Isoliquiritigenin (ISL) and its Formulations: Potential Antitumor Agents.

Isoliquiritigenin (2',4',4-trihydroxychalcone, ISL) is one of the most important chalcone compounds which is mainly derived from licorice root and many other plants. It exhibits a remarkable range of potent biological and pharmacological activities such as antioxidative, antitumor, antiaging, anti-inflammatory, anti-diabetic activities, etc. Numerous research teams have demonstrated that ISL posseses the ability to carry out antigrowth and proliferation in various cancer cells in vitro and in vivo. Meanwhile, the underlying mechanisms of ISL that inhibit cancer cell proliferation have not been well explored. However, the poor bioavailability and low water-soluble limit its clinical application. This review aims at providing a comprehensive overview of the pharmacology antitumor activity of ISL and its mechanisms in different malignancy especially in breast cancer cell line and summarize developments of formulation utilized to overcome the barrier between its delivery characteristics and application in clinics over the past 20 years.

Synthesis, Biological Evaluation, and Docking of Dihydropyrazole Sulfonamide Containing 2-hydroxyphenyl Moiety: A Series of Novel MMP-2 Inhibitors.

In this study, we synthesized a series of dihydropyrazole sulfonamide derivatives containing 2-hydroxyphenyl moiety as antitumor agents to target the matrix metalloproteinase-2 (MMP-2). All of the synthesized compounds were examined by bioactivity assays, in which compound 4c turned out as a potential antagonist of MMP-2 along with potent anticancer activity against four tumor cell lines. Structure-activity relationship analysis was also performed to examine how structural changes impacted the bioactivity. Suggested to be caused by the induction of apoptosis, the antitumor mechanism of 4c was further confirmed by PI combining with annexin V-FITC staining assay using flow cytometry analysis. These new findings along with molecular docking observations suggested that compound 4c could be developed as a potential anticancer agent.

Optimization of substituted 6-salicyl-4-anilinoquinazoline derivatives as dual EGFR/HER2 tyrosine kinase inhibitors.

4-Anilinoquinazolines as an important class of protein kinase inhibitor are widely investigated for epidermal growth factor receptor (EGFR) tyrosine kinase or epidermal growth factor receptor 2 (HER2) inhibition. A series of novel 6-salicyl-4-anilinoquinazoline derivatives 9-27 were prepared and evaluated for their EGFR/HER2 tyrosine kinase inhibitory activity as well as their antiproliferative properties on three variant cancer cell lines (A431, MCF-7, and A549). The bioassay results showed most of the designed compounds exhibited moderate to potent in vitro inhibitory activity in the enzymatic and cellular assays, of which compound 21 revealed the most potent dual EGFR/HER2 inhibitory activity, with IC50 values of 0.12 µM and 0.096 µM, respectively, comparable to the control compounds Erlotinib and Lapatinib. Furthermore, the kinase selectivity profile of 21 was accessed and demonstrated its good selectivity over the majority of the close kinase targets. Docking simulation was performed to position compound 21 into the EGFR/HER2 active site to determine the probable binding pose. These new findings along with molecular docking observations could provide an important basis for further development of compound 21 as a potent EGFR/HER2 dual kinase inhibitor.

[Insulin-like growth factor 1 induces bone mesenchymal stem cells differentiation into cardiomyocyte-like cells].

OBJECTIVE: To explore the ability and mechanism of insulin-like growth factor 1 (IGF-1) induced bone mesenchymal stem cells (BMSCs) differentiation into cardiomyocyte-like cells (CLCs). METHODS: BMSCs were isolated and purified in vitro. BMSCs were treated with control medium and 15 ng/ml IGF-1 for 3, 7, 14 and 21 d, respectively. The expression of Troponin-T (TNT), Troponin-I (TNI) and pIGF-1R were detected by immunocytochemistry and Western blot. In another experimental setting, BMSCs were treated with control medium and 15 ng/ml IGF-1, IGF-1 antagonist I-OMe AG538 (300 nmol/L) and 300 nmol/L I-OMe AG538 + 15 ng/ml IGF-1 for 3 to 48 h, respectively. Phosphorylation status of ERK1/2 and AKT, the two downstream mediators of mitogen-activated protein kinase (MAPK) kinase and phosphatidylinositol 3-kinase (PI3K) pathways, were detected by immunocytochemistry and Western blot. RESULTS: After 3 to 21 d exposure to IGF-1, the expression of pIGF-1R, TNT and TNI were significantly higher in IGF-1 group than those in control group, pIGF-1R peaked 14 d (all P < 0.05). After 3 and 6 h treatment, the ratio of pAKT/AKT (0.17 ± 0.03) and pERK1/2/ERK1/2 (0.06 ± 0.03) were significantly downregulated in I-OMe AG538 group compared to control group (1.00 ± 0.05) (all P < 0.05). The ratio of pAKT/AKT (1.00 ± 0.07) and pERK1/2/ERK1/2 (1.00 ± 0.09) were significantly upregulated in IGF-1 group compared to control group (0.72 ± 0.05) (all P < 0.05), but the ratio of pAKT/AKT (0.31 ± 0.10) and pERK1/2/ERK1/2 (0.39 ± 0.04) were significantly downregulated in I-OMe AG538 group compared to control group (0.63 ± 0.05) (all P < 0.05), the value of gray scale of TNT (195.06 ± 5.98) and TNI (198.32 ± 3.46) in I-OMe AG538 + IGF-1 group were significantly upregulated than that in IGF-1 group for TNT (188.70 ± 5.35) and TNI (176.10 ± 4.96) (all P < 0.05). CONCLUSIONS: IGF-1 could induce BMSCs differentiation into CLCs in vitro by activating MAPK and PI3K signaling pathways.

Novel 1,3,4-oxadiazole thioether derivatives targeting thymidylate synthase as dual anticancer/antimicrobial agents.

A series of novel 1,3,4-oxadiazole thioether derivatives (compounds 9-44) were designed and synthesized as potential inhibitors of thymidylate synthase (TS) and as anticancer agents. The in vitro anticancer activities of these compounds were evaluated against three cancer cell lines by the MTT method. Among all the designed compounds, compound 18 bearing a nitro substituent exhibited more potent in vitro anticancer activities with IC50 values of 0.7±0.2, 30.0±1.2, 18.3±1.4 µM, respectively, which was superior to the positive control. In the further study, it was identified as the most potent inhibitor against two kinds of TS protein (for human TS and Escherichia coli TS, IC50 values: 0.62 and 0.47 µM, respectively) in the TS inhibition assay in vitro and the most potent antibacterial agents with MIC (minimum inhibitory concentrations) of 1.56-3.13 µg/mL against the tested four bacterial strains. Molecular docking and 3D-QSAR study supported that compound 18 can be selected as dual antitumor/antibacterial candidate in the future study.

Novel Schiff-base-derived FabH inhibitors with dioxygenated rings as antibiotic agents.

Fatty acid biosynthesis plays a vital role in bacterial survival and several key enzymes involved in this biosynthetic pathway have been identified as attractive targets for the development of new antibacterial agents. Of these promising targets, ß-ketoacyl-acyl carrier protein (ACP) synthase III (FabH) is the most attractive target that could trigger the initiation of fatty acid biosynthesis and is highly conserved among Gram-positive and -negative bacteria. Designing small molecules with FabH inhibitory activity displays great significance for developing antibiotic agents, which should be highly selective, nontoxic and broad-spectrum. In this manuscript, a series of novel Schiff base compounds were designed and synthesized, and their biological activities were evaluated as potential inhibitors. Among these 21 new compounds, (E)-N-((3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)methylene)hexadecan-1-amine (10) showed the most potent antibacterial activity with a MIC value of 3.89-7.81 µM(-1) against the tested bacterial strains and exhibited the most potent E. coli FabH inhibitory activity with an IC(50) value of 1.6 µM. Docking simulation was performed to position compound 10 into the E. coli FabH active site to determine the probable binding conformation.

Synthesis, biological evaluation and molecular modeling of dihydro-pyrazolyl-thiazolinone derivatives as potential COX-2 inhibitors.

A series of dihydro-pyrazolyl-thiazolinone derivatives (5a-5t) have been synthesized and their biological activities were also evaluated as potential cyclooxygenase-2 (COX-2) inhibitors. Among these compounds, compound 2-(3-(3,4-dimethylphenyl)-5-phenyl-4,5-dihydro-1H-pyrazol-1-yl)thiazol-4(5H)-one (5a) displayed the most potent COX-2 inhibitory activity with IC(50) of 0.5µM, but weak to COX-1. Docking simulation was performed to position compound 5a into the COX-2 active site to determine the probable binding model. Based on the preliminary results, compound 5a with potent inhibitory activity and low toxicity would be a potential and selective anti-cyclooxygenase-2 agent.

Synthesis, biological evaluation of novel 4,5-dihydro-2H-pyrazole 2-hydroxyphenyl derivatives as BRAF inhibitors.

A series of novel 4,5-dihydropyrazole derivatives (3a-3t) containing hydroxyphenyl moiety as potential V600E mutant BRAF kinase (BRAF(V600E)) 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 BRAF(V600E) 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 BRAF(V600E), MCF-7 human breast cancer cell line and WM266.4 human melanoma cell line all showed several compounds had potent activities IC(50) value in low micromolar range, among them, compound 3d and compound 3m showed strong potent anticancer activity, which were proved by that 3d: IC(50) = 1.31 µM for MCF-7 and IC(50) = 0.45 µM for WM266.5, IC(50) = 0.22 µM for BRAF(V600E), 3m: IC(50) = 0.97 µM for MCF-7 and IC(50) = 0.72 µM for WM266.5, IC(50) = 0.46 µM for BRAF(V600E), which were comparable with the positive control Erlotinib.

Discovery of 6-substituted 4-anilinoquinazolines with dioxygenated rings as novel EGFR tyrosine kinase inhibitors.

It had been reported that some dioxygenated rings fusing with the quinazoline scaffold could lead to new EGFR inhibitors. Based on this, several kinds of oxygenated alkane quinazoline derivatives were synthetized and evaluated as EGFR inhibitors. Their antiproliferative activities were tested against four cancer cell lines: A431, MCF-7, A549, and B16-F10. Most derivatives could counteract EGF-induced EGFR phosphorylation, and their potency was comparable to the reference compound Erlotinib. The size of the fused dioxygenated ring was crucial for the biological activity and the heptatomic ring derivative 19 showed potent in vitro inhibitory activity in the enzymatic assay as well as in the cellular assay.

Design, synthesis, biological evaluation and molecular modeling of novel 1,3,4-oxadiazole derivatives based on Vanillic acid as potential immunosuppressive agents.

In present study, a series of novel 1,3,4-oxadiazole derivatives have been designed, synthesized and purified. All of these compounds are reported for the first time, the chemical structures of these compounds were confirmed by means of (1)H NMR, ESI-MS and elemental analyses. Besides, we evaluated their immunosuppressive activity. Most of these synthesized compounds were proved to have potent immunosuppressive activity and low toxicity. Among them, the bioassay results demonstrated that compounds 5c, 5n, 5p, 5o, 6f and 6g exhibited immunosuppressive activities with IC(50) concentration range from 1.25µM to 7.60 µM against the T cells, and the IC(50) of positive control (csa) is 2.12 µM. Moreover, all the title compounds were assayed for PI3K/AKT signaling pathway inhibition using the ELISA assay. We examined the compounds with potent inhibitory activities against IL-1, IL-6 and IL-10 released in ConA-simulated mouse lymph node cells. The results showed compounds 5o and 6f displayed the most potential biological activity against T cells (IC(50)=1.25 µM and 4.75 µM for T cells). The preliminary mechanism of compound 5o inhibition effects was also detected by flow cytometry (FCM). The results of apoptosis and ELISA assay demonstrated that the immunosuppressive activity of compounds 5o and 6f against T cells may be mediated by the inhibition of PI3Kγ/AKT signaling pathway. Molecular docking was performed to position compounds 5o and 6f into PI3Kγ binding site in order to indicate the potential target.

Discovery and modification of sulfur-containing heterocyclic pyrazoline derivatives as potential novel class of ß-ketoacyl-acyl carrier protein synthase III (FabH) inhibitors.

A series of sulfur-containing heterocyclic pyrazoline derivatives (C1-C18; D1-D9) have been synthesized and purified (all are new except one) to be screened for FabH inhibitory activity. Compound C14 showed the most potent biological activity against Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus and Bacillus subtilis (MIC values: 1.56-3.13 µg/mL), being comparable with the positive control, while D6 performed the best in the thiazolidinone series (MIC values: 3.13-6.25 µg/mL). They also demonstrated strong broad-spectrum antimicrobial activity. Compounds C14 and D6 exhibited the most potent E. coli FabH inhibitory activity with IC(50) of 4.6 and 8.4 µM, respectively, comparable with the positive control DDCP (IC(50)=2.8 µM). Docking simulation was performed to position compound C14 and D6 into the E. coli FabH structure active site to determine the probable binding model. The structurally modification of previous compounds and the attempt in innovative target have brought a positive progress.

Design, synthesis and antimicrobial activities of nitroimidazole derivatives containing 1,3,4-oxadiazole scaffold as FabH inhibitors.

Nitroimidazoles and their derivatives have drawn continuing interest over the years because of their varied biological activities, recently found application in drug development for antimicrobial chemotherapeutics and antiangiogenic hypoxic cell radiosensitizers. In order to search for novel antibacterial agents, we designed and synthesized a series of secnidazole analogs based on oxadiazole scaffold (4-21). Among these compounds, 4 and 7-21 were reported for the first time. These compounds were tested for antibacterial activities against Escherichia coli, Pseudomonas aeruginosa, Bacillus subtilis and Staphylococcus aureus. This new nitroimidazole derivatives class demonstrated strong antibacterial activities. Escherichia coli ß-ketoacyl-acyl carrier protein synthase III (FabH) inhibitory assay and docking simulation indicated that the compounds 2-(2-methoxyphenyl)-5-((2-methyl-5-nitro-1H-imidazol-1-yl)methyl)-1,3,4-oxadiazole (11) with MIC of 1.56-3.13 µg/mL against the tested bacterial strains and 2-((2-methyl-5-nitro-1H-imidazol-1-yl)methyl)-5-(2-methylbenzyl)-1,3,4-oxadiazole (12) with MIC of 1.56-6.25 µg/mL were most potent inhibitors of Escherichia coli FabH.

Synthesis, biological evaluation and molecular docking studies of 3-(1,3-diphenyl-1H-pyrazol-4-yl)-N-phenylacrylamide derivatives as inhibitors of HDAC activity.

In present study, a series of 3-(1,3-diphenyl-1H-pyrazol-4-yl)-N-phenylacrylamide derivatives (5a-8d) were designed, synthesized, and evaluated for HDAC inhibition and tumor cell antiproliferation. All of these compounds are reported for the first time, the chemical structures of these compounds were confirmed by means of (1)H NMR, ESI-MS and elemental analyzes. Among the compounds, compound 8c showed the most potent biological activity against HCT116 cancer cell line (IC(50) of 0.42 ± 0.02 µM for HDAC-1 and IC(50)=0.62 ± 0.02 for HCT116). Docking simulation was performed to position compound 8c into the HDAC active site to determine the probable binding model. The results of antiproliferative assay and western-blot demonstrated that compound 8c with potent inhibitory activity in tumor growth inhibition may be a potential anticancer agent against HCT116 cancer cell.

Synthesis, biological evaluation and 3D-QSAR studies of novel 4,5-dihydro-1H-pyrazole niacinamide derivatives as BRAF inhibitors.

A series of novel 4,5-dihydropyrazole derivatives containing niacinamide moiety as potential V600E mutant BRAF kinase (BRAF(V600E)) inhibitors were designed and synthesized. Results of the bioassays against BRAF(V600E) and WM266.4 human melanoma cell line showed several compounds to be endowed potent activities with IC(50) and GI(50) value in low micromolar range, among which compound 27e, (5-(4-Chlorophenyl)-3-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazol-1-yl)6-methylpyridin-3-yl methanone (IC(50)=0.20 µM, GI(50)=0.89 µM) was bearing the best bioactivity comparable with the positive control Sorafenib. Docking simulation was performed to determine the probable binding model and 3D-QSAR model was built to provide more pharmacophore understanding that could use to design new agents with more potent BRAF(V600E) inhibitory activity.

Synthesis, biological evaluation, and molecular docking studies of N,1,3-triphenyl-1H-pyrazole-4-carboxamide derivatives as anticancer agents.

A series of N,1,3-triphenyl-1H-pyrazole-4-carboxamide derivatives have been designed, synthesized and evaluated for their potential antiproliferation activity and Aurora-A kinase inhibitory activity. Among all the compounds, compound 10e possessed the most potent biological activity against HCT116 and MCF-7 cell lines with IC(50) values of 0.39±0.06µM and 0.46±0.04 µM, respectively, which were comparable to the positive control. Compound 10e also exhibited significant Aurora-A kinase inhibitory activity (IC(50)=0.16±0.03 µM). Docking simulation was performed to position compound 10e into the active site of Aurora-A kinase, in order to get the probable binding model for further study. The results of Western-blot assay demonstrated that compound 10e possessed good Aurora-A kinase inhibitory activity against HCT116. Based on the preliminary results, it is deduced that compound 10e with potent Aurora-A kinase inhibitory activity may be a potential anticancer agent.

Synthesis, biological evaluation and molecular docking studies of novel 2-(1,3,4-oxadiazol-2-ylthio)-1-phenylethanone derivatives.

In present study, a series of new 2-(1,3,4-oxadiazol-2-ylthio)-1-phenylethanone derivatives (6a-6x) as potential focal adhesion kinase (FAK) inhibitors were synthesized. The bioassay assays demonstrated that compound 6i showed the most potent activity, which inhibited the growth of MCF-7 and A431 cell lines with IC(50) values of 140 ± 10 nM and 10 ± 1 nM, respectively. Compound 6i also exhibited significant FAK inhibitory activity (IC(50)=20 ± 1 nM). Docking simulation was performed to position compound 6i into the active site of FAK to determine the probable binding model.

Synthesis, biological evaluation, and molecular docking studies of 2,6-dinitro-4-(trifluoromethyl)phenoxysalicylaldoxime derivatives as novel antitubulin agents.

A series of 2,6-dinitro-4-(trifluoromethyl)phenoxysalicylaldoxime derivatives (1h-20h) have been designed and synthesized, and their biological activities were also evaluated as potential antiproliferation and tubulin polymerization inhibitors. Among all the compounds, 2h showed the most potent activity in vitro, which inhibited the growth of MCF-7, Hep-G2 and A549 cell lines with IC(50) values of 0.70 ± 0.05, 0.68 ± 0.02 and 0.86 ± 0.05 µM, respectively. Compound 2h also exhibited significant tubulin polymerization inhibitory activity (IC(50)=3.06 ± 0.05 µM). The result of flow cytometry (FCM) demonstrated that compound 2h induced cell apoptosis. Docking simulation was performed to insert compound 2h into the crystal structure of tubulin at colchicine binding site to determine the probable binding model. Based on the preliminary results, compound 2h with potent inhibitory activity in tumor growth may be a potential anticancer agent.

Synthesis, biological evaluation and molecular docking studies of 1,3,4-oxadiazole derivatives as potential immunosuppressive agents.

A series of 1,3,4-oxadiazole derivatives derived from 4-methoxysalicylic acid or 4-methylsalicylic acid (6a-6z) have been first synthesized for their potential immunosuppressive activity. Among them, compound 6z displayed the most potent biological activity against lymph node cells (inhibition=38.76% for lymph node cells and IC(50)=0.31 µM for PI3Kγ). The preliminary mechanism of compound 6z inhibition effects was also detected by flow cytometry (FCM) and the compound exerted immunosuppressive activity via inducing the apoptosis of activated lymph node cells in a dose dependent manner. Docking simulation was performed to position compound 6z into the PI3Kγ structure active site to determine the probable binding model.

Design, synthesis and biological evaluation of novel chalcone derivatives as antitubulin agents.

A series of novel chalcone derivatives have been designed and synthesized, and their biological activities were also evaluated as potential inhibitors of tubulin. These compounds were assayed for growth-inhibitory activity against MCF-7 and A549 cell lines in vitro. Compound 3d showed the most potent antiproliferative activity against MCF-7 and A549 cell lines with IC(50) values of 0.03 and 0.95 µg/mL and exhibited the most potent tubulin inhibitory activity with IC(50) of 1.42 µg/mL. Docking simulation was performed to insert compound 3d into the crystal structure of tubulin at colchicines binding site to determine the probable binding model. Based on the preliminary results, compound 3d with potent inhibitory activity in tumor growth may be a potential anticancer agent.

Synthesis, biological evaluation, and molecular docking studies of 1,3,4-thiadiazol-2-amide derivatives as novel anticancer agents.

A series of 1,3,4-thiadiazol-2-amide derivatives (5a-5y) have been designed and synthesized, and their biological activities were also evaluated as potential antiproliferation and FAK inhibitors. Among all the compounds, 5h showed the most potent activity in vitro, which inhibited the growth of MCF-7 and B16-F10 cell lines with IC(50) values of 0.45 and 0.31 µM, respectively. Compound 5h also exhibited significant FAK inhibitory activity (IC(50)=5.32 µM). Docking simulation was performed to position compound 5h into the FAK structure active site to determine the probable binding model. The results of antiproliferative and Western-blot assay demonstrated that compound 5h possessed good antiproliferative activity. Therefore, compound 5h with potent FAK inhibitory activity may be a potential anticancer agent.