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1.
Front Oncol ; 12: 959322, 2022.
Article in English | MEDLINE | ID: mdl-36091173

ABSTRACT

Cancer is one of the most serious diseases threatening human health, so it is particularly important to develop effective tumor-targeting drugs. As the first CDK4/6 inhibitor, palbociclib effectively inhibits tumor proliferation by blocking the cell cycle to the G1 phase. 10-HCPT is a Topo I inhibitor; however, its clinical application has been greatly limited due to its high toxicity. Based on the successful development of double target inhibitors, three novel palbociclib derivatives (HP-1, HP-2, and HP-3) were designed and synthesized from Palbociclib and 10-HCPT, and their biological activities were investigated. At first, the possible binding sites of the three compounds to Topo I and CDK4/6 were predicted by molecular docking. Then, we evaluated the anti-proliferative effects of the three palbociclib derivatives. In general, human lung cancer cells were more sensitive to HP-1, HP-2, and HP-3, especially NCI-H460. In addition, cell cycle arrest and apoptosis induction were investigated by flow cytometry. The three palbociclib derivatives, especially HP-1, had obvious cell cycle arrest phenomenon on NCI-H460 cells and induced apoptosis of NCI-H460 cells significantly. In the end, it was proved that these three drugs had obvious cyclin-dependent kinase inhibitory activities. In short, all the data showed that HP-1, HP-2, and HP-3 could play anti-cancer roles by acting on dual targets and had the characteristics of high efficiencies and low toxicities, which opened up a new idea for the study of palbociclib derivatives.

2.
Bioorg Chem ; 93: 103309, 2019 12.
Article in English | MEDLINE | ID: mdl-31585266

ABSTRACT

The antibacterial agents and therapies today are facing serious problems such as drug resistance. Introducing dual inhibiting effect is a valid approach to solve this trouble and bring advantages including wide adaptability, favorable safety and superiority of combination. We started from potential DNA Gyrase inhibitory backbone isatin to develop oxoindolin derivatives as atypical dual Gyrase (major) and FabH (assistant) inhibitors via a two-round screening. Aiming at blocking both duplication (Gyrase) and survival (FabH), most of synthesized compounds indicated potency against Gyrase and some of them inferred favorable inhibitory effect on FabH. The top hit I18 suggested comparable Gyrase inhibitory activity (IC50 = 0.025 µM) and antibacterial effect with the positive control Novobiocin (IC50 = 0.040 µM). FabH inhibitory activity (IC50 = 5.20 µM) was also successfully introduced. Docking simulation hinted possible important interacted residues and binding patterns for both target proteins. Adequate Structure-Activity Relation discussions provide the future orientations of modification. With high potency, low initial toxicity and dual inhibiting strategy, advanced compounds with therapeutic methods will be developed for clinical application.


Subject(s)
Acetyltransferases/antagonists & inhibitors , DNA Gyrase/chemistry , Escherichia coli Proteins/antagonists & inhibitors , Indoles/chemistry , Topoisomerase II Inhibitors/chemistry , 3-Oxoacyl-(Acyl-Carrier-Protein) Synthase , Acetyltransferases/metabolism , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/metabolism , Anti-Bacterial Agents/pharmacology , Binding Sites , DNA Gyrase/metabolism , Drug Evaluation, Preclinical , Escherichia coli/enzymology , Escherichia coli Proteins/metabolism , Fatty Acid Synthase, Type II/antagonists & inhibitors , Fatty Acid Synthase, Type II/metabolism , Indoles/metabolism , Indoles/pharmacology , Microbial Sensitivity Tests , Molecular Docking Simulation , Protein Structure, Tertiary , Structure-Activity Relationship , Topoisomerase II Inhibitors/metabolism , Topoisomerase II Inhibitors/pharmacology
3.
ChemMedChem ; 12(13): 1087-1096, 2017 07 06.
Article in English | MEDLINE | ID: mdl-28599090

ABSTRACT

Vascular endothelial growth factor receptor 2 (VEGFR2) has been proven to play a major role in the regulation of tumor angiogenesis. A series of novel glycyrrhetic acid derivatives were synthesized and evaluated for their VEGFR2 inhibitory activity as well as their antiproliferative properties against four cancer cell lines (MCF-7, HeLa, HepG2, and A549). In vitro biological evaluations against these human tumor cell lines indicate that most of the prepared compounds have antiproliferative activities; compound 3 a (3ß-hydroxy-30-(4-phenyl-1-piperazinyl)olean-12-ene-11,30-dione) exhibited the best inhibitory activity against MCF-7 cells, with an IC50 value of 1.08 µm. Compound 3 a also showed the most potent inhibitory activity against VEGFR2 tyrosine kinase, with an IC50 value of 0.35 µm. Docking simulations were performed with the aim of discovering the binding mode of compound 3 a, and the results indicate that 3 a could bind at the VEGFR2 active site.


Subject(s)
Antineoplastic Agents/pharmacology , Glycyrrhetinic Acid/analogs & derivatives , Glycyrrhetinic Acid/pharmacology , Piperazines/pharmacology , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/toxicity , Apoptosis/drug effects , Cell Line, Tumor , Cell Movement/drug effects , Glycyrrhetinic Acid/chemical synthesis , Glycyrrhetinic Acid/toxicity , Humans , Membrane Potential, Mitochondrial/drug effects , Molecular Docking Simulation , Piperazines/chemical synthesis , Piperazines/toxicity
4.
Biochem Pharmacol ; 96(2): 93-106, 2015 Jul 15.
Article in English | MEDLINE | ID: mdl-25957661

ABSTRACT

The high incidence of cancer and the side effects of traditional anticancer drugs motivate the search for new and more effective anticancer drugs. In this study, we synthesized 17 kinds of aryl dihydrothiazol acyl shikonin ester derivatives and evaluated their anticancer activity through MTT assay. Among them, C13 showed better antiproliferation activity with IC50=3.14 ± 0.21 µM against HeLa cells than shikonin (IC50=5.75 ± 0.47 µM). We then performed PI staining assay, cell cycle distribution, and cell apoptosis analysis for C13 and found that it can cause cell arrest in G2/M phase, which leads to cell apoptosis. This derivative can also reduce the adhesive ability of HeLa cells. Docking simulation and confocal microscopy assay results further indicated that C13 could bind well to the tubulin at paclitaxel binding site, leading to tubulin polymerization and mitotic disruption.


Subject(s)
Antineoplastic Agents/chemistry , Naphthoquinones/chemistry , Thiazoles/chemistry , Tubulin Modulators/chemistry , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Cell Adhesion/drug effects , Cell Cycle Checkpoints/drug effects , Cell Line , Cell Line, Tumor , Cell Proliferation/drug effects , Chlorocebus aethiops , Drug Screening Assays, Antitumor , Esters , Humans , Molecular Docking Simulation , Naphthoquinones/chemical synthesis , Naphthoquinones/pharmacology , Structure-Activity Relationship , Thiazoles/chemical synthesis , Thiazoles/pharmacology , Tubulin/chemistry , Tubulin Modulators/chemical synthesis , Tubulin Modulators/pharmacology
5.
Chirality ; 27(3): 274-80, 2015 Mar.
Article in English | MEDLINE | ID: mdl-25663187

ABSTRACT

In this study, a shikonin ester derivative, compound , was selected to evaluate its anticancer activities and we found that compound exhibited better antitubulin activities against the human HepG2 cell line with an IC50 value of 1.097 µM. Furthermore, the inhibition of tubulin polymerization results indicated that compound demonstrated the most potent antitubulin activity (IC50 = 13.88), which was compared with shikonin and colchicine as positive controls (IC50 = 25.28 µM and 22.56 µM), respectively. Compound was simulated to have good binding site with tubulin and arrested the cell cycle at G2/M phase, which also induces apoptosis in HepG2 cells, in which P53 and members of Bcl-2 protein family were both involved in the progress of apoptosis revealed by western blot. Confocal microscopy observations revealed compound targeted tubulin and altered its polymerization by interfering with microtubule organization. Based on these results, compound functions as a potent anticancer agent targeting tubulin.


Subject(s)
Antineoplastic Agents/pharmacology , Naphthoquinones/pharmacology , Tubulin Modulators/pharmacology , Apoptosis/drug effects , Cell Cycle Checkpoints/drug effects , Cell Line, Tumor , Humans , Inhibitory Concentration 50 , Microtubules/chemistry , Microtubules/drug effects , Molecular Docking Simulation
6.
Bioorg Med Chem ; 21(2): 448-55, 2013 Jan 15.
Article in English | MEDLINE | ID: mdl-23245802

ABSTRACT

A series of novel thiazolyl-pyrazoline derivatives containing benzodioxole (C1-C20) have been designed and synthesized. Among of the synthesized compounds, 2-(5-(benzo[d][1,3]dioxol-5-yl)-3-(4-bromophenyl)-4,5-dihydro-1H-pyrazol-1-yl)-4-(4-bromophenyl)thiazole (C6) displayed the most potent inhibitory activity for HER-2 (IC(50) = 0.18 µM for HER-2). Antiproliferative assay results indicated that compound C6 owned high antiproliferative activity against MCF-7 and B16-F10 in vitro, with IC(50) value of 0.09 and 0.12 µM, respectively, being comparable with the positive control Erlotinib. Docking simulation was further performed to determine the probable binding model. Based on the preliminary results, compound C6 with potent inhibitory activity in tumor growth would be a potential anticancer agent.


Subject(s)
Antineoplastic Agents/chemical synthesis , Benzodioxoles/chemistry , Pyrazoles/chemistry , Thiazoles/chemistry , Antineoplastic Agents/chemistry , Antineoplastic Agents/toxicity , Binding Sites , Cell Line, Tumor , Cell Proliferation/drug effects , Humans , MCF-7 Cells , Molecular Docking Simulation , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/toxicity , Protein Structure, Tertiary , Pyrazoles/chemical synthesis , Pyrazoles/toxicity , Receptor, ErbB-2/antagonists & inhibitors , Receptor, ErbB-2/metabolism , Structure-Activity Relationship
7.
Guang Pu Xue Yu Guang Pu Fen Xi ; 27(1): 126-30, 2007 Jan.
Article in Chinese | MEDLINE | ID: mdl-17390667

ABSTRACT

In the present paper, the simultaneous determination of multi-components in Chinese herbal medicine was performed by artificial neural network-UV spectrometry. The interference of other components was eliminated by self-revising and self-simulation of the virtual component. The double ANN including training and simulation network was established, and the capabilities of self-recognition and self-studying were improved. Therefore, the prediction accuracy of multicomponent content was improved greatly in the complicated Chinese herbal medicine system. The contents of aesculin and aesculetin, which were extracted from 21 Cortex Fraxinis, were predicted. Comparing the results with those of HPLC, the prediction accuracy was more than 90% within the relative errors less than 10%. The measurement precisions of aesculin and aesculetin were 0. 37% and 1. 5% respectively.


Subject(s)
Drugs, Chinese Herbal/chemistry , Neural Networks, Computer , Spectrophotometry/methods , Chromatography, High Pressure Liquid
8.
Anal Sci ; 22(6): 841-4, 2006 Jun.
Article in English | MEDLINE | ID: mdl-16772682

ABSTRACT

The solid-phase chemiluminescence analysis of gold on the surface of an anion-exchange resin was studied. A method for the fast determination of gold using flow injection was established. The anion-exchange resin was used as an adsorbent of gold ion in the form of AuCl4-. The cation-exchange resin was used for the on-line separation of cations in the matrix. To obtain the best results, the preconcentration and separation conditions, chemiluminescence conditions, interfering ions and their elimination conditions were optimized. The linear range of the calibration curve of AuCl4- is from 0 microg ml(-1) to 5.00 microg ml(-1). The detection limit of AuCl4- is 0.012 microg ml(-1). The method has been used for the determination of gold in geological samples (standard ores). The results are in agreement with certified value of gold standard samples with relative standard deviation from 2.22% to 8.97%. Through the use of flow injection, the preconcentration and separation can be performed automatically.

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