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The discovery of mammalian target of rapamycin (mTOR) kinase inhibitors has always been a research hotspot of antitumor drugs. Consensus scoring used in the docking study of mTOR kinase inhibitors usually improves hit rate of virtual screening. Herein, we attempt to build a series of consensus scoring models based on a set of the common scoring functions. In this paper, twenty-five kinds of mTOR inhibitors (16 clinical candidate compounds and 9 promising preclinical compounds) are carefully collected, and selected for the molecular docking study used by the Glide docking programs within the standard precise (SP) mode. The predicted poses of these ligands are saved, and revaluated by twenty-six available scoring functions, respectively. Subsequently, consensus scoring models are trained based on the obtained rescoring results by the partial least squares (PLS) method, and validated by Leave-one-out (LOO) method. In addition, three kinds of ligand efficiency indices (BEI, SEI, and LLE) instead of pIC 50 as the activity could greatly improve the statistical quality of build models. Two best calculated models 10 and 22 using the same BEI indice have following statistical parameters, respectively: for model 10 , training set R 2 = 0.767, Q 2 = 0.647, RMSE = 0.024, and for test set R 2 = 0.932, RMSE = 0.026; for model 22 , raining set R 2 = 0.790, Q 2 = 0.627, RMSE = 0.023, and for test set R 2 = 0.955, RMSE = 0.020. These two consensus scoring model would be used for the docking virtual screening of novel mTOR inhibitors. [ABSTRACT FROM AUTHOR]

Three binuclear phenolate complexes, [Ni2(L1)2(OAc)](BPh4)·DMF (1), [Ni2(L2)2(OAc)](BPh4) (2), and [Ni2(L3)2(OAc)](OH)·3H2O (3), where L1 = 2-{[bis-(2-hydroxy-ethyl)-amino]-methyl}-4-methyl-phenol, L2 = 2-{[bis-(2-hydroxy-ethyl)-amino]-methyl}-4-methoxy-phenol, and L3 = 2-{[bis-(2-hydroxy-ethyl)-amino]-methyl}-4-tert-butyl-phenol), have been synthesized. Single-crystal diffraction reveals that all the metal atoms are in a distorted octahedral geometry. The interactions of the complexes with calf thymus DNA (CT-DNA) have been investigated by UV–vis absorption, fluorescence emission, and circular dichroism spectroscopy and viscosity measurements. Furthermore, DNA cleavage mechanism shows that the complexes may be capable to promote DNA cleavage through oxidative DNA damage pathway, which is indicative of the involvement of hydroxyl radical, singlet oxygen, or singlet oxygen-like entity in the cleavage process. Cytotoxicity studies on the Hela and MCF-7 cancer cell lines show that complexes 1–3 exhibit excellent activity toward the tested tumor cell lines with respect to the standard drug carboplatin, revealing that they have the potential to act as effective metal-based anticancer drugs. [ABSTRACT FROM AUTHOR]

A series of novel phosphoramide mustard sophoridinic acid analogues, consisting of nitrogen mustard group and sophoridinic acid scaffold, have been designed, synthesized and evaluated for their topoisomerase inhibitory activity as well as cytotoxicity against six tumor cell lines (SMMC-7721, LoVo, MCF-7, K562, S180 and H22) and a normal cell line (L929). Among the compounds tested, five were found to be potent inhibitors and exhibited potent cytotoxicity against S180 and H22 cell lines with IC50 values of 1-4 μM. Further mechanistic studies showed that this class of compounds acted as novel topoisomerase I (Topo I) catalytic inhibitors by preventing the binding of Topo I to DNA and inhibiting the cleavage of DNA, and molecular docking studies revealed that the binding energy for these compounds was comparable to that for classic Topo I inhibitors CPT and HCPT, indicating that the compounds have an interaction with DNA and Topo I. [ABSTRACT FROM AUTHOR]

Four complexes, namely [Zn2L1(OAc)2](PF6) ( 1); [Zn2L1(OAc)2](BPh4) ( 2); [Co2L1Cl2](PF6) ( 3); and [Zn2L2(PhCOO)2Cl] ( 4) (L1 = 2,6-bis(((2-(dimethylamino)ethyl)(pyridine-2-ylmethyl)amino)methyl)-4-methoxyphenol; L2 = 2-(((2-(dimethylamino)ethyl)(pyridin-2-ylmethyl)amino)methyl)-4-methoxyphenol), have been synthesized. Single-crystal diffraction reveals that the metal atoms in the four complexes are in different coordination environments. The interactions of the complexes with calf thymus DNA (CT-DNA) have been investigated using UV absorption, fluorescence and circular dichroism spectroscopies and viscosity measurements, and the modes of CT-DNA binding for the complexes have been proposed. Further experiments show that the Zn(II)/H2O2 system displays significant of supercoiled DNA attributed to the peroxide ion coordinated to the Zn(II) ions enhancing their nucleophilicity. This is a rare phenomenon. DNA cleavage mechanism shows that the complexes examined here may be capable of promoting DNA cleavage through an oxidative DNA damage pathway, which is indicative of the involvement of singlet oxygen in the cleavage process. In vitro cytotoxicity of complexes against three human tumor cell lines (HeLa, MCF-7 and HepG2) demonstrates that these complexes have the potential to act as effective metal-based anticancer drugs. Copyright © 2016 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

The antitumor activity shown by many platinum complexes has produced a strong interest in research of new . Among the metal compounds synthesized and tested, have received considerable attention because of their cytotoxic activity against solid tumors. A novel wheel-shaped octanuclear copper(II) complex with a 1,2,4-triazole derivative ligand formulated as [Cu8L4](ClO4)8⋅11H2O ( 1) (L = 3,5-bis((bis(2-hydroxylethyl)amino)methyl)-4 H-1,2,4,-triazole-4-amine) has been synthesized and structurally characterized. In 1, eight Cu atoms are linked through 1,2,4-triazole units and alkoxide bridges to form a centrosymmetric octanuclear Cu(II) metallomacrocycle. The interaction of complex 1 with calf thymus DNA has been studied using UV absorption, fluorescence and circular dichroism spectroscopies, viscosity measurements and cyclic voltammetry. The apparent binding constant ( kapp) value for 1 is 1.59 × 105 M−1. Furthermore, complex 1 displays efficient of supercoiled DNA in the presence of external agents, the rate constant for the conversion of supercoiled to nicked DNA being 2.67 × 10−5 s−1. Interestingly, cytotoxicity studies on the MCF-7 human breast cancer cell line show that the IC50 value of 1 is less than that of cisplatin for the same cell line, revealing that it has the potential to act as an effective metal-based anticancer drug. Copyright © 2016 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

A series of novel nitrogen mustard sophoridinic acid derivatives were designed, synthesized and evaluated for their cytotoxicity. Of the newly synthesized compounds, compound 6 exhibited a potent effect against hepatocellular carcinoma in vitro and in vivo. SAR analysis indicated that introduction of a nitrogen mustard group to the structure of sophoridinic acid significantly enhance the antitumor activity. Moreover, molecular docking study exhibited benzyl group introduced to the nitrogen atom at the 12-position and aryl nitrogen mustard group at the 4′-carboxyl region for compound 6 were beneficial for the higher anticancer activity. This work provides useful information for further structural modifications of these compounds and for the synthesis of new, potent antitumor agents. [ABSTRACT FROM AUTHOR]

Recently, thioredoxin reductase as a target for treatment of tumors has attracted the attention of scientists. 1,2-[Bis(1,2-benzisoselenazolone-3(2 H)-ketone)]ethane (ethaselen, BBSKE, PCT: CN02/00412), designed and synthesized previously, is an effective thioredoxin reductase inhibitor; presently it is in phase II clinical trials, targeting gastric cancer, lung cancer and colon cancer. To seek more novel and effective anticancer drugs, we have developed many selenazole-based compounds. Evaluation of the thioredoxin reductase inhibitory effect and investigation of the mechanism of anticancer drugs require abundant thioredoxin reductase, but since commercial thioredoxin reductase is expensive its use is often limited. Therefore, the preparation of thioredoxin reductase is necessary. Base on the above investigation, in this work we have prepared thioredoxin reductase and evaluated selenazole-based compounds, and found that 44 compounds have high inhibitory effect on thioredoxin reductase with IC50 < 10 µ m, of which 16 compounds have IC50 values below 1 µ m. This is helpful in investigating and elucidating the mechanism of this kind of compound. Copyright © 2012 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Abstract: A series of novel 4,5-dihydropyrazole derivatives (3a–3t) containing hydroxyphenyl moiety as potential V600E mutant BRAF kinase (BRAFV600E) inhibitors were designed and synthesized. Docking simulation was performed to insert compounds 3d (1-(5-(5-chloro-2-hydroxyphenyl)-3-(p-tolyl)-4,5-dihydro-1H-pyrazol-1-yl)ethanone) and 3m ( 1-(3-(4-chlorophenyl)-5-(3,5-dibromo-2-hydroxyphenyl)-4,5-dihydro-1H-pyrazol-1-yl)ethanone) into the crystal structure of BRAFV600E to determine the probable binding model, respectively. Based on the preliminary results, compound 3d and 3m with potent inhibitory activity in tumor growth may be a potential anticancer agent. Results of the bioassays against BRAFV600E, MCF-7 human breast cancer cell line and WM266.4 human melanoma cell line all showed several compounds had potent activities IC50 value in low micromolar range, among them, compound 3d and compound 3m showed strong potent anticancer activity, which were proved by that 3d: IC50 =1.31μM for MCF-7 and IC50 =0.45μM for WM266.5, IC50 =0.22μM for BRAFV600E, 3m: IC50 =0.97μM for MCF-7 and IC50 =0.72μM for WM266.5, IC50 =0.46μM for BRAFV600E, which were comparable with the positive control Erlotinib. [Copyright &y& Elsevier]

Abstract: A series of 1,2,4-triazole derivatives containing 1,4-benzodioxan (5a–5q) have been designed, synthesized, structurally determined, and their biological activities were evaluated as potential MetAP2 inhibitors. All the synthesized compounds were first reported. Among the compounds, compound 5k showed the most potent biological activity against HEPG2 cancer cell line (IC50 =0.81μM for HEPG2 and IC50 =0.93μM for MetAP2), which was comparable to the positive control. Docking simulation by positioning compound 5k into the MetAP2 structure active site was performed to explore the possible binding model. The results of apoptosis and Western-blot assay demonstrated that compound 5k possessed good antitumor activity against HEPG2 cancer cell line. Therefore, compound 5k with potent inhibitory activity in tumor growth inhibition may be a potential antitumor agent against HEPG2 cancer cell. [Copyright &y& Elsevier]