfactory predictive power of the model. In this work, it was very interesting to find that the 3D topology structure of the active site of tubulin from the docking analysis was in good agreement with the 3D-QSAR model from CoMFA for this series of compounds. Some key structural factors of the compounds responsible for cytotoxicity were reasonably presented. These theoretical results can offer useful references for understanding the action mechanism and directing the molecular design of this kind of inhibitor with improved activity.

[Luminescence dynamics analysis on ruthenium polypyridyl complexes bonding to DNA].

Time-resolved spectra of six kinds of ruthenium polypyridyl complexes [Ru(L)2 (R)]2+ (L = bpy, phen, bpy = 2,2'-bipyridine, phen = 1,10-phenanthroline, R = 7-CH3-dppz, 7-F-dppz, dpbpd(NH2)2) bonding to calf thymus DNA in aqueous solution were compared and analyzed by using the three energy level kinetic model. And the effects of the substituent groups on the interaction ways for the ruthenium complexes bonding to DNA were discussed. The result shows that first, the six complexes all show two binding modes on bonding to DNA, i.e. the side-on binding mode and the perpendicular binding mode, and the later one is considered as a main binding way. Second, the properties of substituent groups have an important impact on the relative weight of the two binding modes. The conclusion offers a dynamics argument to study the interaction mechanism for the complex bonding to DNA further.

A theoretical study on the hydrolysis process of two Keppler-type antitumor complexes [TzH][trans-RuCl4(Tz)2] and [2-NH2TzH][trans-RuCl4(2-NH2Tz)2].

The hydrolysis processes of two Keppler-type antitumor ruthenium(III) complexes of [TzH][trans-RuCl4(Tz)2] (TzICR) and [2-NH2TzH][trans-RuCl4(2-NH2Tz)2] ((2-NH2)TzICR) have been investigated by using density functional theory (DFT) method, and the solvent effect was also considered and calculated by conductor-like polarizable calculation model (CPCM). The structural characteristics and the detailed energy profiles for the hydrolysis processes of title complexes have been obtained. The analysis of thermodynamic and kinetic characteristics of hydrolysis reaction suggests the following: For the 1st hydrolysis step, the complex TzICR has a lower hydrolysis rate than the reported drug [ImH][trans-RuCl4Im2](ICR, Im=imidazole). However, complex (2-NH2)TzICR has obviously a higher hydrolysis rate than TzICR and ICR. The result is in good agreement with the experimental one and the related regularity was further explained in theory. For the 2nd hydrolysis step, it is very significant to find that the formation of cis-diaqua products is thermodynamically preferred to that of trans isomers. Combining with the hydrolysis action mechanism of cisplatin, this is related to the so-called "cis effect", in which the cis-diaqua products are advantageous to binding to pertinent biomolecular targets. Therefore, the cis-diaqua products can be expected to be important precursors for the biological actions. These theoretical results would help to understand the action mechanism of these potential drugs with the pertinent biomolecular target.

CoMFA and docking studies of 2-phenylindole derivatives with anticancer activity.

Three-dimensional (3D) quantitative structure-activity relationship (QSAR) and docking studies of 43 tubulin inhibitors, 2-phenylindole derivatives with anticancer activity against human breast cancer cell line MDA-MB 231, have been carried out. The established 3D-QSAR model from the comparative molecular field analysis (CoMFA) in training set shows not only significant statistical quality, but also satisfying predictive ability, with high correlation coefficient value (R(2)=0.910) and cross-validation coefficient value (q(2)=0.705). Moreover, the predictive ability of the CoMFA model was further confirmed by a test set, giving the predictive correlation coefficient (R(2)(pred)) of 0.688. Based on the CoMFA contour maps and docking analyses, some key structural factors responsible for anticancer activity of this series of compounds were revealed as follows: the substituent R(1) should have higher electronegativity; the substituent R(2) should be linear alkyl with four or five carbon atoms in length; and the substituent R(3) should be selected to OCH(3)-kind group whereas should not be selected to CF(3)-kind group. Meanwhile, the interaction information between target and ligand was presented in detail. Such results can offer some useful theoretical references for understanding the action mechanism, designing more potent inhibitors and predicting their activities prior to synthesis.

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.

Two new sesquiterpenoids from the soft coral Sinularia polydactyla (Ehreberg).

Two new sesquiterpenoids, polydactins A (1) and B (2) and a known sesquiterpene, 10alpha-hydroxycadin-4-en-15-al (3), were isolated from the soft coral Sinularia polydactyla (Ehreberg). Their structures were determined mainly by spectroscopic methods. Polydactin A (1) showed moderate cytotoxic activities against human oral epidermoid carcinoma cell lines (KB) and human breast carcinoma (MCF) tumour cell lines (in vitro).

QSAR, action mechanism and molecular design of flavone and isoflavone derivatives with cytotoxicity against HeLa.

The quantitative structure-activity relationship (QSAR) of 32 flavone and isoflavone derivatives with cytotoxicity expressed as pGC50, which is defined as the negative value of the logarithm of necessary molar concentration of this series of compounds to cause 50% growth inhibition against the human cervical epithelioid carcinoma cell line (HeLa), has been studied by using the density functional theory (DFT), molecular mechanics (MM2) and statistical methods. In order to obtain QSAR model with high predictive ability, the original dataset was randomly divided into a training set comprising 26 compounds and a test set comprising the rest 6 compounds. An optimal model for the training set with significant statistical quality (RA2=0.852) and predictive ability (q2=0.818) was established. The same model was further applied to predict pGC50 values of the 6 compounds in the test set, and the resulting predictive correlation coefficient Rpred2 reaches 0.738, further showing that this QSAR model has high predictive ability. It is very interesting to find that the cytotoxicities of these compounds against HeLa appear to be mainly governed by two quantum-chemical factors, i.e., the energy (ELUMO) of the lowest unoccupied molecular orbital (LUMO) and the net charges of C atom at site 6 on aromatic rings (QC6). Here the possible action mechanism of these compounds was analyzed and discussed in detail, in particular, the fact why the flavone derivatives have considerably higher cytotoxicity than isoflavone derivatives was reasonably explained. Based on this QSAR equation, 5 new compounds with higher cytotoxicity have been theoretically designed. Such results can offer useful theoretical references for experimental works.

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.

Effects of the substitution positions of Br group in intercalative ligand on the DNA-binding behaviors of Ru(II) polypyridyl complexes.

Two new polypyridyl ligands containing substituent Br at different positions in the phenyl ring, PBIP [PBIP=2-(4-bromophenyl)imidazo[4,5-f]1,10-phenanthroline], OBIP [OBIP=2-(2-bromophenyl)imidazo[4,5-f]1,10-phenanthroline] and their Ru(II) complexes, [Ru(phen)2PBIP]2+ 1, [Ru(phen)2OBIP]2+ 2 (phen=1,10-phenanthroline), have been synthesized and characterized. The binding strength of the two complexes to calf thymus DNA (CT DNA) was investigated with spectrophotometric methods, viscosity measurements, as well as equilibrium dialysis and circular dichroism spectroscopy. The theoretical calculations for these two complexes were also carried out applying the density functional theory (DFT) method. The experimental results show that the Br group substituting H at different positions of the phenyl ring in the intercalated ligand has significant effects on the spectral properties and the DNA-binding behaviors of Ru(II) complexes. Both the complexes can bind to CT DNA in intercalative mode and interact with CT DNA enantioselectively. Moreover, complex 1 can bind to CT DNA more strongly than complex 2, and complex 2 can become a much better candidate as an enantioselective binder to CT DNA than complex 1. The theoretical calculations show that both intercalative ligands, PBIP and OBIP, in these two complexes are essentially planar, and the obtained electronic structures of the complexes can be used to explain reasonably some of their experimental regularities or trends. Such experimental and theoretical information will be useful in design of novel probes of nucleic acid structures.