Chiral Ru(ii) complexes act as a potential non-viral gene carrier for directional transportation to the nucleus and cytoplasm.

Guanine-rich DNA sequences can spontaneously fold into four-stranded structures called G-quadruplexes (G4s). G4s have been identified extensively in the promoter regions of several proto-oncogenes, including c-myc, as well as telomeres. G4s have attracted an increasing amount of attention in the field of nanotechnology because of their use as versatile building blocks of DNA-based nanostructures. In this study, we report the self-assembly of c-myc G-quadruplex DNA controlled by a pair of chiral ruthenium(ii) complexes coordinated by 2-(4-phenyacetylenephenyl)-1H-imidazo[4,5f][1,10]phenanthroline (PBEPIP), Λ-[Ru(bpy)2(PBEPIP)](ClO4)2 (Λ-RM0627, bpy = bipyridine) and Δ-[Ru(bpy)2(PBEPIP)](ClO4)2 (Δ-RM0627). Λ-RM0627 could promote the high-order self-assembly of c-myc G-quadruplex DNA into a nanowire structure, whereas Δ-RM0627 could induce DNA condensation into G-quadruplex aggregates. Moreover, in vitro studies on human liver carcinoma HepG2 cells showed that the nanowire of c-myc G-quadruplex DNA promoted by Λ-RM0627 could be localized in the nuclei of cells, whereas the nanoparticle of c-myc G-quadruplex DNA generated by Δ-RM0627 was taken up and localized in the cytoplasm. This study provides examples of the enantioselective self-assembly of G4 DNA molecules controlled by chiral ruthenium(ii) complexes and suggests the potential applications of assembled nanostructures as non-viral DNA vectors for gene therapy.

Design, synthesis and evaluation of novel tacrine-multialkoxybenzene hybrids as multi-targeted compounds against Alzheimer's disease.

A series of benzoates (or phenylacetates or cinnamates) - tacrine hybrids (7a-o) were designed, synthesized and evaluated as multi-potent anti-Alzheimer drug candidates. The screening results showed that most of them exhibited a significant ability to inhibit ChEs, certain selectivity for AChE over BuChE and strong potency inhibitory of self-induced ß-amyloid (Aß) aggregation. All IC50 values of biological activity were at the nanomolar range. Especially, compound 7c displayed the greatest ability to inhibit AChE with an IC50 value of 5.63 nM and the highest selectivity with ratio of BuChE/AChE value of 64.6. Moreover, it also exhibited a potent inhibitory of Aß aggregation with an IC50 value of 51.81 nM. A Lineweaver-Burk plot and molecular modeling study showed that compound 7c targeted both the CAS and PAS of ChEs. A structure-activity relationship analysis suggested that the electron density of aromatic ring which was linked with tacrine through acetyl group played a significant role in determining the inhibitory activity.

Cyclometalated iridium(III)-ß-carboline complexes as potent autophagy-inducing agents.

Two cyclometalated Ir(III)-ß-carboline complexes were identified as potent inducers of autophagic cell death. Autophagy induced by these complexes is ROS-mediated and caspase-independent.

Exploration of the binding mode between (-)-zampanolide and tubulin using docking and molecular dynamics simulation.

The binding mode of (-)-zampanolide (ZMP) to tubulin was investigated using docking, molecular dynamics (MD) simulation, and binding free-energy calculations. The docking studies validated the experimental results indicating that the paclitaxel site is the binding site for (-)-ZMP. The 18 ns MD simulation shows the docking mode has changed a lot, whereas it offers more reliable binding data. MM-PBSA binding free-energy calculations further confirmed the results of the MD simulation. The study revealed that hydrophobic interactions play an important role in stabilizing the binding, and the strong hydrogen bond formed with Asp224 enhances the affinity for tubulin. Meanwhile, the results support the assumption that (-)-ZMP can be attacked by His227, leading to a nucleophilic reaction and covalent binding. These theoretical results lead to a greater understanding of the mechanism of action of binding to tubulin, and will therefore aid the design of new compounds with higher affinities for tubulin.

Docking and molecular dynamics studies of the binding between Peloruside A and tubulin.

The molecular docking, MD simulation and binding free energy calculation were performed to explore the probable binding modes between PLA and tubulin. Through docking study, three possible binding sites for PLA were speculated as follows: the taxane site, the alternative site and a new site in α-tubulin. Then, 12.0 ns MD simulations show that these binding modes predicted by docking have been changed more or less, whereas the MD simulations offer more reliable binding details. The MM-PBSA binding free-energy calculations reasonably identify that the taxane site is the most favorable binding site of PLA and the alternative site is the secondary one, which can be used to explain some experimental facts. These studies theoretically resolve the priority of binding sites for PLA and offer the reliable binding modes between PLA and tubulin, and thus help to understanding the action mechanism for this kind of inhibitor.

Ruthenium-Arene-ß-Carboline Complexes as Potent Inhibitors of Cyclin-Dependent Kinase 1: Synthesis, Characterization and Anticancer Mechanism Studies.

A series of Ru(II)-arene complexes (1-6) of the general formula [(η(6)-arene)Ru(L)Cl]PF6 (arene=benzene or p-cymene; L=bidentate ß-carboline derivative, an indole alkaloid with potential cyclin-dependent kinases (CDKs) inhibitory activities) is reported. All the complexes were fully characterized by classical analytical methods, and three were characterized by X-ray crystallography. Hydrolytic studies show that ß-carboline ligands play a vital role in their aqueous behaviour. These complexes are highly active in vitro, with the most active complex 6 displaying a 3- to 12-fold higher anticancer activity than cisplatin against several cancer cell lines. Interestingly, the complexes are able to overcome cross-resistance to cisplatin, and show much lower cytotoxicity against normal cells. Complexes 1-6 may directly target CDK1, because they can block cells in the G2M phase, down-regulate the expression of CDK1 and cyclin B1, and inhibit CDK1/cyclin B in vitro. Further mechanism studies show that the complexes can effectively induce apoptosis through mitochondrial-related pathways and intracellular reactive oxygen species (ROS) elevation.

Theoretical studies on pyrimidine substituent derivatives as dual inhibitors of AP-1 and NF-kappaB.

Theoretical studies on the three-dimensional (3D) quantitative structure-activity relationship (QSAR) and mechanisms of action of a series of pyrimidine substituent derivatives as dual inhibitors of AP-1 and NF-kappaB were carried out using comparative molecular field analysis (CoMFA) and docking methods. The established 3D-QSAR model exhibits a satisfying statistical quality and prediction ability. Docking results show somewhat lower average values of the flexible and rigid energy scores in the chosen binding sites. The docking analysis offers appropriate orientations and conformations of these compounds at the binding sites to both AP-1 and NF-kappaB in good agreement with the 3D-QSAR model from CoMFA. The combined CoMFA and docking study suggests the following substituent selections: substituent R(2) should be a kind of H-N-thienyl or CH(3)-N-thienyl group; substituent R(5) should be a kind of COO-tBu or COOEt group; and substituent R(4) should be a CH(2)CH(3) or 2-thienyl group. The docking analysis also shows that the binding sites fall just at the joint regions between AP-1 (or NF-kappaB) and DNA, where these compounds can effectively prevent free AP-1 and NF-kappaB from binding to DNA, and this may be the reason that derivatives with pyrimidine substituents have an inhibition function. In addition, a very interesting finding was that the binding sites of both AP-1 and NF-kappaB have a common structural characteristic, thereby providing a reasonable explanation for the dual inhibition functions of these compounds towards both AP-1 and NF-kappaB. These theoretical results help to deepen our understanding of the inhibition mechanism of these pyrimidine substituent derivatives, and will aid in directing further drug-molecular design.

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.

Binding orientations, QSAR, and molecular design of thiophene derivative inhibitors.

A theoretical study on binding orientations and quantitative structure-activity relationship of thiophene derivatives as inhibitors towards tubulin has been carried out by using the docking analysis and the comparative molecular field analysis. The appropriate binding orientations and conformations of these compounds interacting with tubulin were revealed by docking study; and a 3D-quantitative structure-activity relationship model showing significant statistical quality and satisfying predictive ability was established, in which the correlation coefficient (R(2)) and cross-validation coefficient (q(2)) are 0.949 and 0.743, respectively. The same model was further applied to predict the pIC(50) values for nine congeneric compounds as external test set, and the predictive correlation coefficient R(pred)(2) reaches 0.929, thus the predictive ability of this 3D-quantitative structure-activity relationship model can be further confirmed. Some key structural factors of the compounds responsible for cytotoxicity were discussed in detail. Based on these structural factors, three new compounds with higher activity have been designed, and their cytotoxicities were also predicted by the established 3D-quantitative structure-activity relationship model from comparative molecular field analysis as well as the docking analysis. We hope these theoretical results can be confirmed by experimental work.

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.

Electronic structures, DNA-binding and spectral properties of Co(III) complexes [Co(bpy)2(L)]3+ (L=pip, odhip, hnoip).

Studies on the electronic structures and trend in DNA-binding affinities of a series of Co(III) complexes have been carried out, using the density functional theory (DFT) at the B3LYP/LanL2DZ level. The optimized geometric structures of these Co(III) complexes in aqueous solution are more close to experimental data than those in vacuo. The electronic structures of these Co(III) complexes were analyzed on the basis of their geometric structures optimized in aqueous solution, and the trend in the DNA-binding constants (K(b)) was reasonably explained. In addition, the electronic absorption spectra of these complexes were calculated and simulated in aqueous solution using the time dependent DFT (TDDFT) at the B3LYP/LanL2DZ level. The calculated absorption spectra of these Co(III) complexes in aqueous solution are in satisfying agreement with experimental results, and the properties of experimental absorption bands have been theoretically explained in detail. Meanwhile, in order to explore the solvent effect on the absorption spectra of these Co(III) complexes, their absorption spectra in vacuo were also calculated, and the results show that the calculated absorption spectra of Co(III) complexes are greatly influenced by the solvent effect.

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.