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Thioredoxin reductase (TrxR), a major component of the thioredoxin system, makes a critical role in regulating cellular redox signaling and is found to be overexpressed in many human cancer cells. TrxR has become an attractive target for anticancer agents. In this work, three Ru(II) complexes with salicylate as ligand, [Ru(phen) 2 (SA)] (phen = 1,10-phenanthroline, SA = salicylate, 1), [Ru(dmb) 2 (SA)] (dmb = 4,4'-dimethyl-2,2'-bipyridine, 2) and [Ru(bpy) 2 (SA)] (bpy = 2,2'-bipyridine, 3), were synthesized and characterized. The anticancer effect exerted by them was evaluated. Complex 1 was found to exhibit obvious anticancer activity, in comparison with cisplatin, against cancer cell lines, while displaying low toxicity to the normal cell line BEAS-2B. The mechanism of complex 1 cancer cell growth suppress was investigated in A549 cells. Complex 1 exerted its anticancer through inducing apoptosis and triggering cell cycle arrest at the G0/G1 phase. Complex 1 can selectively inhibit TrxR activity and thus promote the generation and accumulation of reactive oxygen species (ROS), which subsequently trigger mitochondrial dysfunction and DNA damage, activate oxidative stress-sensitive mitogen activated protein kinase (MAPK), and suppress the protein kinase B (PKB or AKT) signal pathway, resulting in apoptosis in A549 cells., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Anaplastic lymphoma kinase (ALK) is a highly attractive therapeutic target for the treatment of some non-small cell lung cancer patients. This Letter describes the further SAR exploration on the novel 3-sulfonylpyrazol-4-amino pyrimidine scaffold. This work identified a compound 53 with very good in vitro/in vivo efficacies, good DMPK properties together with better hERG tolerability and it is currently being profiled for the evaluation as a potential pre-clinical candidate., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

A new series of 2,4-diamino pyrimidine derivatives with a sulfone-substituted pyrazole right side-chain were discovered as potent anaplastic lymphoma kinase inhibitors. Structure-activity relationship of the left side-chain on phenyl substitutions were explored which delivered many potent ALK inhibitors. Among them, 29a showed favorable pharmacokinetic profiles in rats and dogs together with significant antitumor efficacy in EML4-ALK fusion xenograft model., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

In this paper, we present a new statistical pattern recognition method for classifying cytotoxic cellular responses to toxic agents. The advantage of the proposed method is to quickly assess the toxicity level of an unclassified toxic agent on human health by bringing cytotoxic cellular responses with similar patterns (mode of action, MoOA) into the same class. The proposed method is a model-based hierarchical classification approach incorporating principal component analysis (PCA) and functional data analysis (FDA). The cytotoxic cell responses are represented by multi-concentration time-dependent cellular response profiles (TCRPs) which are dynamically recorded by using the xCELLigence real-time cell analysis high-throughput (RTCA HT) system. The classification results obtained using our algorithm show satisfactory discrimination and are validated using biological facts by examining common chemical mechanisms of actions with treatment on human hepatocellular carcinoma cells (HepG2)., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

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.

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.

Abstract A water-soluble pectic polysaccharide HCA4S1 was isolated from Houttuynia cordata and purified by DEAE Cellulose and Sephacryl S-300 column. HCA4S1 with an average molecular weight of 21.7 kDa mainly consisted of rhamnose, galacturonic acid, galactose, and arabinose. By using partial acid hydrolysis, methylation analysis, and NMR spectra, the structure of this polysaccharide is found to have a backbone consisting of 1,4-linked α‑ d ‑GalA and 1,2,4-linked α‑ l ‑Rha. The latter was substituted at C-4 position by 1,4 linked, 1,6-linked β‑Gal p , or Teminal linked β‑Gal. Bioactivity test showed that this polysaccharide might inhibit the proliferation of A549 lung cancer cell by inducing cell cycle arrest and apoptosis. The expression of cleaved caspase 3 and cyclinB1 was observed to be upregulated after the treatment with this polysaccharide. Collectively, these results suggest that the pectin HCA4S1 from Houttuynia cordata is of potential value in the treatment of lung cancer, though the underlying mechanisms remain to be further confirmed. Highlights • Structure of a rhamnogalacturonan from Houttuynia cordata was characterized. • The main chain of this polysaccharide was alternate 1,4‑α‑ d ‑Gal p A and 1,2‑α‑ l ‑Rha p. • The branches had T-, 1,4-, 1,3, 1,6-linked β‑ d ‑Gal p , and T-, 1,5-linked α‑ l ‑Ara f. • HCA4S1 inhibits lung cancer cell growth by impeding cell cycle and apoptosis. [ABSTRACT FROM AUTHOR]

The hydrolysis process of Ru(III) complex (HL)[trans-RuCl4L(dmso-S)] (L=4-amino-1,2,4-triazole) (1), a potential antitumor complex similar to the well-known antitumor agent (ImH)[trans-RuCl4(dmso-S)(Im)](NAMI-A), was investigated using density functional theory (DFT) with the conductor-like polarizable continuum model (CPCM). The structural characteristics and the detailed energy profiles for the hydrolysis processes of this complex were obtained. For the first hydrolysis step, complex 1 with 4-amino-1,2,4-triazole ligand shows much faster aquation than NAMI-A with imidazole ligand and complex 2 with 4H-1,2,4-triazole ligand, and such a calculated result is in good agreement with the experimental one. For the second hydrolysis step, the formation of cis-diaqua products is found to be thermodynamically preferred over the trans isomers. In addition, on the basis of the analysis of electronic characteristics of species in the hydrolysis process, the trend in abilities (A) of hydrolysis products attacked nucleophilicly by pertinent biomolecules is revealed. These theoretical results will help in understanding the action mechanism of this potential Ru(III) drug with pertinent biomolecular targets. [ABSTRACT FROM AUTHOR]

The hydrolysis process of Ru (III) complex [Htrz][trans-RuCl4(1-H-1,2,4-triazole)(dmso-S)] 1, a potential antitumor complex similar to the well-known anticancer agent [ImH][trans-RuCl4(Im)(dmso-S)] (NAMI-A), has 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). Meanwhile, the hydrolysis process of the NH-tautomeric isomer, [Htrz][trans-RuCl4(4-H-1,2,4-triazole)(dmso-S)] 2, was also modeled and predicted by the same methods. The structural characteristics and the detailed energy profiles for the hydrolysis processes of two isomers have been obtained. The analysis of thermodynamic and kinetic characteristics of hydrolysis reaction suggests the following: for the first hydrolysis step, the Complex 1 has lower hydrolysis rate than the reported anticancer drug NAMI-A, and the result is in accordance with experimental one. However, Complex 1 has obviously higher hydrolysis rate than its isomer Complex 2, and the result was reasonably explained in theory. For the second hydrolysis step, the formation of cis-diaqua species is thermodynamic preferred to that of trans isomers. In addition, the trend in nucleophilic attack abilities (A) of hydrolysis products by pertinent biomolecules was revealed and predicted. © 2009 Wiley Periodicals, Inc. Int J Quantum Chem, 2010 [ABSTRACT FROM AUTHOR]

Abstract: The hydrolysis process of Ru(III) complex [TzH][trans-RuCl4(DMSO)(Tz)]·(DMSO) (TzNAMI), a potential antitumor complex similar to the well-known antitumor agent NAMI-A, has been investigated by using density functional theory (DFT) method, and the solution 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 this complex have been obtained. The analysis of thermodynamic and kinetic characteristics of hydrolysis reaction suggests the following: for the 1st hydrolysis step, the complex TzNAMI with thiazole ligand has slightly lower hydrolysis rate than NAMI-A with imidazole ligands, and such a calculated result is in good agreement with experimental one and reasonably explained in theory. For the 2nd hydrolysis step, the formation of cis-diaqua species is thermodynamically preferred to that of trans isomer. In addition, based on the analysis of electronic characteristics of species in the hydrolysis process, the trend in nucleophilic attack abilities (A) of hydrolysis products by pertinent biomolecules is revealed. [Copyright &y& Elsevier]

Two-dimensional (2D) and three-dimensional (3D) quantitative structure–activity relationships (QSARs) of 23 analogs of 2-Methoxyestradiol with anticancer activity (expressed as pGI50) against MCF-7 human breast cancer cells have been studied by using a combined method of the DFT, MM2 and statistics for 2D, as well as the comparative molecular field analysis (CoMFA) for 3D. The established 2D-QSAR model in training set shows not only significant statistical quality, but also predictive ability, with the square of adjusted correlation coefficient $(R_{\rm A}^{2} = 0.834)$ and the square of the cross-validation coefficient (q2 = 0.779). The same model was further applied to predict pGI50 values of the four compounds in the test set, and the resulting $R_{\rm pred}^{2}$ being as high as 0.827, further confirms that this 2D-QSAR model has high predictive ability for this kind of compound. The 3D-QSAR model also shows good correlative and predictive capabilities in terms of R2(0.927) and q2(0.786) obtained from CoMFA model. The results that 2D- and 3D-QSAR analyses accord with each other, suggest that the electrostatic interaction plays a decisive role in determining the anticancer activity of the studied compounds, and that increasing the negative charge of substituent R2 and the positive charge of substituents linking to C17 as well as decreasing the size of substituent R1 are advantageous to improving the cytotoxicity. Such results can offer some useful theoretical references for directing the molecular design and understanding the action mechanism of this kind of compound with anticancer activity. [ABSTRACT FROM AUTHOR]

Quantitative structure-activity relationship (QSAR) studies of a series of benzo[b]acronycine derivatives as a novel class of antitumor agents have been carried out using the density functional theory (DFT), molecular mechanics (MM+) and statistical methods. Some calculated parameters of geometric structures, electronic structures and molecular properties of the compounds were adopted as generalized descriptors (variables). Via a stepwise regression analysis, some main independent factors affecting the activities of the compounds were selected out, and then the quantitative structure-activity relationship (QSAR) equation was established. The results suggest that the energy difference (Δ εL-H) between the lowest unoccupied molecular orbital and the highest occupied molecular orbital, the net charges of the nitrogen atom N11 and the first atom of the substituent R2, and the hydrophobic parameter (log P1) of the substituent R1 are the main independent factors contributing to the antitumor activities of the compounds. The fitting correlation coefficient (r2) and the cross-validation coefficient (q2) for the model established by this study are 0.865 and 0.721, respectively, showing this model with a good predictability. The QSAR equation can be used to estimate unknown antitumor activity of this kind of compound, and thus design new compounds with high antitumor activities. Here, based on this QASR study, 4 new compounds with predicted high antitumor activities have been theoretically designed and they are expecting experimental verification. [ABSTRACT FROM AUTHOR]

Apigenin and protoapigenone that both have the activities against various cancer cell lines co-exist in Macrothelypteris torresiana , while the extracts of M. torresiana couldn't achieve the fine anti-tumor effects for the existence of potent anti-tumor compounds. This study disclosed an antagonism between the two compounds on the protein level to elucidate the paradox. First, the study established the fingerprint for M. torresiana extract. The following anti-proliferation assay verified that the antagonism occurs between protoapigenone and apigenin. And then Western blot and qt-PCR were applied to evaluate the expression and transcription level of the Akt phosphorylation related targets to validate the antagonism at the protein level. Moreover, CETSA further validated the binding of PDK-1 with apigenin and protoapigenone, as well as the antagonism between the two compounds. Finally, the compound-protein complexes predicted by SYBYL-X gave the visual results for the antagonism. The results demonstrated that: Due to the structural similarity and close binding coefficients to the identical targets, when the cells were treated with apigenin and protoapigenone simultaneously, the Akt phosphorylation inhibition induced by protoapigenone would attenuate significantly. The antagonism disclosed in this paper could be a new explanation for the unsatisfied efficacy of M. torresiana extract. Unlabelled Image [ABSTRACT FROM AUTHOR]

To investigate polysaccharide structure from Lonicera japonica , and study its effects on behavior of pancreatic cells, a homogenous polysaccharide, LJ-02-1, was extracted and purified from flowers of L. japonica by DEAE-cellulose and Sephacryl S-200HR column. The molecular weight was estimated to be 54 kDa. Monosaccharide composition was determined to be rhamnose, galacturonic acid, galactose and arabinose in the molar ratio of 10.77:7.88:15.45:65.89 by analyzing the PMP derivatives of the monosaccharides from 2 M trifluoracetic acid hydrolysis via HPLC. Based on methylation analysis, partial acid hydrolysis, and NMR spectra, the polysaccharide was elucidated to be a rhamnogalacturonan backbone and substituted partly at C-4 of rhamnose. The branches were determined to be T- and 1,4,6-linked β- d -Gal p , T- and 1,5-linked α- l -Ara f . The polysaccharide might inhibit BxPC-3 and PANC-1 pancreatic cancer cells growth at the concentration of 1 mg/mL with inhibitory ratio of 66.7% and 52.1%, respectively. [ABSTRACT FROM AUTHOR]